Podcasts about efs

Two Onc Docs, hosted by Samantha A. Armstrong, MD, and Karine Tawagi, MD, is a podcast dedicated to providing current and future oncologists and hematologists with the knowledge they need to ace their boards and deliver quality patient care. Dr Armstrong is a hematologist/oncologist and assistant professor of clinical medicine at Indiana University Health in Indianapolis. Dr Tawagi is a hematologist/oncologist and assistant professor of clinical medicine at the University of Illinois in Chicago. In this episode, OncLive On Air® partnered with Two Onc Docs to bring a discussion of key data from the phase 3 MATTERHORN trial (NCT04592913), which were presented at the 2025 ASCO Annual Meeting. MATTERHORN was a randomized, double-blind, multinational study evaluating the addition of durvalumab (Imfinzi) to FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) in patients with previously untreated, resectable gastric or gastroesophageal junction adenocarcinoma. In the MATTERHORN trial, 948 patients were randomly assigned 1:1 to receive either durvalumab or placebo in combination with perioperative FLOT, followed by 10 cycles of durvalumab or placebo as adjuvant therapy. The primary end point was event-free survival (EFS); secondary end points included overall survival (OS) and pathological complete response (pCR). The trial met its primary end point. Durvalumab plus FLOT (n = 474) significantly improved EFS vs placebo plus FLOT (n = 474; HR, 0.71; 95% CI, 0.58-0.86; P < .001), representing a 29% reduction in risk of progression, recurrence, or death. The interim OS analysis showed a nonsignificant trend favoring durvalumab (HR, 0.78; 95% CI, 0.62-0.97; P = .025). The pCR rate was 19% (95% CI, 15.75%-23.04%) with durvalumab vs 7.2% (95% CI, 5.02%-9.88%) with placebo. Toxicity profiles were comparable between the 2 groups, though immune-related adverse effects were more frequent with durvalumab. Importantly, the addition of durvalumab did not delay surgery or initiation of adjuvant therapy. Although the MATTERHORN regimen is not yet FDA approved or included in the National Comprehensive Cancer Network guidelines, this trial demonstrates a promising EFS benefit and potential practice-changing implications, pending mature OS data and further molecular subgroup analyses, according to Armstrong and Tawagi.

Vi inleder semestern med att Helena Cashin, kommunikationschef på EFS och chefredaktör för Budbäraren, gästar podden och gör nya spaningar tillsammans med Magnus om vad som är på gång i kristenheten. Spännande och berörande samtal som garanterat engagerar, inte minst om gränslöshet och gränssättning. 

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss important advances in the treatment of prostate, bladder, and kidney cancers that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I am the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute and editor-in-chief of the ASCO Daily News.  I am delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of the GU Center at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that were presented at the 2025 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode.  Jeanny, it is great to have you on the podcast. Dr. Jeanny Aragon-Ching: Oh, thank you so much, Neeraj. Dr. Neeraj Agarwal: Jeanny, let's begin with some prostate cancer abstracts. Let's begin with Abstract 5017 titled, “Phase 1 study results of JNJ-78278343 (pasritamig) in metastatic castration-resistant prostate cancer.” Can you walk us through the design and the key findings of this first-in-human trial? Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So this study, presented by Dr. Capucine Baldini, introduces pasritamig, a first-in-class T-cell redirecting bispecific antibody that simultaneously binds KLK2 on prostate cancer cells and CD3 receptor complexes on T cells. KLK2 is also known as human kallikrein 2, which is selectively expressed in prostate tissue. And for reference, KLK3 is what we now know as the PSA, prostate-specific antigen, therefore making it an attractive and specific target for therapeutic engagement. Now, while this was an early, first-in-human, phase 1 study, it enrolled 174 heavily pretreated metastatic CRPC patients. So many were previously treated with ARPIs, taxanes, and radioligand therapy. So given the phase 1 nature of this study, the primary objective was to determine the safety and the RP2D, which is the recommended phase 2 dose. Secondary objectives included preliminary assessment of antitumor activity. So, pasritamig was generally well tolerated. There were no treatment-related deaths. Serious adverse events were rare. And in the RP2D safety cohort, where patients received the step-up dosing up to 300 mg of IV every 6 weeks, the most common treatment-related adverse events were low-grade infusion reactions. There was fatigue and grade 1 cytokine release syndrome, what we call CRS. And no cases of neurotoxicity, or what we call ICANS, the immune effector cell-associated neurotoxicity syndrome, reported. Importantly, the CRS occurred in just about 8.9% of patients. All were grade 1. No patients required tocilizumab or discontinued treatment due to adverse events. So, this suggests a favorable safety profile, allowing hopefully for outpatient administration without hospitalization, which will be very important when we're thinking about bispecifics moving forward. In terms of efficacy, pasritamig showed promising activity. About 42.4% of evaluable patients achieved a PSA50 response. Radiographic PFS was about 6.8 months. And among patients with measurable disease, the objective response rate was about 16.1% in those with lymph node or bone metastases, and about 3.7% in those with visceral disease, with a median duration of response of about 11.3 months. So, altogether, this data suggests that pasritamig may offer a well-tolerated and active new potential option for patients with metastatic CRPC.   Again, as a reminder, with the caveat that this is still an early phase 1 study. Dr. Neeraj Agarwal: Thank you, Jeanny. These are promising results for a bispecific T-cell engager, pasritamig, in prostate cancer. I agree, the safety and durability observed here stand out, and this opens the door for further development, possibly even in earlier disease settings.  So, shifting now from immunotherapy to the evolving role of genomics in prostate cancer. So let's discuss Abstract 5094, a real-world, retrospective analysis exploring the prognostic impact of homologous recombination repair gene mutations, especially BRCA1 and BRCA2 mutations, in metastatic hormone-sensitive prostate cancer. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So this study was presented by Dr. David Olmos, represents one of the largest real-world analyses we have evaluating the impact of homologous recombination repair, or what we would call HRR, alterations in metastatic hormone-sensitive prostate cancer. So, this cohort included 556 men who underwent paired germline and somatic testing. Now, about 30% of patients had HRR alterations, with about 12% harboring BRCA1 or BRCA2 mutations and 16% having alterations in other HRR genes. Importantly, patients were stratified via CHAARTED disease volume, and outcomes were examined across treatment approaches, including ADT alone, doublet therapy, and triplet therapy. The prevalence of BRCA and HRR alterations were about similar between the metastatic hormone-sensitive prostate cancer and the metastatic castrate-resistant prostate cancer, with no differences observed, actually, between the patients with high volume versus low volume disease.  So, the key finding was that BRCA and HRR alterations were associated with poor clinical outcomes in metastatic hormone-sensitive prostate cancer. And notably, the impact of these alterations may actually be even greater in metastatic hormone-sensitive prostate cancer than previously reported in metastatic CRPC. So, the data showed that when BRCA mutations are present, the impact of the volume of disease is actually limited. So, poor outcomes were observed across the board for both high-volume and low-volume groups. So, the analysis showed that patients with HRR alterations had significantly worse outcomes compared to patients without HRR alterations. Median radiographic progression-free survival was about 20.5 months for the HRR-altered patients versus 30.6 months for the non-HRR patients, with a hazard ratio of 1.6. Median overall survival was 39 months for HRR-altered patients compared to 55.7 months for the non-HRR patients, with a hazard ratio of 1.5. Similar significant differences were observed when BRCA-mutant patients were compared with patients harboring non-BRCA HRR mutations. Overall, poor outcomes were independent of treatment of ARPI or taxanes. Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data reinforce homologous recombination repair mutations as both a predictive and prognostic biomarker, not only in the mCRPC, but also in the metastatic hormone-sensitive setting as well. It also makes a strong case for incorporating genomic testing early in the disease course and not waiting until our patients have castration-resistant disease. Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. And I think this really brings home the point and the lead up to the AMPLITUDE trial, which is LBA5006, a phase 3 trial that builds on this very concept of testing with a PARP inhibitor, niraparib, in the hormone-sensitive space. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the AMPLITUDE trial, a phase 3 trial presented by Dr. Gerhardt Attard, enrolled 696 patients with metastatic hormone-sensitive prostate cancer and HRR gene alterations. 56% of these patients had BRCA1 and BRCA2 mutations. Patients were randomized to receive abiraterone with or without niraparib, a PARP inhibitor. The majority of patients, 78% of these patients, had high-volume metastatic hormone-sensitive prostate cancer, and 87% of these patients had de novo metastatic HSPC. And 16% of these patients received prior docetaxel, which was allowed in the clinical trial. So, with a median follow-up of nearly 31 months, radiographic progression-free survival was significantly prolonged with the niraparib plus abiraterone combination, and median was not reached in this arm, compared to abiraterone alone, which was 29.5 months, with a hazard ratio of 0.63, translating to a 37% reduction in risk of progression or death. This benefit was even more pronounced in the BRCA1 and BRCA2 subgroup, with a 48% reduction in risk of progression, with a hazard ratio of 0.52. Time to symptomatic progression also improved significantly across all patients, including patients with BRCA1, BRCA2, and HRR mutations. Although overall survival data remain immature, early trends favored the niraparib plus abiraterone combination. The safety profile was consistent with prior PARP inhibitor studies, with grade 3 or higher anemia and hypertension were more common but manageable. Treatment discontinuation due to adverse events remained low at 11%, suggesting that timely dose modifications when our patients experience grade 3 side effects may allow our patients to continue treatment without discontinuation. These findings support niraparib plus abiraterone as a potential new standard of care in our patients with metastatic hormone-sensitive prostate cancer with HRR alterations, and especially in those who had BRCA1 and BRCA2 mutations. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. This trial is especially exciting because it brings PARP inhibitors earlier into the treatment paradigm. Dr. Neeraj Agarwal: Exactly. And it is exciting to see the effect of PARP inhibitors in the earlier setting.  So Jeanny, now let's switch gears a bit to bladder cancer, which also saw several impactful studies. Could you tell us about Abstract 4502, an exploratory analysis from the EV-302 trial, which led to approval of enfortumab vedotin plus pembrolizumab for our patients with newly diagnosed metastatic bladder cancer? So here, the authors looked at the outcomes in patients who achieved a confirmed complete response with EV plus pembrolizumab. Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, EV-302 demonstrated significant improvements in progression-free and overall survival for patients previously treated locally advanced or metastatic urothelial cancer, I'll just call it metastatic UC, as a frontline strategy, establishing EV, which is enfortumab vedotin, plus pembro, with pembrolizumab as standard of care in this setting.  So, this year at ASCO, Dr Shilpa Gupta presented this exploratory responder analysis from the phase 3 EV-302 trial. Among 886 randomized patients, about 30.4% of patients, this is about 133, in the EV+P arm, and 14.5% of the patients in the chemotherapy arm, achieved a confirmed complete response. They call it the CCR rates. So for patients who achieved this, median PFS was not reached with EV+P compared to 26.9 months with chemotherapy, with a hazard ratio of 0.36, translating to a 64% reduction in the risk of progression. Overall survival was also improved. So the median OS was not reached in either arm, but the hazard ratio favored the EV+P at 0.37, translating to a 63% reduction in the risk of death. The median duration of complete response was not reached with EV+P compared to 15.2 months with chemotherapy. And among those patients who had confirmed CRs at 24 months, 78% of patients with the EV+P arm remained progression-free, and around 95% of the patients were alive, compared to 54% of patients who were progression-free and 86% alive of the patients in the chemotherapy arm. Safety among responders were also consistent with prior reports. Grade 3 or higher treatment-related adverse events occurred in 62% of EV+P responders and 72% of chemotherapy responders. Most adverse events were managed with dose modifications, and importantly, no treatment-related deaths were reported among those who were able to achieve complete response.  So these findings further reinforce EV and pembro as the preferred first-line therapy for metastatic urothelial carcinoma, offering a higher likelihood of deep, durable responses with a fairly manageable safety profile. Dr. Neeraj Agarwal: Thank you for the great summary, Jeanny. These findings underscore the depth and durability of responses achievable with this combination and also suggest that achieving a response may be a surrogate for long-term benefit in patients with metastatic urothelial carcinoma.  So now, let's move to Abstract 4503, an exploratory ctDNA analysis from the NIAGARA trial, which evaluated perioperative durvalumab, an immune checkpoint inhibitor, in muscle-invasive bladder cancer. So what can you tell us about this abstract? Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, in NIAGARA, presented by Dr. Tom Powles, the addition of perioperative durvalumab to neoadjuvant chemotherapy, gem/cis, significantly improved event-free survival, overall survival, and pathologic complete response in patients with cisplatin-eligible muscle-invasive bladder cancer. Recall that this led to the U.S. FDA approval of this treatment regimen on March 28, 2025.  So, a planned exploratory analysis evaluated the ctDNA dynamics and their association with clinical outcomes, which was the one presented recently at ASCO. So, the study found that the incidence of finding ctDNA positivity in these patients was about 57%. Following neoadjuvant treatment, this dropped to about 22%, with ctDNA clearance being more common in the durvalumab arm, about 41%, compared to the chemotherapy control arm of 31%. Notably, 97% of patients who remained ctDNA positive prior to surgery failed to achieve a pathologic CR. So, this indicates a strong association between ctDNA persistence and lack of tumor eradication. So, postoperatively, only about 9% of patients were ctDNA positive. So, importantly, durvalumab conferred an event-free survival benefit regardless of ctDNA status at both baseline and post-surgery. Among patients who were ctDNA positive at baseline, durvalumab led to a hazard ratio of 0.73 for EFS. So, this translates to a 27% reduction in the risk of disease recurrence, progression, or death compared to the control arm. In the post-surgical ctDNA-positive group, the disease-free survival was also improved with a hazard ratio of 0.49, translating to a 51% reduction in the risk of recurrence.  So, these findings underscore the prognostic value of ctDNA and suggest that durvalumab provides clinical benefit irrespective of molecular residual disease status. So, the data also supports that ctDNA is a promising biomarker for future personalized strategies in the perioperative treatment of muscle-invasive bladder cancer. Dr. Neeraj Agarwal: Thank you, Jeanny. It is great to see that durvalumab is improving outcomes in these patients regardless of ctDNA status. However, based on these data, presence of ctDNA in our patients warrants a closer follow-up with imaging studies, because these patients with positive ctDNA seem to have a higher risk of recurrence. Dr. Jeanny Aragon-Ching: I agree, Neeraj.  Let's round out the bladder cancer discussion with Abstract 4518, which reported the interim results of SURE-02, which is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab in cisplatin-ineligible muscle-invasive bladder cancer. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure, Jeanny. So, Dr Andrea Necchi presented interim results from the SURE-02 trial. This is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab, followed by a response-adapted bladder-sparing treatment and adjuvant pembrolizumab in patients with muscle-invasive bladder cancer.  So, in this interim analysis, 40 patients were treated and 31 patients were evaluable for efficacy. So, the clinical complete response rate was 38.7%. All patients achieving clinical complete response underwent bladder-sparing approach with a repeat TURBT instead of radical cystectomy. Additionally, 51.6% of patients achieved excellent pathologic response with a T stage of 1 or less after neoadjuvant therapy. The treatment was well tolerated, with only 12.9% of patients experiencing grade 3 or higher adverse events without needing dose reduction of sacituzumab. Molecular profiling, interestingly, showed that clinical complete response correlated with luminal and genomically unstable subtypes, while high stromal gene expression was associated with lack of response.  These results suggest that sacituzumab plus pembrolizumab combination has promising activity in this setting, and tolerability, and along with other factors may potentially allow a bladder preservation approach in a substantial number of patients down the line. Dr. Jeanny Aragon-Ching: Yeah, agree with you, Neeraj. And the findings are very provocative and support completing the full trial enrollment and further exploration of this strategy in muscle-invasive bladder cancer in order to improve and provide further bladder-sparing strategies. Dr. Neeraj Agarwal: Agree. So, let's now turn to the kidney cancer, starting with Abstract 4505, the final overall analysis from CheckMate-214 trial, which evaluated nivolumab plus ipilimumab, so dual checkpoint inhibition strategy, versus sunitinib in our patients with metastatic clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So, the final 9-year analysis of the phase 3 CheckMate-214 trial confirms the long-term superiority of nivolumab and ipilimumab over sunitinib for first-line treatment of advanced metastatic renal cell carcinoma. So, this has a median follow-up of 9 years. Overall survival remains significantly improved with the combination. So, in the ITT patient population, the intention-to-treat, the hazard ratio for overall survival was 0.71. So, this translates to a 29% reduction in the risk of death. 31% of patients were alive at this 108-month follow-up compared to 20% only in those who got sunitinib. So, similar benefits were observed in the intermediate- and poor-risk groups with a hazard ratio of 0.69, and 30% versus 19% survival at 108 months.  Importantly, a delayed benefit was also seen in those favorable-risk patients. So, the hazard ratio for overall survival improved from 1.45 in the initial report and now at 0.8 at 9 years follow-up, with 35% of patients alive at 108 months compared to 22% in those who got sunitinib. Progression-free survival also favored the nivo-ipi arm across all risk groups. At 96 months, the probability of remaining progression-free was about 23% compared to 9% in the sunitinib arm in the ITT patient population, 25% versus 9% in the intermediate- and poor-risk patients, and 13% compared to 11% in the favorable-risk patients. Importantly, at 96 months, 48% of patients in the nivo-ipi responders remained in response compared to just 19% in those who got sunitinib. And in the favorable-risk group, 36% of patients who responded remained in response, although data were not available for sunitinib in this subgroup.  So, this data reinforces the use of nivolumab and ipilimumab as a durable and effective first-line effective strategy for standard of care across all risk groups for advanced renal cell carcinoma. Dr. Neeraj Agarwal: Thank you, Jeanny. And of course, since ipi-nivo data were presented, several other novel ICI-TKI combinations have emerged. And I'm really hoping to see very similar data with TKI-ICI combinations down the line. It is really important to note that we are not seeing any new safety signals with the ICI combinations or ICI-based therapies, which is very reassuring given the extended exposure. Dr. Jeanny Aragon-Ching: Absolutely agree with you there, Neeraj.  Now, going on and moving on to Abstract 4514, which is the KEYNOTE-564 trial, and they reported on the 5-year outcomes of adjuvant pembrolizumab in clear cell RCC in patients who are at high risk for recurrence. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the KEYNOTE-564 trial established pembrolizumab monotherapy as the first adjuvant regimen to significantly improve both disease-free survival and overall survival compared to placebo after surgery for patients with clear cell renal cell carcinoma. So, Dr Naomi Haas presented the 5-year update from this landmark trial.  A total of 994 patients were randomized to receive either pembrolizumab or placebo. The median follow-up at the time of this analysis was approximately 70 months. Disease-free survival remained significantly improved with pembrolizumab. The median DFS was not reached with pembrolizumab compared to 68.3 months with placebo, with a hazard ratio of 0.71, translating to a 29% reduction in risk of recurrence. At 5 years, 60.9% of patients receiving pembrolizumab remained disease-free compared to 52.2% with placebo. Overall survival also favored pembrolizumab. The hazard ratio for OS was 0.66, translating to a 34% reduction in risk of death, with an estimated 5-year overall survival rate of 87.7% with pembrolizumab compared to 82.3% for placebo. Importantly, these benefits were consistent across all key subgroups, including patients with sarcomatoid features. In addition, no new serious treatment-related adverse events have been reported in the 3 years since treatment completion.  So, these long-term data confirm pembrolizumab as a durable and effective standard adjuvant therapy for patients with resected, high-risk clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Thank you for that wonderful summary, Neeraj. Dr. Neeraj Agarwal: That wraps up our kidney cancer highlights. Any closing thoughts, Jeanny, before we conclude? Dr. Jeanny Aragon-Ching: It's been so wonderful reviewing these abstracts with you, Neeraj. So, the 2025 ASCO Annual Meeting showcased a lot of transformative data across GU cancers, from first-in-class bispecifics to long-term survival in RCC. And these findings are already shaping our clinical practices. Dr. Neeraj Agarwal: I agree. And we have covered a broad spectrum of innovations in GU cancers with strong clinical relevance.  So, thank you, Jeanny, for joining me today and sharing your insights.  And thank you to our listeners for joining us. You will find links to the abstracts discussed today in the transcript of this episode. If you find these conversations valuable, please take a moment to rate, review, and subscribe to the ASCO Daily News Podcast wherever you listen. Thank you so much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:    Dr. Neeraj Agarwal     @neerajaiims     Dr. Jeanny Aragon-Ching   Follow ASCO on social media:       @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn       Disclosures:   Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas  Dr. Jeanny Aragon-Ching:   Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono   Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,    Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics

