Podcasts about m1a

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JCO PO author Dr. Amar U. Kishan, Professor, Executive Vice Chair, and Chief of Genitourinary Oncology Service in the Department of Radiation Oncology at the University of California, Los Angeles, shares insights into his JCO PO article, “Transcriptomic Profiling of Primary Prostate Cancers and Nonlocalized Disease on Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography: A Multicenter Retrospective Study.”  Host Dr. Rafeh Naqash and Dr. Kishan discuss the relationship between Decipher genomic classifier scores and prostate-specific membrane antigen (PSMA) PET/CT-based metastatic spread. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO articles. I'm your host, Dr. Rafeh Naqash, Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today we are joined by Dr. Amar Kishan, Executive Vice Chair of the Department of Radiation Oncology at the David Geffen School of Medicine at UCLA and UCLA Jonsson Comprehensive Cancer Center, and also the corresponding and senior author of the JCO Precision Oncology article entitled, “Transcriptomic Profiling of Primary Prostate Cancers and Non Localized Disease on Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography/Computed Tomography: A Multicenter Retrospective Study.” Dr. Kishan, welcome to our podcast and thank you for joining us today. Dr. Amar Kishan: Thank you so much for that kind introduction and the invitation to be here today. Dr. Rafeh Naqash: Well, it seems to me that there's a theme that people in the GU space, investigators in the GU space, are very interested in trying to understand risk predictors for prostate cancer. We had somebody, I believe from Huntsman Cancer Center a few months back on a previous podcast, where they were trying to do risk prediction modeling as well. Could you tell us why that's something that the GU community is very interested in? What's the background? Is it because there's no risk prediction approaches currently? And would this somehow influence management in the near future? Dr. Amar Kishan: Yeah, that's a great question. So, I think this goes back to the point that we're in the era of precision medicine now, and many cancers have these molecular stratification