Dr. Vamsi Velcheti and Dr. Nate Pennell discuss novel treatment approaches in small cell and non-small cell lung cancer that were featured at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host of the ASCO Daily News Podcast. I'm a professor of medicine and chief of hematology and oncology at the Mayo Clinic in Jacksonville, Florida. The 2025 ASCO Annual Meeting featured some exciting advancements in small cell lung cancer, targeted therapies for non-small cell lung cancer, and other novel [treatment] approaches. Today, I'm delighted to be joined by Dr. Nate Pennell to discuss some of the key abstracts that are advancing the lung cancer field. Dr. Pennell is the co-director of the Cleveland Clinic Lung Cancer Program and also the vice chair of clinical research at the Taussig Cancer Institute. Our full disclosures are available in the transcript of this episode. Nate, it's great to have you back on the podcast. Thanks so much for being here. Dr. Nate Pennell: Thanks, Vamsi. Always a pleasure. Dr. Vamsi Velcheti: Let's get started, and I think the first abstract that really caught my attention was Abstract 8516, “The Randomized Trial of Relevance of Time of Day of Immunotherapy for Progression-Free and Overall Survival in Patients With Non-Small Cell Lung Cancer.” What are your thoughts about this, Nate? Dr. Nate Pennell: I agree. I thought this was one of the most discussed abstracts, certainly in the lung cancer session, but I think even outside of lung cancer, it got some discussion. So, just to put this in perspective, there have been a number of publications that have all been remarkably consistent, and not just in lung cancer but across multiple cancer types, that immunotherapy, immune checkpoint inhibitors, are commonly used. And all of them have suggested, when looking at retrospective cohorts, that patients who receive immune checkpoint inhibitors earlier in the day – so in the morning or before the early afternoon – for whatever reason, appear to have better outcomes than those who get it later in the day, and this has been repeated. And I think many people just sort of assumed that this was some sort of strange association and that there was something fundamentally different from a prognostic standpoint in people who came in in the morning to get their treatment versus those who came later in the afternoon, and that was probably the explanation. The authors of this randomized trial actually decided to test this concept. And so, about 210 patients with previously untreated advanced non-small cell lung cancer were randomly assigned to get chemo and immune checkpoint inhibitor – either pembrolizumab or sintilimab – and half of them were randomly assigned to get the treatment before 3 PM in the afternoon, and half of them were assigned to get it after 3 PM in the afternoon. And it almost completely recapitulated what was seen in the retrospective cohorts. So, the median progression-free survival in those who got earlier treatment was 13.2 months versus only 6.5 months in those who got it later in the day. So, really enormous difference with a hazard ratio of 0.43, which was statistically significant. And perhaps even more striking, the median overall survival was not reached in the early group versus 17.8 months in the late group with a hazard ratio of 0.43, also highly statistically significant. Even the response rate was 20% higher in the early patients; 75% response rate compared to 56% in the late-time-of-day patients. So very consistent across all measures of efficacy with pretty good matched characteristics across the different groups. And so, I have to tell you, I don't know what to make of this. I certainly was a skeptic about the retrospective series, but now we have a prospective randomized trial that shows essentially the same thing. So, maybe there is a difference between getting treated in the morning, although I have yet to hear someone give a very good mechanistic explanation as to why this would be. What were your thoughts on this? Dr. Vamsi Velcheti: It's indeed fascinating, Nate, and I actually think this was a very interesting abstract. Really, I was caught off guard looking at the data. I mean, if it were a drug, we would be so excited, right? I mean, with those kind of survival benefits. I don't know. I think circadian rhythm probably has something to do with it, like different cytokine profiles at the time of administration. I mean, who knows? But I think it's a randomized trial, and I think I would expect to see a mad rush for treatment appointments early in the morning given this, and at least I want my patients to come in first thing in the morning. It'll be interesting to see. Dr. Nate Pennell: It's important to point out that in this study, everyone got chemo and immunotherapy. And, at least in our cancer center, most patients who are getting platinum-doublet chemotherapy and immunotherapy actually do get treated earlier in the day already, just because of the length of the infusion appointment that's needed. So it really is oftentimes people getting single-agent immunotherapy who are often getting the later, shorter visits. But if you have a choice, I think it would be very reasonable to have people treated earlier in the day. And I do think most of the impressions that I got from people about this is that they would like to see it reproduced but certainly well worth further investigation. And I personally would like to see more investigation into what the rationale would be for this because I still can't quite figure out, yes, if you got it at, say, you know, 5 PM, that's later in the day and I can understand that maybe your immune system is somewhat less receptive at that point than it would be in the morning. But because these checkpoint inhibitors have such long half-lives, it's still in your system the next morning when your immune system is supposedly more receptive. So I don't quite understand why that would be the case. Well, let's move on to the next study. I would like to hear your thoughts on Abstract 8515, “Plasma-Guided, Adaptive First-Line Chemoimmunotherapy for Non-Small Cell Lung Cancer.” Dr. Vamsi Velcheti: Yeah, this was another abstract that seems to be really interesting in my opinion. I think there's kind of a lot of emphasis lately on ctDNA and MRD-based assays to monitor disease. In the lung cancer space, we haven't had a lot of clinical trials looking at this prospectively, and this was one of those pilot studies where they looked at circulating free DNA (cfDNA)-based response-adaptive strategy for frontline patients who are PD-L1 positive. So, patients started with pembrolizumab monotherapy, and based on plasma molecular response after 2 cycles, those patients without response received early treatment intensification with a platinum doublet. So the approach essentially was to reduce the chemotherapy exposure in patients who respond to immunotherapy. And only about 17.5% of the patients on the trial received chemotherapy based on lack of molecular response. So, in this trial, what they found was patients with the cfDNA response had a markedly improved PFS of 16.4 months versus 4.8 months. So essentially, like, this is a really nice study to set a foundation on which we have to do larger studies to incorporate molecular markers trying to look at cfDNA response to inform treatment strategy, either escalation or de-escalation strategies. So, I thought it was a very interesting study. Dr. Nate Pennell: Yeah. I mean, we always have this question for patients, “Should they get immunotherapy alone or combined with chemo?” and I think this certainly is intriguing, suggesting that there may be ways you can monitor people and perhaps rescue those that aren't going to respond to single agent. I'd like to see a randomized trial against, you know, this strategy, perhaps against everyone getting, say, chemoimmunotherapy or make sure that you're not potentially harming people by doing this strategy. But I agree, it's time to move beyond just observing that cell-free DNA is prognostic and important and start using it to actually guide treatment. Dr. Vamsi Velcheti: Yeah, and I would just caution though, like, you know, I think we need more data, but, however, it's certainly a very interesting piece of data to kind of help inform future trials. So, there was another abstract that caught my attention, and I think this would be a very interesting abstract in the EGFR space. Abstract 8506, "Patritumab Deruxtecan (HER3-DXd) in Resistant EGFR-Mutant Advanced Non-Small Cell Lung Cancer Patients After Third-Generation EGFR TKI," it's the HERTHENA-Lung02 study. What do you think about the results of this study? Dr. Nate Pennell: Yeah, this was, I would say, very widely anticipated and ultimately a little disappointing, despite being a positive trial. So, these are patients with EGFR-mutant non-small cell lung cancer who have progressed after a third-generation EGFR TKI like osimertinib. This is really an area of major unmet need. We do have drugs like amivantamab in this space, but still definitely an area where essentially patients move from having a highly effective oral therapy to being in the realm of chemotherapy as their best option. So, this HER3 antibody-drug conjugate, patritumab deruxtecan, had some good single-arm data for this. And we're sort of hoping this would become an available option for patients. This trial was designed against platinum-doublet chemotherapy in this setting and with a primary endpoint of progression-free survival. And it actually was positive for improved progression-free survival compared to chemo with a hazard ratio of 0.77. But when you look at the medians, you can see that the median PFS was only 5.8 versus 5.4 months. It was really a modest difference between the two arms. And on the interim analysis, it appeared that there will not be a difference in overall survival between the two arms. In fact, the hazard ratio at the interim analysis was 0.98 for the two arms. So based on this, unfortunately, the company that developed the HER3-DXd has withdrawn their application to the FDA for approval of the drug, anticipating that they probably wouldn't get past approval without that overall survival endpoint. So, unfortunately, probably not, at least for the near future, going to be a new option for these patients. Dr. Vamsi Velcheti: Yeah, I think this is a space that's clearly an unmet need, and this was a big disappointment, I should say. I think all of us were going into the meeting anticipating some change in the standard of care here. Dr. Nate Pennell: Yeah, I agree. It was something that I was telling patients, honestly, that I was expecting this to be coming, and so now, definitely a bit of a disappointment. But it happens and, hopefully, it will still find perhaps a role or other drugs with a similar target. Certainly an active area. Well, let's leave the EGFR-mutant space and move into small cell. There were a couple of very impactful studies. And one of them was Abstract 8006, “Lurbinectedin Plus Atezolizumab as First-Line Maintenance Treatment in Patients With Extensive-Stage Small Cell Lung Cancer, Primary Results from the Phase III IMforte Trial.” So, what was your impression of this? Dr. Vamsi Velcheti: Yeah, I think this is definitely an interesting study, and small cell, I remember those days when we had barely any studies of small cell at ASCO, and now we have a lot of exciting developments in the small cell space. It's really good to see. The IMforte trial is essentially like a maintenance lurbinectedin trial with atezolizumab maintenance. And the study was a positive trial. The primary endpoint was a PFS, and the study showed improvement in both PFS and OS with the addition of lurbinectedin to atezolizumab maintenance. And definitely, it's a positive trial, met its primary endpoint, but I always am a little skeptical of adding maintenance cytotoxic therapies here in this setting. In my practice, and I'd like to hear your opinion, Nate, most patients with small cell after 4 cycles of a platinum doublet, they're kind of really beaten up. Adding more cytotoxic therapy in the maintenance space is going to be tough, I think, for a lot of patients. But also, most importantly, I think this rapidly evolving landscape for patients with small cell lung cancer with multiple new, exciting agents, actually like some FDA-approved like tarlatamab, also like a lot of these emerging therapeutics like I-DXd and other ADCs in this space. You kind of wonder, is it really optimal strategy to bring on like another cytotoxic agent right after induction chemotherapy, or do you kind of delay that? Or maybe have like a different strategy in terms of maintenance. I know that the tarlatamab maintenance trial is probably going to read out at some point too. I think it's a little challenging. The hazard ratio is also 0.73. As I said, it's a positive trial, but it's just incremental benefit of adding lurbi. And also on the trial, we need to also pay attention to the post-progression second-line treatments, number of patients who received tarlatamab or any other investigational agents.  So I think it's a lot of questions still. I'm not quite sure I'd be able to embrace this completely. I think a vast majority of my patients might not be eligible anyway for cytotoxic chemotherapy maintenance right away, but yeah, it's tough. Dr. Nate Pennell: Yeah. I would call this a single and not a home run. It definitely is real. It was a real overall survival benefit. Certainly not surprising that a maintenance therapy would improve progression-free survival. We've known that for a long time in small cell, but first to really show an overall survival benefit. But I completely agree with you. I mean, many people are not going to want to continue further cytotoxics after 4 cycles of platinum-doublet chemo. So I would say, for those that are young and healthy and fly through chemo without a lot of toxicity, I think certainly something worth mentioning. The problem with small cell, of course, is that so many people get sick so quickly while on that observation period after first-line chemo that they don't make it to second-line treatment. And so, giving everyone maintenance therapy essentially ensures everyone gets that second-line treatment. But they also lose that potentially precious few months where they feel good and normal and are able to be off of treatment. So, I would say this is something where we're really going to have to kind of sit and have that shared decision-making visit with patients and decide what's meaningful to them. Dr. Vamsi Velcheti: Yeah, I agree. The next abstract that was a Late-Breaking Abstract, 8000, “Overall Survival of Neoadjuvant Nivolumab Plus Chemotherapy in Patients With Resectable Non-Small Cell Lung Cancer in CheckMate-816.” This was a highly anticipated read-out of the OS data from 816. What did you make of this abstract? Dr. Nate Pennell: Yeah, I thought this was great. Of course, CheckMate-816 changed practice a number of years ago when it first reported out. So, this was the first of the neoadjuvant or perioperative chemoimmunotherapy studies in resectable non-small cell lung cancer. So, just to review, this was a phase 3 study for patients with what we would now consider stage II or stage IIIA resectable non-small cell lung cancer. And they received three cycles of either chemotherapy or chemotherapy plus nivolumab, and that was it. That was the whole treatment. No adjuvant treatment was given afterwards. They went to resection. And patients who received the chemoimmunotherapy had a much higher pathologic complete response rate and a much better event-free survival. And based on this, this regimen was approved and, I think, at least in the United States, widely adopted.  Now, since the first presentation of CheckMate 816, there have been a number of perioperative studies that have included an adjuvant component of immunotherapy – KEYNOTE-671, the AEGEAN study – and these also have shown improved outcomes. The KEYNOTE study with pembrolizumab also with an overall survival benefit. And I think people forgot a little bit about CheckMate-816. So, this was the 5-year overall survival final analysis. And it did show a statistically and, I think, clinically meaningful difference in overall survival with the 3 cycles of neoadjuvant chemo-nivo compared to chemo with a hazard ratio of 0.72. The 5-year overall survival of 65% in the chemo-IO group versus 55% with the chemo alone. So a meaningful improvement. And interestingly, that hazard ratio of 0.72 is very similar to what was seen in the peri-operative pembro study that included the adjuvant component. So, very much still relevant for people who think that perhaps the value of those neoadjuvant treatments might be really where most of the impact comes from this type of approach. They also gave us an update on those with pathologic complete response, showing really astronomically good outcomes. If you have a pathologic complete response, which was more than a quarter of patients, the long-term survival was just phenomenal. I mean, 95% alive at 5 years if they were in that group and suggesting that in those patients at least, the adjuvant treatment may not be all that important.  So, I think this was an exciting update and still leaves very much the open question about the importance of continuing immunotherapy after surgery after the neoadjuvant component. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think the million-dollar question is: “Is there like a population of patients who don't have complete response but like maybe close to complete response?” So, would you like still consider stopping adjuvant IO? I probably would not be comfortable, but I think sometimes, you know, we all have patients who are like very apprehensive of continuing treatments. So, I think that we really need more studies, especially for those patients who don't achieve a complete CR. I think trying to find strategies for like de-escalation based on MRD or other risk factors. But we need more trials in that space to inform not just de-escalation, but there are some patients who don't respond at all to a neoadjuvant IO. So, there may be an opportunity for escalating adjuvant therapies. So, it is an interesting space to watch out for. Dr. Nate Pennell: No, absolutely. Moving to KRAS-mutant space, so our very common situation in patients with non-small cell lung cancer, we had the results of Abstract 8500, “First-Line Adagrasib With Pembrolizumab in Patients With Advanced or Metastatic KRASG12C-Mutated Non-Small Cell Lung Cancer” from the phase 2 portion of the KRYSTAL-7 study. Why was this an interesting and important study? Dr. Vamsi Velcheti: First of all, there were attempts to kind of combine KRASG12C inhibitors in the past with immune checkpoint inhibitors, notably sotorasib with pembrolizumab. Unfortunately, those trials have led to like a lot of toxicity, with increased especially liver toxicity, which was a major issue. This is a phase 2 study of adagrasib in combination with pembrolizumab, and this is a study in the frontline setting in patients with the G12C-mutant metastatic non-small cell lung cancer. And across all the PD-L1 groups, the ORR was 44%, and the median PFS was 11 months, comparable to the previous data that we have seen with adagrasib in this setting. So it's not like a major improvement in clinical efficacy. However, I think the toxicity profile that we were seeing was slightly better than the previous trials in combination with sotorasib, but you still have a fair amount of transaminitis even in the study. At this point, this is not ready for clinical primetime. I don't think we should be using sotorasib or adagrasib in the frontline or even in the second line in combination with checkpoint inhibitors. Combining these drugs with checkpoint inhibitors in the clinical practice might lead to adverse outcomes. So, we need to wait for more data like newer-generation G12C inhibitors which are also being studied in combination, so we'll have to kind of wait for more data to emerge in this space. Dr. Nate Pennell: I agree, this is not immediately practice changing. This is really an attempt to try to combine targeted treatment with immune checkpoint inhibitor. And I agree with you that, you know, it does appear to be perhaps a little bit better tolerated than some of the prior combinations that have tried in this space. The outcomes overall were not that impressive, although in the PD-L1 greater than 50%, it did have a better response rate perhaps than you would expect with either drug alone. And I do think that the company is focusing on that population for a future randomized trial, which certainly would inform this question better. But in the meantime, I agree with you, there's a lot of newer drugs that are coming along that potentially may be more active and better tolerated. And so, I'd say for now, interesting but we'll wait and see. Dr. Vamsi Velcheti: Yeah, so now moving back again to small cell. So, there was a Late-Breaking Abstract, 8008. This is a study of tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer. They presented the primary analysis of the phase III DeLLphi-304 study. What do you think about this? Dr. Nate Pennell: Yeah, I thought this was really exciting. This was, I would say, perhaps the most important lung study that was presented. Tarlatamab is, of course, the anti-DLL3 bispecific T-cell engager compound, which is already FDA approved based on a prior single-arm phase II study, which showed a very nice response rate as a single agent in previously treated small cell lung cancer and relatively manageable side effects, although somewhat unique to solid tumor docs in the use of these bispecific drugs in things like cytokine release syndrome and ICANS, the neurologic toxicities. So, this trial was important because tarlatamab was approved, but there were also other chemotherapy drugs approved in the previously treated space. And so, this was a head-to-head second-line competition comparison between tarlatamab and either topotecan, lurbinectedin, or amrubicin in previously treated small cell patients with a primary endpoint of overall survival. So, a very well-designed trial. And it did show, I think, a very impressive improvement in overall survival with a median overall survival in the tarlatamab group of 13.6 months compared to 8.3 months with chemotherapy, hazard ratio of 0.6. And progression-free survival was also longer at 4.2 months versus 3.2 months, hazard ratio of 0.72. In addition to showing improvements in cancer-related symptoms that were improved in tarlatamab compared to chemotherapy, there was actually also significantly lower rates of serious treatment-related adverse events with tarlatamab compared to chemotherapy. So, you do still see the cytokine release syndrome, which is seen in most people but is manageable because these patients are admitted to the hospital for the first two cycles, as well as a significant number of patients with neurologic side effects, the so-called ICANS, which also can be treated with steroids. And so, I think based upon the very significant improvement in outcomes, I would expect that this should become our kind of standard second-line treatment since it seems to be much better than chemo. However, tarlatamab is definitely a new drug that a lot of places are not used to using, and I think a lot of cancer centers, especially ones that aren't tied to a hospital, may have questions about how to deal with the CRS. So, I'm curious your thoughts on that. Dr. Vamsi Velcheti: Yeah, thank you, Nate. And I completely agree. I think the data looked really promising, and I've already been using tarlatamab in the second-line space. The durability of response and overall, having used tarlatamab quite a bit - like, I participated in some of the early trials and also used it as standard of care - tarlatamab has unique challenges in terms of like need for hospitalization for monitoring for the first few treatments and make sure, you know, we monitor those patients for CRS and ICANS. But once you get past that initial administration and monitoring of CRS, these patients have a much better quality of life, they're off chemotherapy, and I think it's really about the logistics of actually administering tarlatamab and coordination with the hospital and administration in the outpatient setting. It's definitely challenging, but I think it definitely can be done and should be done given what we are seeing in terms of clinical efficacy here. Dr. Nate Pennell: I agree. I think hospital systems now are just going to have to find a way to be able to get this on formulary and use it because it clearly seems to be more effective and generally better tolerated by patients. So, should move forward, I think. Finally, there's an abstract I wanted to ask you about, Abstract 8001, which is the “Neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone in resectable epidermal growth factor receptor-mutated non-small cell lung cancer: The NeoADAURA Study”. And this is one that I think was also fairly highly anticipated. So, what are your thoughts? Dr. Vamsi Velcheti: You know, I wasn't probably surprised with the results, and I believe we were all expecting a positive trial, and we certainly were handed a positive trial here. It's a phase III trial of osimertinib and chemotherapy or osimertinib in the neoadjuvant space followed by surgery, followed by osimertinib. It's a global phase 3 trial and very well conducted, and patients with stage II to stage IIIB were enrolled in the study. And in the trial, patients who had a neoadjuvant osimertinib with or without chemotherapy showed a significant improvement in major pathologic response rates over chemotherapy alone. And the EFS was also positive for osimertinib and chemotherapy, osimertinib monotherapy as well compared to chemotherapy alone. So overall, the study met its primary endpoint, and I think it sheds light on how we manage our patients with early-stage lung cancer. I think osimertinib, we know that osimertinib is already FDA approved in the adjuvant space, but what we didn't really know is how was osimertinib going to work in the neoadjuvant space. And there are always situations, especially for stage III patients, where we are on the fence about, are these patients already close to being metastatic? They have, like, almost all these patients have micrometastatic disease, even if they have stage III. As we saw in the LAURA data, when you look at the control arm, it was like a very short PFS. Chemoradiation does nothing for those patients, and I think these patients have systemic mets, either gross or micrometastatic disease at onset. So, it's really important to incorporate osimertinib early in the treatment course. And I think, especially for the locally advanced patients, I think it's even more important to kind of incorporate osimertinib in the neoadjuvant space and get effective local control with surgery and treat them with adjuvant. I'm curious to hear your thoughts, Nate. Dr. Nate Pennell: I am a believer and have long been a believer in targeted adjuvant treatments, and, you know, it has always bothered me somewhat that we're using our far and away most effective systemic therapy; we wait until after they go through all their pre-op treatments, they go through surgery, then they go through chemotherapy, and then finally months later, they get their osimertinib, and it still clearly improves survival in the adjuvant setting. Why not just start the osimertinib as soon as you know that the patient has EGFR-mutant non-small cell lung cancer, and then you can move on to surgery and adjuvant treatment afterwards? And I think what was remarkable about this study is that all of these patients almost - 90% in each arm - went to surgery. So, you weren't harming them with the neoadjuvant treatment. And clearly better major pathologic response, nodal downstaging, event-free survival was better. But I don't know that this trial is ever going to show an overall survival difference between neoadjuvant versus just surgery and adjuvant treatment, given how effective the drug is in the adjuvant setting. Nonetheless, I think the data is compelling enough to consider this, certainly for our N2-positive, stage IIIA patients or a IIIB who might be otherwise surgical candidates. I think based on this, I would certainly consider that. Dr. Vamsi Velcheti: Yeah, and especially for EGFR, like even for stage IIIB patients, in the light of the LAURA study, those patients who do not do too well with chemoradiation. So you're kind of delaying effective systemic therapy, as you said, waiting for the chemoradiation to finish. So I think probably time to revisit how we kind of manage these locally advanced EGFR patients. Dr. Nate Pennell: Yep, I agree. Dr. Vamsi Velcheti: Nate, thank you so much for sharing your fantastic insights today on the ASCO Daily News Podcast. It's been an exciting ASCO again. You know, we've seen a lot of positive trials impacting our care of non-small cell lung cancer and small cell lung cancer patients. Dr. Nate Pennell: Thanks for inviting me, Vamsi. Always a pleasure to discuss these with you. Dr. Vamsi Velcheti: And thanks to our listeners for your time today. You will find links to all of the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review, subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today's speakers:    Dr. Vamsi Velcheti   @VamsiVelcheti    Dr. Nathan Pennell   @n8pennell   Follow ASCO on social media:     @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn   ASCO on BlueSky   Disclosures:   Dr. Vamsi Velcheti:   Honoraria: ITeos Therapeutics   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus   Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Nathan Pennell:     Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron    Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi 

The Surprising Link Between Biblical Spies and Modern Warfare The Torah doesn't celebrate team players. It celebrates disruptors. This week on Madlik, we explore the story of Caleb, a biblical figure who defied groupthink with fierce truth. In our latest episode, we dive into the fascinating tale of the biblical scouts and focus on Caleb Ben Yefuneh, who possessed a "ruach acheret" - a different spirit. We unpack what this spirit means and why being a holy troublemaker might be exactly what God wants. In light of Israel's recent surprise attack on Iran, we explore what it means to not just read reality, but to shape it. We unpack how Caleb found his unique spirit and why being a holy troublemaker might be exactly what God wants. This episode offers profound insights into leadership, faith, and the courage to stand alone. It's a must-listen for anyone interested in biblical wisdom and possibly an insight into a culture of disruptive thinking. Key Takeaways The Power of Perspective: We explore how Caleb's unique viewpoint allowed him to see possibilities where others saw obstacles. The Importance of Adaptability: We discuss how Caleb's ability to evolve his thinking set him apart from his peers. The Value of Inner Strength: We examine how Caleb's name reflects his full heart and unwavering loyalty to his mission. Timestamps [00:00] - Introduction to the episode and framing Caleb as a disruptor with a "different spirit." [01:55] - Reference to current events in Israel and the strategic parallels with biblical stories. [03:50] - Introduction to the Parsha and the story of the spies in the Book of Numbers. [05:30] - Analysis of the name change from Hoshea to Joshua and the significance of names. [07:45] - The scouts return and report, beginning the debate over the land and its inhabitants. [10:20] - Caleb's bold statement and contrast with the fearful report from the other spies. [13:10] - Discussion on how facts were interpreted and the deeper implications of “Efs.” [17:45] - Breakdown of Caleb's unique spirit and how it's represented in the text. [24:00] - Commentary on how Caleb might have changed over time and internal conflict. [30:25] - Final reflections on interpreting facts, attitudes in leadership, and modern military parallels. Links & Learnings Sign up for free and get more from our weekly newsletter https://madlik.com/ Safaria Source Sheet: https://www.sefaria.org/sheets/657424 Transcript on episode web page: https://madlik.com/2025/06/18/a-different-spirit/

I dagens avsnitt blir det Teologiskt Forum med Tomas Nygren och Johannes Börjesson från Johannelunds Teologiska Högskola kring temat Pneumatologi. Vi följer upp pingsthelgen och talar om den helige Ande. Vad finns det för missförstånd och missbruk vi behöver observera? Vad finns det för sanningar som vi behöver återerövra och återupprätta om den tredje personen i gudomen? Vi pratar karismatik, andeutgjutelse och hur man söker förnyelse och uppfyllelse av den helige Ande. 

La Journée mondiale du don du sang se déroulera ce samedi 14 juin. Cette année, l'Etablissement du Sang Français (EFS) fête également ses 25 ans d'engagement au servie de la santé publique. En 2023 environ 1,6 millions de dons de sang ont été réalisés en France, ce qui permet chaque année à 1 million de patients d'être soignés, tout cela grâce aux dons bénévoles de généreux citoyens.Les interviews sont également à retrouver sur les plateformes Spotify, Deezer, Apple Podcasts, Podcast Addict ou encore Amazon Music.Hébergé par Ausha. Visitez ausha.co/politique-de-confidentialite pour plus d'informations.

La Journée mondiale du don du sang se déroulera ce samedi 14 juin. Cette année, l'Etablissement du Sang Français (EFS) fête également ses 25 ans d'engagement au servie de la santé publique. En 2023 environ 1,6 millions de dons de sang ont été réalisés en France, ce qui permet chaque année à 1 million de patients d'être soignés, tout cela grâce aux dons bénévoles de généreux citoyens.Les interviews sont également à retrouver sur les plateformes Spotify, Deezer, Apple Podcasts, Podcast Addict ou encore Amazon Music.Hébergé par Ausha. Visitez ausha.co/politique-de-confidentialite pour plus d'informations.

In this episode of Just Schools, Dr. Jon Eckert speaks with Lionel Cable and Joi Taylor Johnson from New Hope Christian Academy in Memphis, Tennessee. New Hope, founded nearly 30 years ago is an urban, college-preparatory elementary school providing students with a challenging, intellectual, and Christ-centered education Joi, a New Hope alum and now Director of Development, shares how the school helped shape her leadership and calling. The conversation highlights New Hope's innovative scholarship model, its farm and forest learning spaces, and the school's vision for expansion. The episode ends with a powerful piece of advice from Lionel's sister, “Do the exact opposite of what you want to do and watch what God does through you.” The Just Schools Podcast is brought to you by the Baylor Center for School Leadership. Be encouraged. Connect with us: Center for School Leadership at Baylor University Jon Eckert LinkedIn Baylor MA in School Leadership   Jon: Well, Lionel and Joi, it is a blessing to have you here today. I'd love for you to just give our listeners a little bit of an idea of what New Hope Christian Academy is all about, where it's at, what its history is, and what your hopes are as you move forward. Lionel: First, thanks so much, Jon, for having me and Joi this morning. So New Hope is going on 30 years old. We were founded in the basement of a church downtown Memphis in 1995, 1996. Basically, it was established because there were no high quality, just private or public education options for kids in the downtown corridor. So we were founded to just offer teaching, learning, discipleship to families in need at the time. So over the past 30 years, we've grown to a little over 420 kids. 80% of our families, they have to qualify for free and reduced lunch. So the core of our mission truly is impoverished families and reaching out to them because we know in order to change that trajectory, it's two things. One, gets at the heart and that's the gospel, and then two high quality academics. If we can bridge those two things together, obviously that's going to change the trajectory of family, but then also change the trajectory of Memphis. Jon: And you have kids from age three all the way through sixth grade currently with the hope of expanding in the coming years. Is that correct? Lionel: Yeah, absolutely. Past 30 years due to our funding model, which is simply on a sliding scale, it was an impossible thing to expand. Now, with the passing of the Voucher Law in the state of Tennessee, the doors are now wide open for us to expand. So after next school year, we will be adding seventh and eighth grade. Jon: Yes. And so it's great to have your director of development on here because she has a vested interest in New Hope. So Joi, can you tell us a little bit about how you ended up back here professionally at New Hope? Joi: Yes, it's such a beautiful story honestly. I graduated from New Hope in 2007 and graduated from the sixth grade, and New Hope gave me a scholarship to go on to another independent school here in Memphis named ECS, Evangelical Christian School. And from there I went to the University of Memphis and I was all about social work and helping others. And from there, I helped start a program called the Choose 901 Alumni Program. And the alumni that we were helping were exactly the alumni from New Hope Christian Academy. And so I've kind of just always been in the works, helping our alumni get internships, jobs, and just connecting them to different opportunities and networks here in the city of Memphis. But as time went on, I kind of yearned to be back home. I wanted to be here and trying to advance the mission of New Hope. We want this school to be known all around the Memphis community and even further, because there's just so many great things happening here. This is the place that helped raise me honestly and cultivate the type of leadership and servant leadership that I have to this day. So it just made complete sense for me to come back and give my twenties, my thirties away to a school that helped make me who I am. Jon: I love that. And you mentioned this scholarship that happened after you left New Hope to go to another school. That is an unusual model. Joi: It's different. Jon: So can you talk a little bit about that Joi? How does that work? Joi: Yeah, so New Hope has always been a main proponent of school choice. Whether the actual vouchers have been passed or not, they've always just had a heart to connect students to quality education. Low-income students, underserved students to quality, Christ-centered education. And so they have always been connected to several foundations and donors who really care about what's happening in the Memphis community. And so they did the thing, they made sure it happened, and they've been doing it for 30 years now, funding scholars to go to different schools all around the city. Jon: That's such a beautiful thing, especially in a place like Memphis. Memphis is an amazing city, but it's also one of the most racially polarized cities that I've ever seen. And when they integrated Shelby County schools and they tried to connect with other counties, there was a lot of strife in that. And what I love about New Hope is it's, hey, each kid deserves an education that best fits that kid. And so ultimately you have people that have put money behind doing that, and then you have a school that's living out that mission pre-K through sixth grade, and now that's expanding with some additional opportunities. But even when it wasn't, it wasn't ever just about New Hope, but that's what I love. It was about the kids you were serving, and so therefore you're willing to use resources that a lot of schools would hold for themselves. And you're putting that scholarship with kids over the next six years to get you to the University of Memphis so that you can get through successfully. Do you know of other schools that have that model? I've been in a lot of schools and I don't know if I've ever heard that. Are you familiar with anybody else? Or Lionel, where did that idea come from? Was that just the community that you were in, or did that come from another school's model? Lionel: Yeah, so 30 years ago know when we opened, we wanted to go through 12th grade. However, the demand for high quality Christian urban education, it exploded, so we grew faster than what we intended. So the founder, Steven Carpenter, no, I can tell you the scholarship program, that was not a part of his original design for the school. It was around year four or five, we need to figure out are we going to expand or are we going to just send the kids somewhere else? And ultimately our checkbook said, okay, it's cheaper and actually easier to send the kids to our surrounding schools rather than add a grade at the time. So the model stuck. But I will tell you, Jon, you mentioned just Memphis being such a unique place. In the private sector, there are not a lot of urban ED private schools here. As a matter of fact, they're exact opposite of us. So I would like to think that our children know 30 years ago, they were really the first black and brown kids to go to some of these predominantly white spaces. So there were struggles there, but there was also opportunity for growth in terms of how New Hope could better support our kids when they left us to go to some of these other schools. So we created what was called the Alumni Support Office. There's three people in that office right now who spend 95% of their time on the campuses of the other schools to stay connected with the kids, to act as that bridge, to also act as a cheerleader, but then to also act as an advocate so that the children don't lose themselves in these spaces so that their identity can remain and then also so that they can cross the finish line. So with that particular model, we've had great success. Over the last 30 years, we have a 99.9% graduation rate from high school. 99.9% of our kids get accepted into college, 70% of which are actually working on their college degree or post-secondary. So I'd like to think it was a combination of the New Hope Scholarship opening the door, but then also that continued support that the organization offers all the way through to the finish line. Jon: Well, it's such a beautiful example of building the kingdom because it's not just a gift to your students, it's a gift to those campuses that were impoverished by the lack of diversity. They were not the kingdom because they were only serving a segment of the population. And so you enrich those campuses with the gift of your students. And so that's always one of the things when we study Brown vs Board of Education and the language of that, it's always like, well, how the black and brown kids are being harmed. And the counter argument to that is, all of the students who were not able to be exposed to different cultures and different kinds of kids and people within their own community, that's impoverishing to everyone. So you have been a gift financially in the scholarship to those schools, but to send kids out who are well-prepared in an academically rigorous setting with a heart grounded in Christ, like what a beautiful gift that is to Memphis. And so sometimes we hear all of the polarizing stories and the separation, and even in school choice discussions, it's this othering of, "how could you be for that or how could you be for this?" And it's like, "No, we want each kid to become more like Christ." And we do that best when we do that in community. And I feel like that's what you're living out. Now. Joi, can you talk a little bit about that experience of going to ECS? We've worked with ECS, a really fascinating school. How helpful was that office to you? Obviously you were successful, you went on to college, you're part of that 99.9% that Lionel talked about, but what was that experience like as a student? Joi: Honestly, it was really difficult. When I graduated, it was still in the early years of our alumni scholarship or support office, and so they were really still trying to understand how to get involved and be on the campus and really understand the difficulties we were experiencing as alumni going to these schools, because as Lionel stated, that New Hope is a predominantly black and brown school. And so when you leave this place and go to a predominantly white school, I mean, when I say culture shock, that's seriously what I was feeling as a seventh grader. We're already teenagers and crazy and feeling all kinds of ways. And so being in a completely new environment without my family really, we went through kindergarten through sixth grade together. And so leaving them and being placed in a completely new situation, it was really hard. It was really, really difficult. But the ASO office, they were there and they walked with me through all of those obstacles and difficulties and challenges that I faced, and they really encouraged me to just keep going because I was going to come out gold in the end. Even though it was some hard times, there was a lot of beauty in that as well. I tell a lot of people, the ECS definitely helped me academically. I mean, when it came to college, I was so ready. I didn't even blink to some of the work that they were throwing at me. But also spiritually. I mean, it really gave me that foundation of the Bible and knowing these verses and scriptures. Whenever I'm in these science classes or philosophy classes, and they really want to deter you from thinking that Jesus is the Savior and he is the creator, it really just gave me a foundation to know who I am, whose I am, I'm a daughter of the King, and it just really gave me a push to really get through everything. So I think I came out gold from doing all of that and trying to navigate it. Jon: Yeah, that joy through struggle is something that I think our current students have a hard time understanding. I mean, we want adversity. We don't want trauma. And so certainly going outside of your comfort zone to a new campus with support, that's adversity. We don't want it to bleed into trauma because I think through that adversity, we grow and become more of who we're created to be. And that's part of learning. I mean, that's the zone of proximal development. It's where you're at on your own versus what you can do with others through struggle, and that's where real joy is, and that's where transformation happens. So you would do some interesting things, Lionel, at your school with the forest and the farm. These aren't typical things that you think of in urban settings. Can you talk a little bit about what you're doing there and what the idea behind all that is? Lionel: Yeah, it was 2013, Mary Leslie Ramsey, who was the teacher that came up with the idea. We had recently been gifted the land from Habitat for Humanity, it's right across the street. They wanted to actually turn it into a subdivision, but found out it was on a floodplain, so couldn't do anything with it, so they gave it to us. She woke up one day with the head of school at the time and said, "Hey, the Lord has given me a vision. Do you see it? Do you see it?" And he kept saying, "I don't see a thing," because there was nothing there. And she said, "No, do you see this farm and this forest?" So she talked him into it, and obviously we didn't have a budget at the time to get it started. So we partnered with the Memphis Botanic Garden and they gave us all of the plantings that they were going to throw away. And it just really started with this small idea. Since Frayser is a fresh food desert, and the majority of our kids are either apartment dwellers or they don't necessarily go outside like they should, Mary Leslie just, she had the idea, "Okay, we've got to get our kids outside and we've got to expose them to something completely different than what they're used to." So that's when the farm and the forest was birthed. Currently, it is sitting on about five and a half acres. About one and a half of those acres, that's the actual farm. And it's more agricultural than it is animals. So our kids grow anything and everything from cabbage to strawberries to harvest their own honey. I mean, you name it, it is there. I'd like to think of it as the Garden of Eden because in the middle of Frayser, you wouldn't expect just this beautiful farm and forest that is there. We've got a full-time horticulturist who pours into that, and our teachers are able to go out there and do some applicable things with everything that is growing out there. With what's happening in the classroom, the forest piece is about four, four and a half acres, and we look at that as more of our play space. There are birdwatching observatories, there's about 1.7 miles of a walking trail that has been excavated there. I mean, just a beautiful space. And it's a way for our kids to really connect with our Lord. I mean, there's no better way to put your hands in the ground to plant something and just see how good God is by something coming up out of the ground. Jon: So you've got to tell me, how good are your kids at avoiding the instant gratification trap that gets really exposed in gardening. So they see something that is not even close to ripe, like that's it. I want to try it. Are they good at leaving it and letting it develop to its fullness of what the Lord wanted before they indulge? Or do they give in to that childlike instant gratification of the underdeveloped prefrontal cortex? Lionel: Yeah. Yeah, I think it's pretty developed. Jon: Okay. Lionel: Probably not at the beginning. And let me tell you why. So a part of Mary Leslie's strategy was also to give back to the Frayser community, so our kids understand the things that we plant, it's going towards a common good. So with this being a fresh food desert, every Friday, starting in late March all the way through, I'd say the end of October, we have what is called a pay what you can stand. And we invite the entire Frayser community to come in and grab as much produce as they'd like, and they can pay something or they can get it for free. So our kids know that, hey, we got to wait. We want that fruit to get ripe or those vegetables to be fully developed because it's going towards a good cause. Jon: That is so beautiful. The reason why I ask is last week I was at a school that's in a juvenile detention center down here in Texas, and they have violent youth offenders. They have quite a range of kids from age 13 to 18, and they have a garden. And in the English class, they were writing about weeds and the weeds they have in their own lives and then going out and weeding and tilling this garden. It was this beautiful lesson, but there was a very underdeveloped cucumber that one of the guys picked up and started munching for about 15 seconds. Until then, it's all out all over the ground because it was not ready. And the guy who's in charge of the garden says, "Yeah, they lose about 90% of the produce to kids not being able to delay that gratification to the point that it is ripe." And I think your point about they're doing this for someone else, that changes the calculus, that changes what it is. And now these kids are in juvenile detention through a series of tragic circumstances, bad decisions. Some of it may be related to not being able to delay gratification or not having the security of believing that something will be there the next day and not just taking what's available right now. But it was a fascinating lesson. So when you started talking about what your kids do, I was like, "Oh, I got to hear it." I had not thought about what a great lesson in delayed gratification gardening is. Because you take that too early and that thing that's going to be amazing in a week is inedible in the moment. So I love that. I love that. Joi, you're telling the story from a development fundraising perspective. Anything you want to add to what New Hope's doing that you think is particularly compelling? Joi: Yes. When I was a student at New Hope, we always craved for a middle school or a high school. We wanted to be at New Hope for as long as we possibly can. So for me to be here at New Hope, at the start of the transition of us actually bringing in a middle school, I mean, that's amazing to me. It feels like my sixth grade dreams are coming true right before my eyes. So I'm excited that I get to extend this type of opportunity to the current fifth graders who are here now. And then to the rest of the generations who are coming through, that they really get a chance to be involved and get this, it's like an incubator for Christ-Centered leadership and learning service and different activities that they get a longer chance to kind of experience that before they enter into high school where it really gets crazy. Middle school is just the beginning, but high school, I feel like we give them a chance to be prepared and cultivate their social emotional learning process needs that they have, so that when they are in those frightening or new situations, that they feel more prepared how to navigate these things. And so I think that's one of the best things that I'm excited about preparing or clearing out a new pathway for our students to really get time here with us here at New Hope. And then of course, it's our 30th anniversary. That's a huge deal. I don't know if we ever thought we would see this kind of day, but we're so blessed and thankful that we've made it. God has been with us the whole time. We've had a lot of obstacles, but we've come out on top every single time because his hand has been over us. And so I want to offer more partnerships and relationships to the community, especially right now. We have a really hectic education system going on, atmosphere in Memphis right now. So I really feel like this is a great time to amp up New Hope and tell more people about it because they are getting fearful and worried about what their child's education really will look like in the future. But we have been stable. We've been here for 30 years, and hopefully we can open our doors to more people. Jon: Yes. Love it. Love it. And the fact that you can describe middle school as a dream and not a nightmare, is a true testimony to the work of the spirit at New Hope. So love it. As a former middle school teacher and a middle school kid, I think I would have loved being at your farm and forest and in the culture you've built at New Hope. So that's a beautiful thing. We always end with a lightning round where I'll just ask a few questions and we just keep the answers to about a sentence if you can. I'm terrible at this, but if you can, that's better than me. So the first question is, what's the worst piece of advice you've ever received, as an educator or as a student, but just worst piece of advice you've ever gotten? Lionel: I guess I'll go first, Joi. Joi: Go ahead. Lionel: Honestly, I don't think I've ever gotten really bad advice. It may not have worked out because there's learning and failure. I just learned not to do that again, but I learned from it. So to answer your question, no bad advice. Jon: Well, one thing, Lionel, I would say that the piece I always give is people tell you to stay in your lane. And I feel like that's bad advice many times. And if New Hope would have stayed in its lane, you wouldn't have scholarships to send people off to school. You wouldn't exist. You wouldn't have a farm, you wouldn't have the wood. So I'm applying my bad advice that I received to New Hope as a counter example, and I'm grateful for educators that step up and speak out about, here's what we need, here's what we need to flourish, and here's what we need to do together. So I'll apply my bad advice to your good counter example. So thank you for that. Joi, what about you? Have you gotten any bad advice or are you as blessed as Lionel is to never have received bad advice? Joi: No, I think I have gotten bad advice before. Being in this new situation, raising money for an independent black school in Memphis, I think people have definitely told me that there are certain groups of people and populations I shouldn't ask money for support from or any type of activity from. But we're learning that our parents, our grandparents, the people in our community might be great people who can give and be a part of this whole mission that we have going on in New Hope. It doesn't have to be one specific person or they have to look a certain way. This is an opportunity for all. Jon: That's good. All right. Best advice you've either given or received? Joi: I will say the best advice that I think I've gotten actually come from Lionel. It was a couple of years ago, I was still in my previous job and antsy to get back home and to do work here at New Hope. And I talked to Lionel about it, "Like, why is it this not working out? I want to be here." And he told me to be still and wait on the Lord. And that's been the best advice because look where I am a couple of years later. I'm here and an opportunity to really lead in a big way, bigger than what I was trying to do earlier. So being still. Jon: Psalm 46:10, always good advice. All right. Lionel, what about you? Lionel: Yeah, you may have heard this one already, Jon. I think this advice came from my sister. About 10, 15 years ago, I had an opportunity, between two schools, to be the principal. One, was the highest performing school in the district, the other was the seventh worst performing school in the entire state of Tennessee. I was offered both jobs. Go out to the car, called my sister, I'm like, "Hey, I think I'm going to decline the worst school. I just want to go to the best school." And keep in mind, Jon, I had no experience at a failing school at all. Simple advice from her. She said, "Lionel, God has really blessed you in your career. Why don't you do the exact opposite of what you want to do and watch what God does through you?" Jon: That's amazing. Lionel: At that point, I accepted the job at the other place, and that's all she wrote. I mean, it was the best decision of my life. Jon: Yeah, love that. You have told me that. And it's always a good story to hear that again. Because I think so often I want my desires to always be aligned with Christ. And the more I am praying, the more I'm in the word, the more that is likely. But so often, my selfish desires get in the way of what He wants. And so love that. Okay. What do you see as the biggest challenge for New Hope specifically for the next 30 years? What would you say? And then we'll go back to what's your greatest hope? But we'll start with the challenge first. Lionel: Yeah. Prior to this year, it was the funding model. I mean, it's flipped on its head. 93% of our dollars came from donations. Past 30 years, we've never been in the red. Praise God, thankful for that. Now that ESA's vouchers, all of that is here, there is a path forward. So I think the challenge is how can we leverage our 30 years of experience and create more new hopes? New Hope, we serve 44 different zip codes in Memphis. In the north Memphis area is where we planted our flag, but South Memphis is the most impoverished area in the city. And my dream, my desire, my hope is that we can plant our flag in South Memphis and create a New Hope South Memphis, and then hopefully a New Hope East Memphis. So many children here, Jon, they need teaching, learning, and discipleship, and they need hope. And New Hope can certainly provide that through the gospel, but then also change that family's trajectory just through high quality academics and just building that foundation. So in short, to answer your question, the challenge is, how do we get more dollars? How do we leverage the dollars we have? How do we create these partnerships so that New Hope can grow well beyond Frayser, which is where we are now? Jon: Joi, anything you'd add to that challenge? Joi: He is the visionary leader of New Hope Christian Academy, so I stand behind him. That's our goal and vision. That's what we're doing. Jon: That's great. So then what's your greatest hope for New Hope or education in general, what's your greatest hope? Lionel: Oh, that's a loaded question, Jon. Jon: I know. We ask good ones for the lightning round and try to get you to give a parsimonious answer. Lionel: Oh. For Memphis specifically, and I think there's two parts to that. Memphis specifically, I'm hopeful that the education system will look more like the Kingdom, in particularly the private schools. Because it's not, Jon. I mean, again, New Hope and Collegiate, which is our sister school, we're the only ones that are high poverty, high concentration of black and brown children. Other schools are the complete opposite. And I always say, if you don't like diversity, you don't like heaven, you're not going to like heaven. And the thing is, I mean, I'm hopeful that in the independent school space that there will be room for growth so that it can look more like the Kingdom and that the leaders will be more Kingdom minded. As it relates to just education? We need more urban Christian education. I think that's the key. In the core of the city, we need high quality options for families because that's where the concentration of brokenness is, and in every major city in America. So I'm very hopeful, you know that the lens will look towards just again, high quality urban Christian education in cities across America. Jon: Oh, yes. Love that. Rebecca McLaughlin says, "Don't miss the fact that Christianity is the most diverse multicultural movement in the history of the world. And the church is becoming increasingly black and brown in 2025." So that's a great word and appreciate your heart behind that. Joi, anything you'd add to your hope for where things are headed? Joi: Yes. I think when people think of Memphis, their mind goes to our crime rate, our history, our music, and our food. And I think one thing about Memphis that most people miss is that this is a place with a lot of opportunity. And I'm grateful that the ESAs and EFS has made their way to the Shelby County area because crime is a big issue here. Safety is a big issue here. But I do know that that's directly related and linked to poverty. And I know that poverty can be changed with quality education. And so I think this is a great time for us to really capitalize on, now's the time. New Hope is the place for parents and community members to pour into and send people to, and maybe even replicate a school like that in their own city or their own state, that this kind of gospel and movement that we're trying to spread actually spreads everywhere. Jon: That's great. This resonates with what the Spreading Hope Network does. They're based out of Minneapolis. I'm sure they're aware of you and hopefully you're aware of them. Love the heart, love the work you're doing. Our team, they got to visit, it all came back. Bill Sterrett was enamored with the farm and the forest. Loved it. The team loved it. So anybody that gets a chance to get through Memphis and visit, I know they find a welcome team there that is just doing good work. And it's an encouragement and there's great joy in the work that we get to do with kids. So thank you for your time. Appreciate your work on our advisory board, Lionel. Joi, it's great to meet you virtually. Hopefully we'll meet you in person soon, and thanks for all you do. Joi: Sure. Thank you. Lionel: Thank you.  

Välkommen till Martinson Möter en podcast från fadderbarns organisationen Compassion – där varje samtal vill öppna upp en ny värld av tröst och tro, heligt hopp, mat och mod!I dagens avsnitt får du möta Marie Louise Nilsson en inspiratör med både eld i hjärtat och skärpa i blicken och värme i rösten. Hon är prästen med över 25 års erfarenhet inom EFS. En ledare för ledare. En vägvisare för församlingsbultande hjärta som längtar efter mer av Jesus.Marie Louise brinner nämligen för att hela Sverige ska få höra om Jesu stora kärlek. Det är också därför hon gör det hon gör på Alpha Sverige, en plattform där frågorna får plats och sökarna hittar hem. Uppvuxen i lilla Sätaröd utanför Kristianstad, mellanlandad i Åres fjäll och nu med sitt hjärta planterat i Göteborg tillsammans med familjen hon älskar. Hon är chokladälskaren som aldrig säger nej till en latte i handen och förvandlar varje butik till en "boutique" med glimten i ögat. Och ja, hon har sommarjobbat på Vero Moda, dock nästan utan lön, men… med en helt ny garderob. Vill du höra mer om det får du lyssna på förra avsnittet. För nu går vi raskt framåt, livet, ledarskap och latte avhandlas i höga hastigheter!Vi reser med henne genom flytten till pandemins Göteborg 2020, blickar tillbaka mot Undersåkers snötyngda gator och rör oss mot det som är djupast sant: Relationer. Äkthet. Öppenhet. DVS det som är viktigt på riktigt. Så spänn fast dig. För vi vill inte bara ha ett samtal. Babbla på ytan. Det här är en inbjudan till mod. Det är en inbjudan att våga leva ärligt, leva för Kristus – och låta kärleken få sista ordet. Och vad händer egentligen med ett hjärta när man öppnar sitt liv – som Marie Louise gjort – för ett fadderbarn från Kenya?Välkommen in i snälla, men sanna samtal. Välkommen till Martinson Möter med Marie Louise Nilsson! Hosted on Acast. See acast.com/privacy for more information.

I dagens avsnitt rör vi oss från påvar till radikaliserade pojkar och frågande präster. Magnus gästas återigen av Joel Halldorf. Som professor i kyrkohistoria fungerar Joel via tidningar, tv och radio som hela Sveriges fortbildare i religiösa frågor. De senaste veckorna har han ledsagat oss genom Påve Franciskus begravning och konklaven fram till Påve Leo XIV via sin substack Vit Rök. Magnus och Joel tar sats i händelserna i Vatikanen för att styra vidare samtalet in mot det religiösa skeendet i vårt land, inte minst bland unga män. Statistiken ger en fingervisning om att vi kanske står på tröskeln till en stilla väckelse. Vad behöver vi som kyrka göra för att denna rörelse inte ska gå oss förbi? Vilka saker behöver vi vara uppmärksamma på och vaka över?  

Judith Fagrell är präst i Skara domkyrkopastorat och skriver sedan många år om kyrkan i bland annat tidskriften Pilgrim, tidningen Dagen, Kyrkans tidning och SPT. Just nu aktuell med boken “Att söka rötter - ett teologiskt svar på Svenska kyrkans kris”. Idag fortsätter Judith samtalet med Magnus om rörelsen bland ungdomar som söker sig till kyrkan. Judith skriver: »Om vi inte vill ha en kyrka som lever i evig adolescens måste vi odla självkritik, och i det ingår att problematisera vår självbild. Vem inkluderas i det kyrkliga "viet"? Det exklusiva "viet" får till och med mig, som är präst, att ibland fundera på om jag tillhör – är det då så konstigt att våra unga scrollar vidare till något mer greppbart, inrutat, inbjudande?« 

Sona Nanotech Inc chief medical officer Dr Carman Giacomantonio joined Steve Darling from Proactive to announce a critical advancement as the company prepares for its first-in-human clinical study. Sona has successfully completed bacterial endotoxin testing on its biocompatible gold nanorods using the Limulus Amebocyte Lysate (LAL) method, a widely accepted industry standard for evaluating medical and pharmaceutical products. The testing was conducted at a GLP-accredited U.S. laboratory operated by a leading global provider of MedTech and pharmaceutical testing services. The results showed that all tested samples passed with endotoxin levels below detection limits, ensuring that Sona's nanorods meet stringent safety standards. In addition, Positive Product Controls confirmed the test's validity, with recovery values between 98% and 130%, indicating no assay interference—a further validation of the product's safety profile. The EFS, which is pending ethics committee approval, is expected to begin patient enrollment and first dosing early this summer. The study will utilize the same batch of gold nanorods that passed the endotoxin screening, reinforcing confidence in the material's clinical readiness. With its novel biocompatible nanotechnology platform, Sona is pioneering a new generation of targeted medical therapies. This latest development places the company a step closer to clinical validation and eventual commercialization of its proprietary nanomaterials. #proactiveinvestors #sonananotechinc #cse #sona #otcqb #snanf #CancerTreatment #MedicalInnovation #HyperthermiaTherapy #GoldNanoparticles #Immunotherapy #TargetedTherapy #CancerResearch #Biotech #MedicalBreakthrough #GoldNanorods

Det är dags för ett nytt teologiskt forum tillsammans med Johannelundteologerna Tomas Nygren och Stefan Lindholm. Vi fortsätter samtalet om ungdomar, radikalisering och sanningsbegreppet – vad är objektiv och subjektiv sanning när det kommer till den kristna läran och bekännelsen? Vilka livslögner har vår generation köpt och gjort till sanningar och hur avslöjar man dem? Hur skapar vi sammanhang med både rymlighet och tydlighet?   

Since the MacLeod report was first published in 2009, Engage for Success (EFS) has become a flourishing all-volunteer collective for those passionate about colleague engagement. A senior lecturer at Nottingham Business School, Dr. Sarah Pass is a practice-oriented academic who concentrates on employee experience and engagement. As a member of the Engage for Success (EFS) Advisory Board, she co-leads the EFS annual survey, which benchmarks the engagement levels of the UK working population. In this episode, Sarah and Jen discuss the findings of the latest EFS survey, explore the four enablers of engagement and dig into why colleague voice is so important when seeking to build motivation and goodwill at work.   About Dr Sarah Pass Dr Sarah Pass is a practice-oriented academic who concentrates on employee experience and engagement. She is a member of the Engage for Success (EFS) Advisory Board and co-leads the EFS annual survey, which benchmarks the engagement levels of the UK working population. Sarah leads EFS projects focusing on different aspects and influences of engagement in practice and is also Chair of the EFS East Midlands Area Network. Sarah is a Fellow of the RSA, an Academic Associate of the CIPD, and a member of the Involvement and Participation Association (IPA) Working Insights Group. In 2023, Sarah was ranked by HR Magazine as an Influential Thinker in HR. Sarah currently works as a Senior Lecturer at Nottingham Business School (NTU).   Find Sarah on LinkedIn:  https://www.linkedin.com/in/sarahpass/ Sarah at Nottingham Business School: https://www.ntu.ac.uk/staff-profiles/business/sarah-pass Engage for Success: https://engageforsuccess.org/

När EFS 1861 tog ett beslut om att sända missionärer för tjänst bland "hednafolken" så var drivkraften förankrad i missionsbefallningen. Jesu egna sändningsord - gå ut i hela världen.... Lange var en av tre som 1866 landsteg i Massawa i nuvarande Eritrea.

När EFS 1861 tog ett beslut om att sända missionärer för tjänst bland "hednafolken" så var drivkraften förankrad i missionsbefallningen. Jesu egna sändningsord - gå ut i hela världen.... Lange var en av tre som 1866 landsteg i Massawa i nuvarande Eritrea.

Efter en ofrivillig paus är vi tillbaka och tar tag i vårens stora snackis! Helena Cashin, EFS kommunikationschef och Budbärarens chefredaktör är tillbaka och samtalar med Magnus om ungdomar som flockas till kyrkan och kyrkans ibland oförberedda eller ängsliga mottagande. Debatten pågår som bäst och har uppmärksammats långt utanför kyrkans egna forum. Samtalet är viktigt och här finns flera viktiga perspektiv att ta hänsyn till. Kanske framförallt att en föräldralös kyrka förmodligen alltid kommer förbli barnlös. 

At the 2025 American Urological Association (AUA 2025) Meeting in Las Vegas, UROONCO BCa chief editor Dr. Benjamin Pradere (FR) talked to Dr. Neal Shore (US) about the CREST study results: Sasanlimab in combination with bacillus calmette-guérin (BCG) improves event-free survival (EFS) versus bacillus calmette-guérin as standard of care in high-risk non- muscle-invasive bladder cancer (NMIBC). Dr. Shore explains the study rational, the results of the study, and the take home messages he presented during the meeting.

På mandag stilte Daniel spørsmålet: «Hva er roten til fangenskapet vi erfarer i våre liv – og finnes det håp for meg?». Vi så på følgende overskrifter: -       Vårt fangenskap (Joh 8:34): Den dypeste roten til vårt fangenskap på ulike områder av livet, er hva Skriften kaller synd.-       Våre fiender (Matt 4:1-11; Joh 8:44; Efs 4:26f; 1. Joh 2:15f): Gjennom Jesu fristelser og den kristne tradisjon, ser vi at synden primært angriper oss gjennom tre fiender: djevelen, kjødet og verden. Djevelen plager oss med løgner, som spiller på forvrengte lidenskaper i oss, som igjen finner veien inn i verden og kulturen rundt oss – sammen danner dette en ond og selvforsterkende sirkel. -       Vår frelser (Hebr. 9:26; Kol. 2:15): Den kristne fortelling ender ikke i sorg, men i seier! Ved Jesu død og oppstandelse, så blir Han vår stedfortreder og seierherre! Kampen mot våre tre «sjels fiender» er virkelige, men den fantastiske sannheten er at den kristne kjemper fra frihet og ikke for frihet – siden Jesus har vunnet seier! Evangeliets frihet er det dypeste svaret til ethvert fangenskap i våre liv. Denne frihet erfarer vi ved: -       Å ta imot evangeliet (høre)-       Tro evangeliet-       Trå ut i evangeliet Du er skapt til et liv i frihet og Jesus er vår seier!____Hovedtekst: Se prekenoppsummering.____1.     Gå gjennom de ulike overskriftene: Les tekstene og snakk om hvordan de ulike områdene treffer våre liv.  2.     Hvilke områder i ditt liv trenger du at Jesus «bryter lenken» som holder deg fast? 3.     Avslutt med å be for hverandre inn i de områdene!

Send us a textYou've done the ultrasounds, the shots, the bloodwork — and then retrieval day comes, and... nothing. Zero eggs. What just happened?In this episode of Taco Bout Fertility Tuesday, Dr. Mark Amols dives into one of the most confusing and emotionally crushing outcomes in IVF: Empty Follicle Syndrome (EFS). But before you panic, know this — most cases aren't what they seem.We'll break down:The difference between true vs. false EFSWhy true EFS is rarer than a unicorn eating tacosHow trigger shot timing and hormone levels can lead to confusionWhat doctors actually mean when they say “empty follicle”Real strategies for preventing and managing this situationWhether you've heard the term before or are just trying to understand your IVF journey better, this episode will give you clarity, peace of mind, and as always — a side of science and salsa.Thanks for tuning in to another episode of 'Taco Bout Fertility Tuesday' with Dr. Mark Amols. If you found this episode insightful, please share it with friends and family who might benefit from our discussion. Remember, your feedback is invaluable to us – leave us a review on Apple Podcasts, Spotify, or your preferred listening platform. Stay connected with us for updates and fertility tips – follow us on Facebook. For more resources and information, visit our website at www.NewDirectionFertility.com. Have a question or a topic you'd like us to cover? We'd love to hear from you! Reach out to us at TBFT@NewDirectionFertility.com. Join us next Tuesday for more discussions on fertility, where we blend medical expertise with a touch of humor to make complex topics accessible and engaging. Until then, keep the conversation going and remember: understanding your fertility is a journey we're on together.

In this episode of the InfosecTrain podcast, we explore AWS Cloud Storage Services, their key features, and how businesses can leverage them for scalability, security, and cost efficiency.

Det är återigen dags för teologisk verkstad och idag samtalar Tomas, Stefan och Magnus om begreppsparet lag och evangelium. Martin Luther behandlade frågan ingående och det är ett av hans viktiga bidrag. Luther menade: »Skillnaden mellan lag och evangelium är den kristna trons främsta kännetecken. Alla som räknar sig som kristna bör känna till och kunna redogöra för denna skillnad. Annars kommer man blanda ihop dem och inte att känna till och bevara någondera, varken det ena eller det andra.« Hur kan vi förstå och kommunicera lag och evangelium i vår tid och vilken tröst kan det skänka eller vilka potentiella problem kan det skapa? 

Pastor Simon Holst från Bet:L i Skövde gästar dagens avsnitt och med utgångspunkt i hans senaste text i Tidningen Dagen samtalar han med Magnus om missiologi för vår tid. En negativ värld behöver inte vara något negativt för kyrkan, utan kan bli tvärtom bli till en guldålder för de kyrkor som vågar stå för och predika ett frimodigt evangelium, lyder Simons spaning. Utifrån tre tids epoker som i texten kallas för positiv värld, neutral värld och negativ värld diskuterar Magnus och Simon hur kyrkan kan finna ett lämpligt och gångbart föredöme i profeten Daniel som verkade i Babylon.  

Magnus gör ett kärt återseende med Aminah Fallgren och lyssnar till hennes fantastiska berättelse! För drygt 20 år sedan dök Aminah upp i kyrkan där Magnus var pastor. Då som en drogmissbrukare sedan 12-års ålder som hade alla sina ägodelar i en väska. Idag har hon varit drogfri i 20 år, blivit beroendeterapeut, är VD och driver egen framgångsrik behandlingsverksamhet som hjälpt åtskilliga. Förutom Aminahs egen inspirerande berättelse om befrielse, tillfrisknande och nya möjligheter, så samtalar Magnus och Aminah om den kamp som alla människor utkämpar med skam, sökande efter bekräftelse, kärlek och frihet. Missa inte ett ärligt och härligt samtal som berör! 

Det är åter dags för ett teologiskt forum med Johannelunds teologerna Tomas Nygren och Stefan Lindholm. I dagens avsnitt samtalas det om nattvarden. Det något högst påtagligt och verkligt som sker i nattvarden och inte bara symboliskt. Därför kallas sakramenten nådemedel – kanaler genom vilka Gud sänker sin nåd och åstadkommer vad han lovar. Kan man därför säga att nattvarden skapar den verklighet den gestaltar? Häng med i dagens samtal! 

Emission Factors (EFs), as we know them, are over. Bold statement? Maybe. True? Absolutely (in our opinion). In this episode, we break down why traditional emission factors are rapidly being replaced by Product Carbon Footprints (PCFs) and what this shift means for businesses.The limitations of traditional emission factorsWhy PCFs provide more accurate, supplier-specific dataWhere businesses need to focus their efforts as PCFs scale upKey considerations when transitioning from EFs to PCFs

EFS kommunikationschef och Budbärarens chefredaktör, Helena Cashin, är tillbaka i podden för en ny runda spaningar tillsammans med Magnus. Dagens avsnitt är fullspäckat och matnyttigt, det spänner över frågorna om kyrkan och gemenskapen såväl som kyrkan och gudsbilder. Har vi skapat en gudsbild som är en projektion av oss själva och våra egna trauman eller önskningar? Vi är hyfsat bra på gudstjänst men vad händer med gemenskapen? Vad innebär det att forma kristna gemenskaper?  

Podden gästas idag av Samuel Björling, musikinspiratör vid EFS Sverigeavdelning. Magnus och Samuel samtalar om kyrkans sång och musik, lovsång och förkunnande sång framförd av solist, nytt såväl som gammalt. Samuel är ansvarig för senaste musiksläppet på Cantio: en EP med namnet ”Hela vägen går han med mig” och konferensen med samma namn. Magnus och Samuel berättar också om de ”helkyrkliga inspirationsdagar” de erbjuder församlingar samt den helkyrkliga mässan som fler och fler visar intresse av. 

Litteraturvetaren och litteraturredaktören på Svenska Dagbladet, Josefin de Gregorio, gästar podden igen för att göra om sin bejublade medverkan förra året. Josefin presenterar en »inne- & utelista« för 2025 utifrån kristenheten. Magnus och Josefin samtalar utifrån listan om många spännande ämnen som kontemplation, framgångsteologi, kristna som bråkar på internet, avgudadyrkan, väckelse och barnens närvaro i kyrkan. Här finns mycket spännande!

Ängelholm Pingstförsamlings pastor Sven Wiborn predikar över Joh 11:21-27 i EFS-kyrkan som avslutning på den ekumeniska böneveckan. Samverkar i gudstjänsten gör även Ängelholms församling, Rönnekyrkan och ELM Ängelholm.

Ängelholm Pingstförsamlings pastor Sven Wiborn predikar över Joh 11:21-27 i EFS-kyrkan som avslutning på den ekumeniska böneveckan. Samverkar i gudstjänsten gör även Ängelholms församling, Rönnekyrkan och ELM Ängelholm.

durée : 00:05:54 - L'invité de la rédaction de "ici Sud Lorraine" - La collecte du plasma est la priorité de l'établissement français du sang (EFS) en 2025. Pour mobiliser les Français, Fréderic Pacoud, le président de l'EFS est en visite ce vendredi à Remiremont (Vosges), où il rencontre donneurs et élus locaux. Il a pris le temps de répondre à nos questions.

Det är dags för en ny omgång teologiprat med Johannelund teologerna Tomas Nygren och Stefan Lindholm. I dagens avsnitt avhandlas dopet som sakrament och vad det förmedlar från Gud och hur det förhåller sig till tron. Räcker dopet eller vilken roll spelar tron? Ska man bygga sitt dop på sin tro eller sin tro på sitt dop - vad Gud har skänkt och gjort i dopet oberoende av med min egen medverkan? Hur kan vi berikas från olika teologiska perspektiv - kan lutheraner lära sig något av baptister och tvärtom? 

Ida-Maria Brengesjö är evangelist och församlings-utvecklare inom Equmeniakyrkan och aktuell med boken »När taket måste brytas upp«. Idag gästar hon podden och samtalar med Magnus om frågor kring kyrkans rymlighet och öppenhet – leder det till flummighet eller går det att kombinera tydlighet med generös rymlighet? 

Executive functions are the skills that allow us to plan for and meet goals, manage time effectively, remember what we've heard and read, and exercise self-control. Peg Dawson, Ed.D., shares strategies you can use to improve your EFs and cement habits. Executive Functioning in Adults: More Resources Self-Test: Do You Have a Working Memory Deficit? Read: 7 Executive Function Deficits Tied to ADHD Read: How Adults with ADHD Think eBook: The Adult's Guide to Stronger Executive Functions Access the video and slides for podcast episode #531 here: https://www.additudemag.com/webinar/executive-functioning-adults-adhd-strategies/ Thank you for listening to ADDitude's ADHD Experts podcast. Please consider subscribing to the magazine (additu.de/subscribe) to support our mission of providing ADHD education and support.

Själens slagfältEtt personligt och närgånget samtal med Magnus Persson, präst och inspiratör i EFS. Om sjukdom, kamp och ovisshet. Vi delar personliga erfarenheter och jag fångar upp Magnus starka beskrivning om själens slagfält när en plötslig sjukdom gör att styrka blir svaghet. I samarbete med Magnus podcast: Re:formera.

Guest: Anais Nebel: Group Culture and Communications Manager, Lipsy Anaïs is a culture leader and brand strategy expert, passionate about people empowerment. She leads culture and communications for Lipsy, a fashion and beauty group made up of 7 brands including Victoria's Secret UK and Gap UK. Anaïs is known for creating out-of-the box engagement campaigns that create vibrant connections and bring the soul of a company to life. This special episode was recorded following Jo and Anais interview on stage at the 2024 Employee Engagement Summit at the Brewery in London and is hosted by Jo Moffatt, Engage for Success Advisory Board member and regular EFS radio show host. Engage for Success are media partners for Engage Business Media's industry-leading events, including the Future of Work Conference and the Employee Engagement Summit. • The key drivers that led to Lipsy London taking action to add self-empowerment to their wellbeing strategy • Why Lipsy London decided to run a photoshoot initiative • Any challenges in getting employee buy-in • Highlighting the key results that have been seen following the photoshoot • What's next for self-empowerment at Lipsy? • The achievements and impact that create the most pride Join us as we discuss how Lipsy London's recent wellbeing initiative empowered employees through self-confidence. Host: Jo Moffatt

Guest: Anais Nebel: Group Culture and Communications Manager, Lipsy Anaïs is a culture leader and brand strategy expert, passionate about people empowerment. She leads culture and communications for Lipsy, a fashion and beauty group made up of 7 brands including Victoria's Secret UK and Gap UK. Anaïs is known for creating out-of-the box engagement campaigns that create vibrant connections and bring the soul of a company to life. This special episode was recorded following Jo and Anais interview on stage at the 2024 Employee Engagement Summit at the Brewery in London and is hosted by Jo Moffatt, Engage for Success Advisory Board member and regular EFS radio show host. Engage for Success are media partners for Engage Business Media's industry-leading events, including the Future of Work Conference and the Employee Engagement Summit. •    The key drivers that led to Lipsy London taking action to add self-empowerment to their wellbeing strategy •    Why Lipsy London decided to run a photoshoot initiative  •    Any challenges in getting employee buy-in •    Highlighting the key results that have been seen following the photoshoot •    What's next for self-empowerment at Lipsy?  •    The achievements and impact that create the most pride Join us as we discuss how Lipsy London's recent wellbeing initiative empowered employees through self-confidence. Host: Jo Moffatt

Smith Anniversaries, a retirement announcement, EFS updates, customer service news, Brake Safety Week, Clean Inspection Roll Call, Shout Outs with Julie, and Doug's Dad Joke of the Week! #smithtransportdotcom #peterbilt #cld #truckers 

Smith Transport brings you the latest July monthly newscast brings news from Customer Service with scorecards and on-time pick-up and deliveries, Safety has clean inspections and safety tips on rider program and pet policy.  Joe from Operations talks about EFS cards, service, and the increase in freight. Maintenance talks about ways to save your truck batteries.  Recruiting has new openings on our dedicated fleet in Bedford, PA.  Jenn is here with Smith-A-Versaries, and of course we have Dougs 'Dad Joke of the Week'  #safety #service #peterbilt #award #cdl #trucker #trucking #smithtransportdotcom

Guest: Christina Lewis: Gender Equity ERG Lead/Head of Global Rider Experience, Deliveroo Christina leads Deliveroo's Gender Equity Employee Resource Group alongside her role as Head Of Global Rider Experience. In her ERG role, Christina spearheaded the first woman-focused mentoring scheme, as well as introducing accelerate, Deliveroo's programme for high potential women. Christina leads a team of 10 ERG members, focusing on gender equity at Deliveroo. This special episode was recorded live on stage at the 2024 Employee Engagement Summit at the Brewery in London. It takes the form of a ‘Fireside Chat' hosted by Jo Moffatt, Engage for Success Advisory Board member and regular EFS radio show host. Engage for Success are media partners for Engage Business Media's industry-leading events, including the Future of Work Conference and the Employee Engagement Summit. Christina Lewis, Deliveroo's Gender Equity ERG lead and award-winning ‘WiHTL Woman To Watch 2024' explains how ERG groups can boost company culture & employee engagement, drive impact for underrepresented groups, give grassroot insight, as well as the pitfalls to avoid. Join us as we discuss how volunteer led employee resource groups help support company culture and employee proposition. Host: Jo Moffatt

Guest: Christina Lewis: Gender Equity ERG Lead/Head of Global Rider Experience, Deliveroo Christina leads Deliveroo's Gender Equity Employee Resource Group alongside her role as Head Of Global Rider Experience. In her ERG role, Christina spearheaded the first woman-focused mentoring scheme, as well as introducing accelerate, Deliveroo's programme for high potential women. Christina leads a team of 10 ERG members, focusing on gender equity at Deliveroo. This special episode was recorded live on stage at the 2024 Employee Engagement Summit at the Brewery in London. It takes the form of a ‘Fireside Chat' hosted by Jo Moffatt, Engage for Success Advisory Board member and regular EFS radio show host. Engage for Success are media partners for Engage Business Media's industry-leading events, including the Future of Work Conference and the Employee Engagement Summit. Christina Lewis, Deliveroo's Gender Equity ERG lead and award-winning ‘WiHTL Woman To Watch 2024' explains how ERG groups can boost company culture & employee engagement, drive impact for underrepresented groups, give grassroot insight, as well as the pitfalls to avoid. Join us as we discuss how volunteer led employee resource groups help support company culture and employee proposition. Host: Jo Moffatt

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in the neoadjuvant immunotherapy space that were presented at the 2024 ASCO Annual Meeting, including promising outcomes in high-risk melanoma from the NADINA trial, as well as other new treatment options for patients with advanced cancers.    TRANSCRIPT Dr. Diwakar Davar: Hello and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I am an associate professor of medicine and the clinical director of the Melanoma Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I am delighted to have my colleague and friend Dr. Jason Luke on the podcast today to discuss key late-breaking abstracts and advances in immunotherapy that were presented at the 2024 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the associate director of clinical research, and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh Hillman Cancer Center.   You will find our full disclosures in the transcript of this episode.  Jason, it's always a pleasure to hear your insights on the key trials in these spaces and to have you back as a guest on this podcast that highlights some of the work, especially advances, that were just presented. Dr. Jason Luke: Well, thanks very much for the invitation. I always love joining the podcast. Dr. Diwakar Davar: We'll start very quickly by talking about some advances and really interesting things that happened both in the context of melanoma but also in immunotherapy in general. And we'll start with what I think was certainly one highlight for me, which was LBA2, the late-breaking abstract on the NADINA trial. It was featured in the Plenary Session, and in this abstract, Dr. Christian Blank and colleagues reported on the results of this phase 3 trial of neoadjuvant ipi-nivo. This is the flipped dose of ipi1/nivo3 versus adjuvant nivolumab in PD-1 naive, macroscopic, resectable, high-risk stage 3 melanoma.  By way of background, neoadjuvant immunotherapy for those listening is an area of increasing interest for drug developers and development for both approved and novel agents. Neoadjuvant immunotherapy has been studied with multiple approved agents, including PD-1 monotherapy, PD-1 LAG-3, PD-1 CTLA-4, T-VEC, as well as investigational agents and multiple randomized and non-randomized studies. The benchmark pathologic response rates with these agents range from 17% PCR with PD-1 monotherapy, 45% to 55% PCR with PD-1 CTLA-4 combination therapy, and slightly higher 57% PCR with PD-1 LAG-3 has recently reported by Dr. Rodabe Amaria from MD Anderson. However, as we embark on phase 3 comparisons for various neoadjuvant compared to adjuvant immunotherapy trials and combinations, we're increasingly moving towards event-free survival as the primary endpoint for neoadjuvant versus adjuvant studies. And this was most recently studied in the context of SWOG S1801, a study that was led by Dr. Sapna Patel.  So, Jason, before we start on NADINA, can you briefly summarize the SWOG S1801 trial and the event-free survival statistic reported by Dr. Patel and her colleagues? Dr. Jason Luke: Well, absolutely. And these data were reported at ESMO about two years ago and then in the New England Journal last year. The S1801 study answered a very simple question: What would happen if you took three of the doses of standard adjuvant therapy with pembrolizumab and moved them prior to surgery? And on a high level, the study is as simple as that. And many of us were somewhat skeptical of this trial design because we thought that just moving the doses earlier may not actually have a major impact.  In the study, you alluded to the event-free survival statistic, and that alludes to what was considered an event. And so, without reading all of it, there were several different aspects that were included in terms of time, based on the date of randomization until the first of a series of events, such as disease progression, toxicity from treatment, if the patient was unable to go to surgery or had surgical complications, or if they had delay in starting the adjuvant therapy due to toxicity, and obviously, recurrence of melanoma or death from any cause. In that context, merely moving the 3 doses of pembrolizumab to the neoadjuvant setting saw an improvement in this two-year event free survival to 72% for the neoadjuvant therapy compared to 49% for the adjuvant therapy. That was quite an outstanding change. And again, noting the power of neoadjuvant treatment, really dictating the impact of anti PD-1, again, just with 3 doses moving from adjuvant into the neoadjuvant setting, and I think all of us were somewhat surprised to see that magnitude of a benefit. But it set up the current study very well, where we now look at combination therapy. Dr. Diwakar Davar: So let's move on to the phase 3 NADINA trial. Do you want to perhaps discuss the study design, particularly focusing on the EFS primary endpoint and maybe also touching on the different schedules? So, SWOG S1801 was a neoadjuvant study of 3 cycles of pembrolizumab and how did that compare and contrast to the neoadjuvant combination that was studied in NADINA? Dr. Jason Luke: Well, as you alluded to, NADINA investigated the regimen of nivolumab plus ipilimumab and compared that against adjuvant therapy with nivolumab alone. So, in the study, as you alluded, the dose and schedule of the two drugs used was nivolumab at 3 milligrams per kilogram, and ipilimumab with 1 milligram per kilogram. That was based on a series of signal finding and safety studies that had been previously done by the same group of authors identifying that as the optimal treatment regimen. And it's worth noting that's slightly different than the labeled indication that's generally used for those same drugs for metastatic melanoma, albeit that the NCCN also endorses this schedule. So, in the trial, 423 patients were randomized, 1:1 to receive either neoadjuvant therapy with those 2 doses of nivolumab plus ipilimumab as compared with standard adjuvant therapy with nivolumab following surgery.   Now, one interesting tweak was that there was an adaptive nature to the study, meaning that patients had a fiducial placed at the index lymph node, and after the neoadjuvant therapy in that arm, that lymph node was removed. And if the patient had a major pathological response, they did not go on to receive the adjuvant portion of the treatment. So it was adaptive because those patients who did very well to the neoadjuvant did not require the adjuvant portion. And in those patients who did not achieve a major pathological response, they could go on to have the adjuvant therapy. And that also included the BRAF therapy for those whose tumors were BRAF mutants.  It's also worth pointing out that the definition of event free survival was slightly different than in the S1801 study that was alluded to just a second ago. And here, EFS was defined from the date of randomization until progression due to melanoma or due to treatment. So that's slightly different than the definition in the S1801 trial. So, a somewhat complicated study, but I really applaud the authors because I think this study does mirror what we would likely be doing in actual clinical practice.  Dr. Diwakar Davar: So, just to briefly summarize the efficacy, and then to get your comments on this, the path response, the PCR rate was 47%. The major pathologic response rate, which is the proportion of patients with between 0% to 1/10% of residual viable tumors, was about 12%. And for a major pathologic response rate of 0% to 10% of 59%. And then the rest of the patients had either pathologic partial response, which was 10% to 50%, or pathologic non response or 50% or greater residual viable tumor, all assessed using central pathology grades. The one year RFS was 95% in the FDR patient population versus 76% in the pathologic partial response patient population, 57% in the pathologic non response patient population. So how do you view these results? Can you context the FDR rates and the EFS rates from NADINA relative to nivo-rela and also potentially SWOG 1801? Dr. Jason Luke: Well, I think these are very exciting results. I think that for those of us that have been following the field closely, they're actually not especially surprising because they mirror several studies that have come before them. When we put them in context with other studies, we see that these rates of major pathological response are consistent with what we've seen in phase 2 studies. They're relatively similar. Or I should say that the results from nivolumab and relatlimab, which was also pursued in a phase 2 study of somewhat similar design, are somewhat similar to this. So, combination immunotherapy does look to deliver a higher major pathological response than pembrolizumab alone, as was known in S1801. Which of course, the caveat being is these are cross control comparisons that we need to be careful about. So I think all of these are active regimens, and I think adding a second agent does appear to enhance the major pathologic response rates. When we look at the event free survival, we see something similar, which is that numerically it looks to be that combination immunotherapy delivers a higher event free survival rate. And that looks to be rather meaningful given the difference in the hazard ratios that were observed between these various studies. And here in the NADINA study, we see that 0.3 hazard ratio for EFS is just extremely impressive.  So the abstract then, from ourselves, out of these specific studies, what does this mean more broadly in the real world, where patients exist and the rest of the landscape for clinical trials? I think we can't take enough time to stop for a second and just think about what a revolution we've come forward in with immune checkpoint blockade and melanoma. When I started my career, now, more than 15 years ago, melanoma was the cancer that made cancer bad. And now here we say, in the highest risk of perioperative patients, we can deliver 2 doses of nivolumab and ipilimumab, and essentially half of the patients then don't need to go on, and more than half the patients don't need to go on to have a full surgery and don't need adjuvant therapy. And from what we could tell of a very, very low risk of every heavy recurrence of melanoma. Of course, there's the other half of patients where we still need to do better, but these are just fantastic results and I think highly meaningful for patients.   In the context of ongoing clinical trials, another abstract that was presented during the meeting was the update to the individualized neoantigen therapy, or V940 with pembrolizumab or against pembrolizumab alone. That's the KEYNOTE-942 study. In that study, they presented updated data at two and a half years for relapse free survival, noting a 75% rate without relapse. So those results are also highly intriguing. And these are in a similar population of very high risk patients. And so I think most of us believe that neoadjuvant therapy with this study in NADINA is now confirmed as the priority approach for patients who present with high-risk stage 3 disease. So that would be bulky disease picked up on a scan or palpable in a clinic. I think essentially all of us now believe patients should get preoperative immunotherapy. We can debate which approach to take, and it may vary by an individual patient's ability to tolerate toxicity, because, of course, multi agent immunotherapy does have increased toxicity relative to anti PD-1 alone. But we'll have to wait now for the full phase 3 results from the V940 individualized neoantigen therapy. And if those come forward, that will be an extremely attractive approach to think about for patients who did not achieve a major pathological response to neoadjuvant therapy, as well as of course to the other populations of patients with melanoma where we otherwise currently give adjuvant therapy stage 2B all the way through stage 4 resected. It's an amazing time to think about perioperative therapy in melanoma. Dr. Diwakar Davar: So this is clearly outstanding data, outstanding news. Congratulations to the investigators for really doing what is an investigative initiated trial conducted across multiple continents with a huge sample size. So this clearly appears to be, at this point in time at least, a de facto standard. But is this going to be FDA-approved, guideline-approved, or is it possible in your mind? Dr. Jason Luke: Well, that's an interesting question. This study was not designed with the intent to necessarily try to register this treatment regimen with the FDA. One would have to take a step back and say, with how powerful these data appear, it sort of seemed like it would be too bad if that doesn't happen. But all the same, I think the community and those of us who participate in guideline recommendations are fully supportive of this. So, I think we will see this move into compendium listings that support insurance approval, I think, very, very quickly. So, whether or not this actually becomes formally FDA approved or is in the guidelines, I think this should become the standard approach that is considered for patients, again presenting with high-risk stage 3 disease.  Dr. Diwakar Davar: Fantastic. So now we're going to go in and talk about a slightly different drug, but also from the melanoma context, and that is the safety and efficacy of RP1 with nivolumab in the context of patients with melanoma who are PD-1 failures. So, this is Abstract 9517. And in this abstract, our academic colleagues essentially talked about these data, and we'll start by describing what RP1 is. RP1 essentially is a HSV-1 based oncolytic immunotherapy. And RP1 expresses GM-CSF as well as a fusogenic protein, GALV-GP-R-. And in this abstract, Dr. Michael Wong from MD Anderson and colleagues are reporting the results of IGNYTE, which is a phase I trial of intratumoral RP1 co-administered with systemic nivolumab in patients with advanced metastatic treatment refractory cutaneous melanoma. And the data presented in this abstract represents data from a registration directed, abbreviated as RD, registration directed cohort of RP1 plus nivolumab in PD-1 refractory melanoma. So, let's start with the description of the cohort.  Dr. Jason Luke: Right. So, in this study, there were a total of 156 patients who were presented, and that included an initial safety and dose finding group of 16, as well as the RD cohort, as you noted, of 140 patients. And it's important to point out that this was a cohort that was selected for a very strict definition of progression on anti PD-1, or a combination immunotherapy as their immediately prior treatment. So, all of the patients in the cohort had exposure to anti PD-1, and 46% of them had anti PD-1 plus anti CTLA4, nivolumab and ipilimumab as their immediately prior therapy. This was also a group of relatively high-risk patients when one considers stage. So, within the stage 4 population, the entry here included 51% who had stage M1B, C, and D melanoma. And that is worth pointing out because this is an injectable therapy. So, trials like this in the past have tended to be biased towards earlier stage, unresectable or metastatic melanoma, meaning stage 3B, 3C, 3D and then stage 4m1a. Again, to emphasize the point here, these were pretreated patients who had a strict definition of anti PD-1 resistance, and over half of them, in fact, had high-risk visceral metastatic disease.  In that context, it's very interesting to observe that the overall response rate was described in the total population, as 31%, and that included 12% who achieved complete response. And so, again, to make sure it's clear, we're talking about a treatment where the oncolytic virus is injected into one or multiple sites of recurrent disease, and then the patients administer nivolumab as per standard. And so, I think these data are quite intriguing. Again, such a high- risk population and their maturity now, with a follow-up of over a year, I think, makes this look to be a very interesting treatment option.  Dr. Diwakar Davar: I guess on that topic of mature follow-up, it probably would be important for us to inform our audience that the top line data for the primary analysis was actually just released, I think, earlier today, and wherein the central confirmed objective response rate was 34% by modified RECIST and 33% by RECIST, clearly indicating that these responses, as you noted, very treatment refractory patient population, these responses were clearly very durable. So, you mentioned that there were responses seen in uninjected visceral lesions, responses seen in both PD-1 and PD-1 CTLA-4 refractory patients. Can you talk a little bit about the response rate in these high-risk subgroups, the uninjected visceral lesions, the patients who had both combination checkpoint and epidural refractory response rate by primary PD-1 resistance.  Dr. Jason Luke: Sure. You know, I think, again, to emphasize this point in the study, we saw that there were responses in the non-injected lesions, and I think it's really important to emphasize that. Some have referred to this as a putative abscopal like effect, similar to what is described in radiation. But it implies that local treatment with the oncolytic virus is triggering a systemic immune response. In the higher risk patient population, we'll note that whereas the overall response rate in PD-1 refractory patients was 34%, in the combination of PD-1 and CTLA-4 refractory patients, the response rate was 26%. So, [this is] still very good. And when we looked at that split by stage, as I alluded to before, in the population of patients that had, what you might call earlier unresectable diseases, so 3B through 4A, the response rate was 38%, and in the stage 4 M1b through M1d, it was 25%. So slightly lower, but still very good. And that would be as expected, because, of course, the patients with visceral metastatic disease have more advanced disease, but those response rates look quite good. Again, looking at the combination refractory population as well as the more high-risk disease. Dr. Diwakar Davar: So, clearly, these are very promising data and exciting times for multiple investigators in the field and the company, Replimune, as well. So, what are the next steps? I believe that a registration trial is planned, essentially, looking at this with the goal of trying to get this combination registered. Can you tell us a little bit about IGNYTE-3, the trial design, the control arm, and what you foresee this trial doing over the next couple of years?  Dr. Jason Luke: So, as this agent has been maturing, it's worth pointing out that the company that makes this molecule, called RP1, but I guess now we'll have to get used to this name vusolimogene oderparepvec as the actual scientific term, they have been having ongoing discussions with the FDA, and there is the potential that this agent could come forward on an accelerated path prior to the results being released from a phase 3 trial. That being said, the phase 3 confirmatory study, which is called the IGNYTE-3 study, is in the process of being launched now. And that's a study investigating this molecule in combination with nivolumab, as was alluded to earlier, and a randomized phase 3 design, where that combination is compared with a physician's choice, essentially a chemotherapy-based option.   In that study, it will be 400 patients with stage 3B through stage 4; patients will have progressed on anti PD-1, either as a combination or in sequence, and then come on the study to be randomized to either vusolimogene oderparepvec plus nivolumab versus that physician's choice. And the physician's choice includes chemotherapy agents, but also nivolumab plus relatlimab as another option, or an anti PD-1 monotherapy, if that's deemed to be a reasonable option by the treating investigator. And the primary endpoint of that study is overall survival. And unfortunately, in this highly refractory patient population, that's something that may not take long to identify with key secondary endpoints of progression free survival, as well as overall response rate. I'm quite enthusiastic about this study, given these data, which have now been centrally confirmed as you alluded to before. I think this is a very exciting area of investigation and really crossing my fingers that this may be perhaps the first locally administered therapy which does appear to have a systemic impact that can hold up in phase 3. Dr. Diwakar Davar: Very, very, very exciting results. And I guess it's worthwhile pointing out that this company also has got, I think, multiple studies planned with both RP1 and cutaneous squamous cell carcinoma in a solid organ transplant patient population where single agent activity has already been reported by Dr. Migden at prior meetings, as well as a novel trial of potentially RP2 metastatic uveal melanoma. So we'll now pivot to Abstract 6014. So, 6014 is a drug by a company known as Merus. Essentially, it's a very novel agent. Merus essentially is a company that is specialized in making bicyclics and tricyclics. And these are not bicycles or tricycles, but rather drugs that essentially are bispecific antibodies. And Merus essentially has come up with petosemtamab. I think we're going to have to figure out better names for all of these drugs at some point. But petosemtamab, or MCLA-158, essentially is a bicyclic, targeting both EGFR as well as LGR-5. So EGR-5, of course, is a known oncogenic driver in multiple tumor types, squamous, including non small cell lung cancer, cutaneous squamous cell carcinoma, but also head and neck squamous cell carcinoma. And LGR-5 essentially is leucine-rich repeat-containing G-protein coupled receptor 5, but it's a receptor in cancer stem cells and certainly highly expressed in head neck squam. And MCLA-158, or petosemtamab is a IgG one bispecific with ADCC-activity because of IgG1 backbone co-targeting EGFR and LGR5. Merus had earlier results that evaluated petosemtamab monotherapy. They defined the RP2D and second- and third-line head and neck blastoma patients with a respectable response rate of 37% investigator-assessed ORR with six months median DoR, and this was published by Ezra Cohen about a year or so ago.  In this abstract, Dr. Fayette and colleagues report on the results of the MCLA-158-CL01 trial, which is a trial of pembrolizumab plus petosemtamab in one front line head and neck squamous cell population. So maybe let's start with the description of the cohort. And it is a small trial, but we'll be able, I think, to dig into a little bit about why this might be exciting. Dr. Jason Luke: Yes. So, as alluded to, it's not the biggest trial as yet, but there were 26 patients with anti PD-1 treatment naive head and neck squamous cell carcinoma. And all the patients in the study did receive, as you alluded to, pembrolizumab plus petosemtamab. Based on the label for pembrolizumab, all the patients in this study were PDL-1 positive. So that's one point that it's worth pointing out to make sure that that's understood. This is the population of patients who would be expected to benefit from pembrolizumab in the first place. Now, in the abstract, they reported out only 10 response evaluable patients, but they updated that in the actual slides of presentation at the meeting. So among 24 patients that were alluded to, 67% were described as having had a response, although some of those were yet to be confirmed responses. And when it was evaluated by PDL-1 status, there didn't seem to be a clear enrichment of response in the PD-1 positive more than 20% group, as compared to the 1-19% group. That isn't especially surprising because that was a trend that one would see, presumably with pembrolizumab alone. But overall, I think these data are pretty exciting in terms of a preliminary study. Dr. Diwakar Davar: You know, you mentioned that the objective response rate was high, almost 60-something%. The prognosis of these patients is generally poor. The OS is typically thought of as between 6-15 months. And based on KEYNOTE-048, which was led by Dr. Burtness and colleagues, the standard of care in the setting is pembrolizumab +/- platinum based chemotherapy regimens. Allowing for the fact that we only have 10 patients here, how do you think these results stack up against KEYNOTE-048? And you made a very important point earlier, which was, by definition, pembro is on label only for the CPS. So PDL-1 score, at least in head and neck squamous cell carcinoma CPS and not TPS. But in the CPS 1% or greater patient population, where pembro is on label, how do these results stack up against the KEYNOTE-048 results. Dr. Jason Luke: Right. KEYNOTE-048 is considered the seminal study that dictates frontline treatment in head and neck cancer. And before we dive into this too far, we do want to acknowledge that here we're comparing 26 patients versus a phase 3 trial. So, we're not trying to get too far ahead of ourselves, but this is just a preliminary comparison. But in KEYNOTE-048, as you alluded to, two regimens were superior to chemotherapy. One was the pembrolizumab monotherapy, as well as pembrolizumab plus chemotherapy. So again, the study overall survival, of course, was much higher, the PDL-1 positive subgroup, which is what dictated the unlabeled use of this. But response to pembro monotherapy in that population of patients is still modest. We're talking about upwards of 20-30%. So, if you compare that to, again, preliminary evidence here from this trial of only 24 patients, that response rate of 60% seems extremely high. And so even if that were to come down somewhat in a larger data series of patients, that still looks to be quite promising as a treatment regimen, that might eventually even be chemotherapy sparing for this population of patients. I think this raises a lot of eyebrows that perhaps this dual targeting approach, EGFR and LDR-5, may bring something really important to the field that evolves it. Dr. Diwakar Davar: So, what are the next steps for petosemtamab? You mentioned that the activity was interesting. Are we going to see a larger trial? Any thoughts on where things are going to go?  Dr. Jason Luke: Well, based on the phase 2 data of petosemtamab alone, even without pembrolizumab, the molecule had already been given fast track designation by FDA, which means allowing for greater communication between the drug sponsor in the FDA and designing a seminal study design. One would assume that this trial will be rapidly expanded quite greatly, perhaps to 100 or 200 patients, to try to flush out what the real response rate is in a more meaningful number of patients. But I think these data will probably also trigger the design and probably near-term evaluation or expedited acceleration of a phase III clinical trial design that would potentially validate this against the current standard of care. So, I'm pretty excited. I think we'll see a lot more about this agent in the relatively near future. Dr. Diwakar Davar: So, finally, we'll pivot to the last abstract that we're going to talk about, which is Abstract 2504. It's a relatively interesting target, CCR8 monoclonal antibody. But this is the efficacy and safety of LM-108, and LM-108 is an anti CCR8 monoclonal antibody that is being developed by LaNova Medicine. And the results that are described, actually a pool set of results of combinations of LM-108 with anti PD-1, two separate anti PD-1, in patients with gastric cancer, mostly done ex-U.S., which is interesting because of this patient population, and it's a pool result of several, 3 phase 1 and 2 studies.  LM-108 is an Fc-optimized anti CCR8 monoclonal antibody that selectively depletes tumor infiltrating Tregs. The abstract reported a pooled analysis of three phase 1, 2 trials with 3 different NCT numbers that all evaluated the efficacy of LM-108 and anti PD-1 in patients with gastric cancer. So, let's start with the description of the cohort. Maybe, Jason, you can tell us a little bit about before you start, as you describe the cohort, sort of what we know, editorially speaking, about the difficulty with which Tregs depletion has been tried and obviously failed up until now in the tumor microenvironment. Dr. Jason Luke: Right. I think that's a really interesting comment. And so, for decades, in fact, targeting regulatory T-cell to alleviate immune exclusion in the tumor microenvironment has been of interest in immuno-oncology. And in preclinical mouse models, it seems quite clear that such an approach can deliver therapeutic efficacy. However, by contrast, in human clinical trials, various different Treg depleting strategies have been attempted, and there's really little to no evidence that depleting Tregs from human tumors actually can deliver therapeutic responses. And by that we're referring to CD-25 antibodies. The drug ipilimumab, the CTLA-4 antibody, was punitively described as a Tregs depleter preclinically, but that doesn't seem to be the case in patients. And so, in that background, this is quite an eye raiser that an anti CCR8 antibody could be driving this effect. Now, before we talk about the results of this trial, I will point out, however, that given the Fc-optimization, it's entirely possible that the Tregs are being depleted by this mechanism, but that more could also be going on. Because Fc gamma RII binding by this antibody that could be nonspecific also has the potential to trigger immune responses in the tumor microenvironment, probably mediated by myeloid cells. So I think more to come on this. If this turns out to be the first meaningful Tregs depletor that leads to therapeutic efficacy, that would be very interesting. But it's also possible this drug could have multiple mechanisms.  So, having said all of that, in the clinical trial, which was a pooled analysis, like you mentioned, of LM-108 in combination with anti PD-1 of a couple different flavors, there were 48 patients treated either with LM-108, with pembrolizumab, or with toripalimab, which is another anti PD-1 antibody. On the drug combination was, generally speaking, pretty well tolerated, noting grade 3 treatment related adverse events in the range of 38%, which is somewhat expected given combination immunotherapy. We talked about nivolumab and ipilimumab before, which, of course, gives even higher rates of immune-related adverse events, with the most common toxicities being anemia, lipase elevations, rash, ALC decrease; albeit, quite manageable. Dr. Diwakar Davar: So, what about the objective response rate? Can you contextualize the efficacy? And as you do that, maybe we'll think about what you'd expect in the context of, say, gastric cancer, especially in patients who've never really had a prior checkpoint inhibitor before. What do you think about the ORR? What do you think about the relative efficacy of this combination? Dr. Jason Luke: Well, so, in the study, they described overall response rate in the 36 patients as 36% and described immediate progression for survival of about 6.5 months. And so that was among patients who were treatment naive. And in second-line patients, they actually described an even higher response rate, although it was only 11 patients, but they're at 64%. And so, I think those data look to be somewhat interesting. When I was actually scrutinizing the actual data presented, it was of some interest to note that the quality of responses seemed to be about as good on the lower dose of LM-108, so 3 milligrams per kilogram as compared to 10 milligrams per kilogram. I think there's definitely more to learn here to try to optimize the dose and to fully understand what the overall efficacy of this treatment combination would be.  I would emphasize that in this disease, I think novel treatment strategies are certainly warranted. While anti PD-1 with chemotherapy has moved the needle in terms of standard of care treatment, it's really only a minor subset of patients who derive durable long-term benefit like we normally associate with immune checkpoint blockade. I think these are preliminary data. They're very intriguing.   You alluded to earlier that this population of patients was an Asian data set, and it is well known that the efficacy of chemotherapy and immunotherapy does appear to be somewhat enhanced in Asian populations, and that goes to distributions of metastasis and tumor microenvironment effects, etc. Very difficult to try to tease any of that out in this abstract, other than to look at these data and suggest that this is pretty interesting, both from a novel therapeutic approach, we talked about the Tregs consideration, but also straight up on the efficacy because I think if these data could hold up in a larger number of patients, and particularly in a western population of patients, I think it would be very intriguing. Dr. Diwakar Davar: Certainly, ASCO 2024 had a lot of interesting data, including data from targeted agents, the LAURA trial, ADCs. But just focusing on the immune therapy subset, we certainly saw a lot of great advances in patients who were treated with neoadjuvant as well as relapse refractory disease in the context of RP1 and then a couple of newer agents such as this petosemtamab as well as LM-108. And of course, we cannot forget to highlight the extended DMFS data from the pembro vaccine study from KEYNOTE-942.  Jason, as always, thank you for taking a little bit of time out of your extremely busy schedule to come and give us insights as to how these agents are impacting the landscape. We really value your input and so thank you very much.  Dr. Jason Luke: Thank you for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for your time today. You will find the links to all the abstracts that we discussed in the transcript of this episode. And finally, if you value the insights that you hear on this podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. So, thank you.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers:   Dr. Diwakar Davar   @diwakardavar   Dr. Jason Luke   @jasonlukemd      Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:       Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy       Dr. Jason Luke:    Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine    Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure    Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)    Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

Dr. Adele Diamond, PhD, FRSC, is a trailblazer in developmental cognitive neuroscience, pioneering research on 'executive functions' (EFs) crucial for problem-solving and creativity. Her interdisciplinary approach explores the impact of biological and environmental factors on cognitive development, leading to groundbreaking insights that have transformed early education and improved treatment for conditions like ADHD. Through her work, Dr. Diamond emphasizes the vital role of holistic approaches, advocating for the integration of physical activity and the arts to nurture cognitive abilities and overall well-being.Connect with Adele on Her Website.You can explore more of Hernan's work on his website, https://www.hernanchousa.com/.The music enriching our show is the creative work of Sebastian Klauer. You can reach him at klauersebas@gmail.com.

Welcome to part five in the AWS Certification Exam Prep Mini-Series! Whether you're an aspiring cloud enthusiast or a seasoned developer looking to deepen your architectural acumen, you've landed in the perfect spot. In this six-part saga, we're demystifying the pivotal role of a Solutions Architect in the AWS cloud computing cosmos. In this episode, Dave and Caroline chat with Anya Derbakova, a Senior Startup Solutions Architect at AWS, known for weaving social media magic, and Ted Trentler, a Senior AWS Technical Instructor with a knack for simplifying the complex. Unravel the strategies and best practices for designing cost-optimized architectures on AWS. Covering 20% of the exam's scored content, this episode zeroes in on maximizing efficiency and reducing costs across your cloud infrastructure. Discover the art of balancing performance with cost-effectiveness as we delve into AWS cost management services, cost-optimized storage and compute solutions, and the nuances of designing database and network architectures that won't break the bank. In this episode, you'll learn about: • Utilizing AWS cost management service features and tools, including cost allocation tags, multi-account billing, and the AWS Free Tier. • Designing cost-optimized storage solutions with AWS services like Amazon FSx, EFS, S3, and EBS, including data lifecycle policies and backup strategies. • Rightsizing and optimizing compute resources to meet your workload requirements efficiently, from instance selection to utilizing serverless and distributed compute strategies. • Strategies for cost-optimized database solutions, focusing on caching, data retention, capacity planning, and replication to enhance performance while managing costs. • Crafting network architectures that minimize costs associated with data transfer, leveraging AWS services and features to reduce expenses while maintaining robust connectivity. Whether you're fine-tuning existing systems or building from the ground up, we'll provide you with the tools and insights to make cost-aware decisions without sacrificing functionality! Anya on LinkedIn: https://www.linkedin.com/in/annadderbakova/ Ted on Twitter: https://twitter.com/ttrentler Ted on LinkedIn: https://linkedin/in/tedtrentler Caroline on Twitter: https://twitter.com/carolinegluck Caroline on LinkedIn: https://www.linkedin.com/in/cgluck/ Dave on Twitter: https://twitter.com/thedavedev Dave on LinkedIn: https://www.linkedin.com/in/davidisbitski AWS SAA Exam Guide - https://d1.awsstatic.com/training-and-certification/docs-sa-assoc/AWS-Certified-Solutions-Architect-Associate_Exam-Guide.pdf Party Rock for Exam Study - https://partyrock.aws/u/tedtrent/KQtYIhbJb/Solutions-Architect-Study-Buddy All Things AWS Training - Links to Self-paced and Instructor Led https://aws.amazon.com/training/ AWS Skill Builder – Free CPE Course - https://explore.skillbuilder.aws/learn/course/134/aws-cloud-practitioner-essentials AWS Free Workshops - https://workshops.aws/ Running a Minecraft server on Amazon ECS with Spot Pricing: https://github.com/vatertime/minecraft-spot-pricing Subscribe: Spotify: https://open.spotify.com/show/7rQjgnBvuyr18K03tnEHBI Apple Podcasts: https://podcasts.apple.com/us/podcast/aws-developers-podcast/id1574162669 Stitcher: https://www.stitcher.com/show/1065378 Pandora: https://www.pandora.com/podcast/aws-developers-podcast/PC:1001065378 TuneIn: https://tunein.com/podcasts/Technology-Podcasts/AWS-Developers-Podcast-p1461814/ Amazon Music: https://music.amazon.com/podcasts/f8bf7630-2521-4b40-be90-c46a9222c159/aws-developers-podcast Google Podcasts: https://podcasts.google.com/feed/aHR0cHM6Ly9mZWVkcy5zb3VuZGNsb3VkLmNvbS91c2Vycy9zb3VuZGNsb3VkOnVzZXJzOjk5NDM2MzU0OS9zb3VuZHMucnNz RSS Feed: https://feeds.soundcloud.com/users/soundcloud:users:994363549/sounds.rss

This episode is a discussion with Dr. Adele Diamond about executive functions (EFs), with a focus on children and the developing brain. The conversation covers a wide range of topics, including models of EFs, three core EFs (inhibitory control, working memory, and cognitive flexibility), the differential development of EF components during childhood, the ability of early EFs to predict later life outcomes, relationships between EFs and fluid intelligence, assessment of EFs, task impurity, and interventions to improve EFs in children. Show notes are available at www.NavNeuro.com/138 _________________ If you'd like to support the show, here are a few easy ways: 1) Get APA-approved CE credits for listening to select episodes: www.NavNeuro.com/INS  2) Tell your friends and colleagues about it 3) Subscribe (free) and leave an Apple Podcasts rating/review: www.NavNeuro.com/itunes 4) Check out our book Becoming a Neuropsychologist, and leave it an Amazon rating   Thanks for listening, and join us next time as we continue to navigate the brain and behavior! [Note: This podcast and all linked content is intended for general educational purposes only and does not constitute the practice of psychology or any other professional healthcare advice and services. No professional relationship is formed between hosts and listeners. All content is to be used at listeners' own risk. Users should always seek appropriate medical and psychological care from their licensed healthcare provider.]

Evelyn Osman, Principal Platform Engineer at AutoScout24, joins Corey on Screaming in the Cloud to discuss the dire need for developers to agree on a standardized tool set in order to scale their projects and innovate quickly. Corey and Evelyn pick apart the new products being launched in cloud computing and discover a large disconnect between what the industry needs and what is actually being created. Evelyn shares her thoughts on why viewing platforms as products themselves forces developers to get into the minds of their users and produces a better end result.About EvelynEvelyn is a recovering improviser currently role playing as a Lead Platform Engineer at Autoscout24 in Munich, Germany. While she says she specializes in AWS architecture and integration after spending 11 years with it, in truth she spends her days convincing engineers that a product mindset will make them hate their product managers less.Links Referenced:LinkedIn: https://www.linkedin.com/in/evelyn-osman/TranscriptAnnouncer: Hello, and welcome to Screaming in the Cloud with your host, Chief Cloud Economist at The Duckbill Group, Corey Quinn. This weekly show features conversations with people doing interesting work in the world of cloud, thoughtful commentary on the state of the technical world, and ridiculous titles for which Corey refuses to apologize. This is Screaming in the Cloud.Corey: Welcome to Screaming in the Cloud. I'm Corey Quinn. My guest today is Evelyn Osman, engineering manager at AutoScout24. Evelyn, thank you for joining me.Evelyn: Thank you very much, Corey. It's actually really fun to be on here.Corey: I have to say one of the big reasons that I was enthused to talk to you is that you have been using AWS—to be direct—longer than I have, and that puts you in a somewhat rarefied position where AWS's customer base has absolutely exploded over the past 15 years that it's been around, but at the beginning, it was a very different type of thing. Nowadays, it seems like we've lost some of that magic from the beginning. Where do you land on that whole topic?Evelyn: That's actually a really good point because I always like to say, you know, when I come into a room, you know, I really started doing introductions like, “Oh, you know, hey,” I'm like, you know, “I'm this director, I've done this XYZ,” and I always say, like, “I'm Evelyn, engineering manager, or architect, or however,” and then I say, you know, “I've been working with AWS, you know, 11, 12 years,” or now I can't quite remember.Corey: Time becomes a flat circle. The pandemic didn't help.Evelyn: [laugh] Yeah, I just, like, a look at that the year, and I'm like, “Jesus. It's been that long.” Yeah. And usually, like you know, you get some odd looks like, “Oh, my God, you must be a sage.” And for me, I'm… you see how different services kind of, like, have just been reinventions of another one, or they just take a managed service and make another managed service around it. So, I feel that there's a lot of where it's just, you know, wrapping up a pretty bow, and calling it something different, it feels like.Corey: That's what I've been low-key asking people for a while now over the past year, namely, “What is the most foundational, interesting thing that AWS has done lately, that winds up solving for this problem of whatever it is you do as a company? What is it that has foundationally made things better that AWS has put out in the last service? What was it?” And the answers I get are all depressingly far in the past, I have to say. What's yours?Evelyn: Honestly, I think the biggest game-changer I remember experiencing was at an analyst summit in Stockholm when they announced Lambda.Corey: That was announced before I even got into this space, as an example of how far back things were. And you're right. That was transformative. That was awesome.Evelyn: Yeah, precisely. Because before, you know, we were always, like, trying to figure, okay, how do we, like, launch an instance, run some short code, and then clean it up. AWS is going to charge for an hour, so we need to figure out, you know, how to pack everything into one instance, run for one hour. And then they announced Lambda, and suddenly, like, holy shit, this is actually a game changer. We can actually write small functions that do specific things.And, you know, you go from, like, microservices, like, to like, tiny, serverless functions. So, that was huge. And then DynamoDB along with that, really kind of like, transformed the entire space for us in many ways. So, back when I was at TIBCO, there was a few innovations around that, even, like, one startup inside TIBCO that quite literally, their entire product was just Lambda functions. And one of their problems was, they wanted to sell in the Marketplace, and they couldn't figure out how to sell Lambda on the marketplace.Corey: It's kind of wild when we see just how far it's come, but also how much they've announced that doesn't change that much, to be direct. For me, one of the big changes that I remember that really made things better for customers—thought it took a couple of years—was EFS. And even that's a little bit embarrassing because all that is, “All right, we finally found a way to stuff a NetApp into us-east-1,” so now NFS, just like you used to use it in the 90s and the naughts, can be done responsibly in the cloud. And that, on some level, wasn't a feature launch so much as it was a concession to the ways that companies had built things and weren't likely to change.Evelyn: Honestly, I found the EFS launch to be a bit embarrassing because, like, you know, when you look closer at it, you realize, like, the performance isn't actually that great.Corey: Oh, it was horrible when it launched. It would just slam to a halt because you got the IOPS scaled with how much data you stored on it. The documentation explicitly said to use dd to start loading a bunch of data onto it to increase the performance. It's like, “Look, just sandbag the thing so it does what you'd want.” And all that stuff got fixed, but at the time it looked like it was clown shoes.Evelyn: Yeah, and that reminds me of, like, EBS's, like, gp2 when we're, like you know, we're talking, like, okay, provision IOPS with gp2. We just kept saying, like, just give yourself really big volume for performance. And it feel like they just kind of kept that with EFS. And it took years for them to really iterate off of that. Yeah, so, like, EFS was a huge thing, and I see us, we're still using it now today, and like, we're trying to integrate, especially for, like, data center migrations, but yeah, you always see that a lot of these were first more for, like, you know, data centers to the cloud, you know. So, first I had, like, EC2 classic. That's where I started. And I always like to tell a story that in my team, we're talking about using AWS, I was the only person fiercely against it because we did basically large data processing—sorry, I forget the right words—data analytics. There we go [laugh].Corey: I remember that, too. When it first came out, it was, “This sounds dangerous and scary, and it's going to be a flash in the pan because who would ever trust their core compute infrastructure to some random third-party company, especially a bookstore?” And yeah, I think I got that one very wrong.Evelyn: Yeah, exactly. I was just like, no way. You know, I see all these articles talking about, like, terrible disk performance, and here I am, where it's like, it's my bread and butter. I'm specialized in it, you know? I write code in my sleep and such.[Yeah, the interesting thing is, I was like, first, it was like, I can 00:06:03] launch services, you know, to kind of replicate when you get in a data center to make it feature comparable, and then it was taking all this complex services and wrapping it up in a pretty bow for—as a managed service. Like, EKS, I think, was the biggest one, if we're looking at managed services. Technically Elasticsearch, but I feel like that was the redheaded stepchild for quite some time.Corey: Yeah, there was—Elasticsearch was a weird one, and still is. It's not a pleasant service to run in any meaningful sense. Like, what people actually want as the next enhancement that would excite everyone is, I want a serverless version of this thing where I can just point it at a bunch of data, I hit an API that I don't have to manage, and get Elasticsearch results back from. They finally launched a serverless offering that's anything but. You have to still provision compute units for it, so apparently, the word serverless just means managed service over at AWS-land now. And it just, it ties into the increasing sense of disappointment I've had with almost all of their recent launches versus what I felt they could have been.Evelyn: Yeah, the interesting thing about Elasticsearch is, a couple of years ago, they came out with OpenSearch, a competing Elasticsearch after [unintelligible 00:07:08] kind of gave us the finger and change the licensing. I mean, OpenSearch actually become a really great offering if you run it yourself, but if you use their managed service, it can kind—you lose all the benefits, in a way.Corey: I'm curious, as well, to get your take on what I've been seeing that I think could only be described as an internal shift, where it's almost as if there's been a decree passed down that every service has to run its own P&L or whatnot, and as a result, everything that gets put out seems to be monetized in weird ways, even when I'd argue it shouldn't be. The classic example I like to use for this is AWS Config, where it charges you per evaluation, and that happens whenever a cloud resource changes. What that means is that by using the cloud dynamically—the way that they supposedly want us to do—we wind up paying a fee for that as a result. And it's not like anyone is using that service in isolation; it is definitionally being used as people are using other cloud resources, so why does it cost money? And the answer is because literally everything they put out costs money.Evelyn: Yep, pretty simple. Oftentimes, there's, like, R&D that goes into it, but the charges seem a bit… odd. Like from an S3 lens, was, I mean, that's, like, you know, if you're talking about services, that was actually a really nice one, very nice holistic overview, you know, like, I could drill into a data lake and, like, look into things. But if you actually want to get anything useful, you have to pay for it.Corey: Yeah. Everything seems to, for one reason or another, be stuck in this place where, “Well, if you want to use it, it's going to cost.” And what that means is that it gets harder and harder to do anything that even remotely resembles being able to wind up figuring out where's the spend going, or what's it going to cost me as time goes on? Because it's not just what are the resources I'm spinning up going to cost, what are the second, third, and fourth-order effects of that? And the honest answer is, well, nobody knows. You're going to have to basically run an experiment and find out.Evelyn: Yeah. No, true. So, what I… at AutoScout, we actually ended up doing is—because we're trying to figure out how to tackle these costs—is they—we built an in-house cost allocation solution so we could track all of that. Now, AWS has actually improved Cost Explorer quite a bit, and even, I think, Billing Conductor was one that came out [unintelligible 00:09:21], kind of like, do a custom tiered and account pricing model where you can kind of do the same thing. But even that also, there is a cost with it.I think that was trying to compete with other, you know, vendors doing similar solutions. But it still isn't something where we see that either there's, like, arbitrarily low pricing there, or the costs itself doesn't really quite make sense. Like, AWS [unintelligible 00:09:45], as you mentioned, it's a terrific service. You know, we try to use it for compliance enforcement and other things, catching bad behavior, but then as soon as people see the price tag, we just run away from it. So, a lot of the security services themselves, actually, the costs, kind of like, goes—skyrockets tremendously when you start trying to use it across a large organization. And oftentimes, the organization isn't actually that large.Corey: Yeah, it gets to this point where, especially in small environments, you have to spend more energy and money chasing down what the cost is than you're actually spending on the thing. There were blog posts early on that, “Oh, here's how you analyze your bill with Redshift,” and that was a minimum 750 bucks a month. It's, well, I'm guessing that that's not really for my $50 a month account.Evelyn: Yeah. No, precisely. I remember seeing that, like, entire ETL process is just, you know, analyze your invoice. Cost [unintelligible 00:10:33], you know, is fantastic, but at the end of the day, like, what you're actually looking at [laugh], is infinitesimally small compared to all the data in that report. Like, I think oftentimes, it's simply, you know, like, I just want to look at my resources and allocate them in a multidimensional way. Which actually isn't really that multidimensional, when you think about it [laugh].Corey: Increasingly, Cost Explorer has gotten better. It's not a new service, but every iteration seems to improve it to a point now where I'm talking to folks, and they're having a hard time justifying most of the tools in the cost optimization space, just because, okay, they want a percentage of my spend on AWS to basically be a slightly better version of a thing that's already improving and works for free. That doesn't necessarily make sense. And I feel like that's what you get trapped into when you start going down the VC path in the cost optimization space. You've got to wind up having a revenue model and an offering that scales through software… and I thought, originally, I was going to be doing something like that. At this point, I'm unconvinced that anything like that is really tenable.Evelyn: Yeah. When you're a small organization you're trying to optimize, you might not have the expertise and the knowledge to do so, so when one of these small consultancies comes along, saying, “Hey, we're going to charge you a really small percentage of your invoice,” like, okay, great. That's, like, you know, like, a few $100 a month to make sure I'm fully optimized, and I'm saving, you know, far more than that. But as soon as your invoice turns into, you know, it's like $100,000, or $300,000 or more, that percentage becomes rather significant. And I've had vendors come to me and, like, talk to me and is like, “Hey, we can, you know, for a small percentage, you know, we're going to do this machine learning, you know, AI optimization for you. You know, you don't have to do anything. We guaranteed buybacks your RIs.” And as soon as you look at the price tag with it, we just have to walk away. Or oftentimes we look at it, and there are truly very simple ways to do it on your own, if you just kind of put some thought into it.Corey: While we want to talking a bit before this show, you taught me something new about GameLift, which I think is a different problem that AWS has been dealing with lately. I've never paid much attention to it because it is the—as I assume from what it says on the tin, oh, it's a service for just running a whole bunch of games at scale, and I'm not generally doing that. My favorite computer game remains to be Twitter at this point, but that's okay. What is GameLift, though, because you want to shining a different light on it, which makes me annoyed that Amazon Marketing has not pointed this out.Evelyn: Yeah, so I'll preface this by saying, like, I'm not an expert on GameLift. I haven't even spun it up myself because there's quite a bit of price. I learned this fall while chatting with an SA who works in the gaming space, and it kind of like, I went, like, “Back up a second.” If you think about, like, I'm, you know, like, World of Warcraft, all you have are thousands of game clients all over the world, playing the same game, you know, on the same server, in the same instance, and you need to make sure, you know, that when I'm running, and you're running, that we know that we're going to reach the same point the same time, or if there's one object in that room, that only one of us can get it. So, all these servers are doing is tracking state across thousands of clients.And GameLift, when you think about your dedicated game service, it really is just multi-region distributed state management. Like, at the basic, that's really what it is. Now, there's, you know, quite a bit more happening within GameLift, but that's what I was going to explain is, like, it's just state management. And there are far more use cases for it than just for video games.Corey: That's maddening to me because having a global session state store, for lack of a better term, is something that so many customers have built themselves repeatedly. They can build it on top of primitives like DynamoDB global tables, or alternately, you have a dedicated region where that thing has to live and everything far away takes forever to round-trip. If they've solved some of those things, why on earth would they bury it under a gaming-branded service? Like, offer that primitive to the rest of us because that's useful.Evelyn: No, absolutely. And honestly, I wouldn't be surprised if you peeled back the curtain with GameLift, you'll find a lot of—like, several other you know, AWS services that it's just built on top of. I kind of mentioned earlier is, like, what I see now with innovation, it's like we just see other services packaged together and releases a new product.Corey: Yeah, IoT had the same problem going on for years where there was a lot of really good stuff buried in there, like IOT events. People were talking about using that for things like browser extensions and whatnot, but you need to be explicitly told that that's a thing that exists and is handy, but otherwise you'd never know it was there because, “Well, I'm not building anything that's IoT-related. Why would I bother?” It feels like that was one direction that they tended to go in.And now they take existing services that are, mmm, kind of milquetoast, if I'm being honest, and then saying, “Oh, like, we have Comprehend that does, effectively detection of themes, keywords, and whatnot, from text. We're going to wind up re-releasing that as Comprehend Medical.” Same type of thing, but now focused on a particular vertical. Seems to me that instead of being a specific service for that vertical, just improve the baseline the service and offer HIPAA compliance if it didn't exist already, and you're mostly there. But what do I know? I'm not a product manager trying to get promoted.Evelyn: Yeah, that's true. Well, I was going to mention that maybe it's the HIPAA compliance, but actually, a lot of their services already have HIPAA compliance. And I've stared far too long at that compliance section on AWS's site to know this, but you know, a lot of them actually are HIPAA-compliant, they're PCI-compliant, and ISO-compliant, and you know, and everything. So, I'm actually pretty intrigued to know why they [wouldn't 00:16:04] take that advantage.Corey: I just checked. Amazon Comprehend is itself HIPAA-compliant and is qualified and certified to hold Personal Health Information—PHI—Private Health Information, whatever the acronym stands for. Now, what's the difference, then, between that and Medical? In fact, the HIPAA section says for Comprehend Medical, “For guidance, see the previous section on Amazon Comprehend.” So, there's no difference from a regulatory point of view.Evelyn: That's fascinating. I am intrigued because I do know that, like, within AWS, you know, they have different segments, you know? There's, like, Digital Native Business, there's Enterprise, there's Startup. So, I am curious how things look over the engineering side. I'm going to talk to somebody about this now [laugh].Corey: Yeah, it's the—like, I almost wonder, on some level, it feels like, “Well, we wound to building this thing in the hopes that someone would use it for something. And well, if we just use different words, it checks a box in some analyst's chart somewhere.” I don't know. I mean, I hate to sound that negative about it, but it's… increasingly when I talk to customers who are active in these spaces around the industry vertical targeted stuff aimed at their industry, they're like, “Yeah, we took a look at it. It was adorable, but we're not using it that way. We're going to use either the baseline version or we're going to work with someone who actively gets our industry.” And I've heard that repeated about three or four different releases that they've put out across the board of what they've been doing. It feels like it is a misunderstanding between what the world needs and what they're able to or willing to build for us.Evelyn: Not sure. I wouldn't be surprised, if we go far enough, it could probably be that it's just a product manager saying, like, “We have to advertise directly to the industry.” And if you look at it, you know, in the backend, you know, it's an engineer, you know, kicking off a build and just changing the name from Comprehend to Comprehend Medical.Corey: And, on some level, too, they're moving a lot more slowly than they used to. There was a time where they were, in many cases, if not the first mover, the first one to do it well. Take Code Whisperer, their AI powered coding assistant. That would have been a transformative thing if GitHub Copilot hadn't beaten them every punch, come out with new features, and frankly, in head-to-head experiments that I've run, came out way better as a product than what Code Whisperer is. And while I'd like to say that this is great, but it's too little too late. And when I talk to engineers, they're very excited about what Copilot can do, and the only people I see who are even talking about Code Whisperer work at AWS.Evelyn: No, that's true. And so, I think what's happening—and this is my opinion—is that first you had AWS, like, launching a really innovative new services, you know, that kind of like, it's like, “Ah, it's a whole new way of running your workloads in the cloud.” Instead of you know, basically, hiring a whole team, I just click a button, you have your instance, you use it, sell software, blah, blah, blah, blah. And then they went towards serverless, and then IoT, and then it started targeting large data lakes, and then eventually that kind of run backwards towards security, after the umpteenth S3 data leak.Corey: Oh, yeah. And especially now, like, so they had a hit in some corners with SageMaker, so now there are 40 services all starting with the word SageMaker. That's always pleasant.Evelyn: Yeah, precisely. And what I kind of notice is… now they're actually having to run it even further back because they caught all the corporations that could pivot to the cloud, they caught all the startups who started in the cloud, and now they're going for the larger behemoths who have massive data centers, and they don't want to innovate. They just want to reduce this massive sysadmin team. And I always like to use the example of a Bare Metal. When that came out in 2019, everybody—we've all kind of scratched your head. I'm like, really [laugh]?Corey: Yeah, I could see where it makes some sense just for very specific workloads that involve things like specific capabilities of processors that don't work under emulation in some weird way, but it's also such a weird niche that I'm sure it's there for someone. My default assumption, just given the breadth of AWS's customer base, is that whenever I see something that they just announced, well, okay, it's clearly not for me; that doesn't mean it's not meeting the needs of someone who looks nothing like me. But increasingly as I start exploring the industry in these services have time to percolate in the popular imagination and I still don't see anything interesting coming out with it, it really makes you start to wonder.Evelyn: Yeah. But then, like, I think, like, roughly a year or something, right after Bare Metal came out, they announced Outposts. So, then it was like, another way to just stay within your data center and be in the cloud.Corey: Yeah. There's a bunch of different ways they have that, okay, here's ways you can run AWS services on-prem, but still pay us by the hour for the privilege of running things that you have living in your facility. And that doesn't seem like it's quite fair.Evelyn: That's exactly it. So, I feel like now it's sort of in diminishing returns and sort of doing more cloud-native work compared to, you know, these huge opportunities, which is everybody who still has a data center for various reasons, or they're cloud-native, and they grow so big, that they actually start running their own data centers.Corey: I want to call out as well before we wind up being accused of being oblivious, that we're recording this before re:Invent. So, it's entirely possible—I hope this happens—that they announce something or several some things that make this look ridiculous, and we're embarrassed to have had this conversation. And yeah, they're totally getting it now, and they have completely surprised us with stuff that's going to be transformative for almost every customer. I've been expecting and hoping for that for the last three or four re:Invents now, and I haven't gotten it.Evelyn: Yeah, that's right. And I think there's even a new service launches that actually are missing fairly obvious things in a way. Like, mine is the Managed Workflow for Amazon—it's Managed Airflow, sorry. So, we were using Data Pipeline for, you know, big ETL processing, so it was an in-house tool we kind of built at Autoscout, we do platform engineering.And it was deprecated, so we looked at a new—what to replace it with. And so, we looked at Airflow, and we decided this is the way to go, we want to use managed because we don't want to maintain our own infrastructure. And the problem we ran into is that it doesn't have support for shared VPCs. And we actually talked to our account team, and they were confused. Because they said, like, “Well, every new service should support it natively.” But it just didn't have it. And that's, kind of, what, I kind of found is, like, there's—it feels—sometimes it's—there's a—it's getting rushed out the door, and it'll actually have a new managed service or new service launched out, but they're also sort of cutting some corners just to actually make sure it's packaged up and ready to go.Corey: When I'm looking at this, and seeing how this stuff gets packaged, and how it's built out, I start to understand a pattern that I've been relatively down on across the board. I'm curious to get your take because you work at a fairly sizable company as an engineering manager, running teams of people who do this sort of thing. Where do you land on the idea of companies building internal platforms to wrap around the offerings that the cloud service providers that they use make available to them?Evelyn: So, my opinion is that you need to build out some form of standardized tool set in order to actually be able to innovate quickly. Now, this sounds counterintuitive because everyone is like, “Oh, you know, if I want to innovate, I should be able to do this experiment, and try out everything, and use what works, and just release it.” And that greatness [unintelligible 00:23:14] mentality, you know, it's like five talented engineers working to build something. But when you have, instead of five engineers, you have five teams of five engineers each, and every single team does something totally different. You know, one uses Scala, and other on TypeScript, another one, you know .NET, and then there could have been a [last 00:23:30] one, you know, comes in, you know, saying they're still using Ruby.And then next thing you know, you know, you have, like, incredibly diverse platforms for services. And if you want to do any sort of like hiring or cross-training, it becomes incredibly difficult. And actually, as the organization grows, you want to hire talent, and so you're going to have to hire, you know, a developer for this team, you going to have to hire, you know, Ruby developer for this one, a Scala guy here, a Node.js guy over there.And so, this is where we say, “Okay, let's agree. We're going to be a Scala shop. Great. All right, are we running serverless? Are we running containerized?” And you agree on those things. So, that's already, like, the formation of it. And oftentimes, you start with DevOps. You'll say, like, “I'm a DevOps team,” you know, or doing a DevOps culture, if you do it properly, but you always hit this scaling issue where you start growing, and then how do you maintain that common tool set? And that's where we start looking at, you know, having a platform… approach, but I'm going to say it's Platform-as-a-Product. That's the key.Corey: Yeah, that's a good way of framing it because originally, the entire world needed that. That's what RightScale was when EC2 first came out. It was a reimagining of the EC2 console that was actually usable. And in time, AWS improved that to the point where RightScale didn't really have a place anymore in a way that it had previously, and that became a business challenge for them. But you have, what is it now, 2, 300 services that AWS has put out, and out, and okay, great. Most companies are really only actively working with a handful of those. How do you make those available in a reasonable way to your teams, in ways that aren't distracting, dangerous, et cetera? I don't know the answer on that one.Evelyn: Yeah. No, that's true. So, full disclosure. At AutoScout, we do platform engineering. So, I'm part of, like, the platform engineering group, and we built a platform for our product teams. It's kind of like, you need to decide to [follow 00:25:24] those answers, you know? Like, are we going to be fully containerized? Okay, then, great, we're going to use Fargate. All right, how do we do it so that developers don't actually—don't need to think that they're running Fargate workloads?And that's, like, you know, where it's really important to have those standardized abstractions that developers actually enjoy using. And I'd even say that, before you start saying, “Ah, we're going to do platform,” you say, “We should probably think about developer experience.” Because you can do a developer experience without a platform. You can do that, you know, in a DevOps approach, you know? It's basically build tools that makes it easy for developers to write code. That's the first step for anything. It's just, like, you have people writing the code; make sure that they can do the things easily, and then look at how to operate it.Corey: That sure would be nice. There's a lack of focus on usability, especially when it comes to a number of developer tools that we see out there in the wild, in that, they're clearly built by people who understand the problem space super well, but they're designing these things to be used by people who just want to make the website work. They don't have the insight, the knowledge, the approach, any of it, nor should they necessarily be expected to.Evelyn: No, that's true. And what I see is, a lot of the times, it's a couple really talented engineers who are just getting shit done, and they get shit done however they can. So, it's basically like, if they're just trying to run the website, they're just going to write the code to get things out there and call it a day. And then somebody else comes along, has a heart attack when see what's been done, and they're kind of stuck with it because there is no guardrails or paved path or however you want to call it.Corey: I really hope—truly—that this is going to be something that we look back and laugh when this episode airs, that, “Oh, yeah, we just got it so wrong. Look at all the amazing stuff that came out of re:Invent.” Are you going to be there this year?Evelyn: I am going to be there this year.Corey: My condolences. I keep hoping people get to escape.Evelyn: This is actually my first one in, I think, five years. So, I mean, the last time I was there was when everybody's going crazy over pins. And I still have a bag of them [laugh].Corey: Yeah, that did seem like a hot-second collectable moment, didn't it?Evelyn: Yeah. And then at the—I think, what, the very last day, as everybody's heading to re:Play, you could just go into the registration area, and they just had, like, bags of them lying around to take. So, all the competing, you know, to get the requirements for a pin was kind of moot [laugh].Corey: Don't you hate it at some point where it's like, you feel like I'm going to finally get this crowning achievement, it's like or just show up at the buffet at the end and grab one of everything, and wow, that would have saved me a lot of pain and trouble.Evelyn: Yeah.Corey: Ugh, scavenger hunts are hard, as I'm about to learn to my own detriment.Evelyn: Yeah. No, true. Yeah. But I am really hoping that re:Invent proves me wrong. Embarrassingly wrong, and then all my colleagues can proceed to mock me for this ridiculous podcast that I made with you. But I am a fierce skeptic. Optimistic nihilist, but still a nihilist, so we'll see how re:Invent turns out.Corey: So, I am curious, given your experience at more large companies than I tend to be embedded with for any period of time, how have you found that these large organizations tend to pick up new technologies? What does the adoption process look like? And honestly, if you feel like throwing some shade, how do they tend to get it wrong?Evelyn: In most cases, I've seen it go… terrible. Like, it just blows up in their face. And I say that is because a lot of the time, an organization will say, “Hey, we're going to adopt this new way of organizing teams or developing products,” and they look at all the practices. They say, “Okay, great. Product management is going to bring it in, they're going to structure things, how we do the planning, here's some great charts and diagrams,” but they don't really look at the culture aspect.And that's always where I've seen things fall apart. I've been in a room where, you know, our VP was really excited about team topologies and say, “Hey, we're going to adopt it.” And then an engineering manager proceeded to say, “Okay, you're responsible for this team, you're responsible for that team, you're responsible for this team talking to, like, a team of, like, five engineers,” which doesn't really work at all. Or, like, I think the best example is DevOps, you know, where you say, “Ah, we're going to adopt DevOps, we're going to have a DevOps team, or have a DevOps engineer.”Corey: Step one: we're going to rebadge everyone with existing job titles to have the new fancy job titles that reflect it. It turns out that's not necessarily sufficient in and of itself.Evelyn: Not really. The Spotify model. People say, like, “Oh, we're going to do the Spotify model. We're going to do skills, tribes, you know, and everything. It's going to be awesome, it's going to be great, you know, and nice, cross-functional.”The reason I say it bails on us every single time is because somebody wants to be in control of the process, and if the process is meant to encourage collaboration and innovation, that person actually becomes a chokehold for it. And it could be somebody that says, like, “Ah, I need to be involved in every single team, and listen to know what's happening, just so I'm aware of it.” What ends up happening is that everybody differs to them. So, there is no collaboration, there is no innovation. DevOps, you say, like, “Hey, we're going to have a team to do everything, so your developers don't need to worry about it.” What ends up happening is you're still an ops team, you still have your silos.And that's always a challenge is you actually have to say, “Okay, what are the cultural values around this process?” You know, what is SRE? What is DevOps, you know? Is it seen as processes, is it a series of principles, platform, maybe, you know? We have to say, like—that's why I say, Platform-as-a-Product because you need to have that product mindset, that culture of product thinking, to really build a platform that works because it's all about the user journey.It's not about building a common set of tools. It's the user journey of how a person interacts with their code to get it into a production environment. And so, you need to understand how that person sits down at their desk, starts the laptop up, logs in, opens the IDE, what they're actually trying to get done. And once you understand that, then you know your requirements, and you build something to fill those things so that they are happy to use it, as opposed to saying, “This is our platform, and you're going to use it.” And they're probably going to say, “No.” And the next thing, you know, they're just doing their own thing on the side.Corey: Yeah, the rise of Shadow IT has never gone away. It's just, on some level, it's the natural expression, I think it's an immune reaction that companies tend to have when process gets in the way. Great, we have an outcome that we need to drive towards; we don't have a choice. Cloud empowered a lot of that and also has given tools to help rein it in, and as with everything, the arms race continues.Evelyn: Yeah. And so, what I'm going to continue now, kind of like, toot the platform horn. So, Gregor Hohpe, he's a [solutions architect 00:31:56]—I always f- up his name. I'm so sorry, Gregor. He has a great book, and even a talk, called The Magic of Platforms, that if somebody is actually curious about understanding of why platforms are nice, they should really watch that talk.If you see him at re:Invent, or a summit or somewhere giving a talk, go listen to that, and just pick his brain. Because that's—for me, I really kind of strongly agree with his approach because that's really how, like, you know, as he says, like, boost innovation is, you know, where you're actually building a platform that really works.Corey: Yeah, it's a hard problem, but it's also one of those things where you're trying to focus on—at least ideally—an outcome or a better situation than you currently find yourselves in. It's hard to turn down things that might very well get you there sooner, faster, but it's like trying to effectively cargo-cult the leadership principles from your last employer into your new one. It just doesn't work. I mean, you see more startups from Amazonians who try that, and it just goes horribly because without the cultural understanding and the supporting structures, it doesn't work.Evelyn: Exactly. So, I've worked with, like, organizations, like, 4000-plus people, I've worked for, like, small startups, consulted, and this is why I say, almost every single transformation, it fails the first time because somebody needs to be in control and track things and basically be really, really certain that people are doing it right. And as soon as it blows up in their face, that's when they realize they should actually take a step back. And so, even for building out a platform, you know, doing Platform-as-a-Product, I always reiterate that you have to really be willing to just invest upfront, and not get very much back. Because you have to figure out the whole user journey, and what you're actually building, before you actually build it.Corey: I really want to thank you for taking the time to speak with me today. If people want to learn more, where's the best place for them to find you?Evelyn: So, I used to be on Twitter, but I've actually got off there after it kind of turned a bit toxic and crazy.Corey: Feels like that was years ago, but that's beside the point.Evelyn: Yeah, precisely. So, I would even just say because this feels like a corporate show, but find me on LinkedIn of all places because I will be sharing whatever I find on there, you know? So, just look me up on my name, Evelyn Osman, and give me a follow, and I'll probably be screaming into the cloud like you are.Corey: And we will, of course, put links to that in the show notes. Thank you so much for taking the time to speak with me. I appreciate it.Evelyn: Thank you, Corey.Corey: Evelyn Osman, engineering manager at AutoScout24. I'm Cloud Economist Corey Quinn, and this is Screaming in the Cloud. If you've enjoyed this podcast, please leave a five-star review on your podcast platform of choice, whereas if you've hated this podcast, please leave a five-star review on your podcast platform of choice, and I will read it once I finish building an internal platform to normalize all of those platforms together into one.Corey: If your AWS bill keeps rising and your blood pressure is doing the same, then you need The Duckbill Group. We help companies fix their AWS bill by making it smaller and less horrifying. The Duckbill Group works for you, not AWS. We tailor recommendations to your business, and we get to the point. Visit duckbillgroup.com to get started.

Kate Moyle is a Psychosexual Therapist and EFS & ESSM Certified Psycho-Sexologist, and author of The Science of Sex. In our conversation, we discussed: Most common questions Kate gets asked about relationships or sex from clients The tiny habit that can keep desire and attraction alive in your relationship after the honeymoon phase Prioritizing quality vs frequency when spending time together How to keep sex novel and interesting in longer-term relationships (without making a huge effort) The shocking facts about what happens in your relationship once you have children (and what to do about it) How women and men see sex differently and much more Learn more about Kate: Website: https://www.katemoyle.co.uk/ Instagram: https://www.instagram.com/katemoyletherapy The Science of Sex: https://www.amazon.com/Science-Sex-Every-Question-Answered/dp/0744069602 If you enjoy the podcast, would you please consider leaving a short review on ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Apple Podcasts/iTunes⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ and a rating on our ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Spotify show⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠? It takes less than 60 seconds, and it really makes a difference. Past guests on Growth Minds include: ⁠⁠⁠⁠⁠⁠⁠⁠⁠Robert Kiyosaki⁠⁠⁠⁠⁠⁠⁠⁠⁠ (Rich Dad Poor Dad), ⁠⁠⁠⁠⁠⁠⁠⁠⁠Steve Aoki⁠⁠⁠⁠⁠⁠⁠⁠⁠, ⁠⁠⁠⁠⁠⁠⁠⁠⁠Robert Greene⁠⁠⁠⁠⁠⁠⁠⁠⁠, ⁠⁠⁠⁠⁠⁠⁠⁠⁠Dr. Jason Fung⁠⁠⁠⁠⁠⁠⁠⁠⁠, ⁠⁠⁠⁠⁠⁠⁠⁠⁠Dr. Steven Gundry⁠⁠⁠⁠⁠⁠⁠⁠⁠, ⁠⁠⁠⁠⁠⁠⁠⁠⁠Neil deGrasse Tyson⁠⁠⁠⁠⁠⁠⁠⁠⁠, ⁠⁠⁠⁠⁠⁠⁠⁠⁠Dennis Rodman⁠⁠⁠⁠⁠⁠⁠⁠⁠, ⁠⁠⁠⁠⁠⁠⁠⁠⁠Wim Hof⁠⁠⁠⁠⁠⁠⁠⁠⁠, ⁠⁠⁠⁠⁠⁠⁠⁠⁠Robin Sharma⁠⁠⁠⁠⁠⁠⁠⁠⁠, ⁠⁠⁠⁠⁠⁠⁠⁠⁠Vanessa Van Edwards⁠⁠⁠⁠⁠⁠⁠⁠⁠, ⁠⁠⁠⁠⁠⁠⁠⁠⁠King Bach⁠⁠⁠⁠⁠⁠⁠⁠⁠, Daniel Pink, Dr. William Davis, Doctor Mike, Lewis Howes (School of Greatness), Tom Bilyeu (Impact Theory), Andrew Yang, Dr. Paul Conti, Charles Hoskinson (Ethereum), Dr. Drew (After Dark), Jo Koy, Jordan Belfort (Wolf of Wall Street), Gad Saad, Adam Carolla, Louis the Child, Vishen Lakhiani (Mindvalley), Bret Weinstein (DarkHorse Podcast), James Nestor, Dave Rubin, Scott Adams (Real Coffee with Scott Adams), and more.

ADHD makes it harder to convert intentions into actions. Ari Tuckman, Psy.D., MBA, outlines a more useful way of thinking about executive functions that involves tweaking your environment, choosing the right tools, and other ways to externalize EFs. Free Resources on Executive Functions and ADHD: Download: Is It Executive Function Disorder? Read: 7 Deficits Tied to ADHD Read: ADHD Minds Are Trapped in Now (& Other Time Management Truths) Access the video and slides for this episode here: https://www.additudemag.com/webinar/executive-function-strategies-time-memory-adhd/ Thank you for listening to ADDitude's ADHD Experts podcast. Please consider subscribing to the magazine (additu.de/subscribe) to support our mission of providing ADHD education and support.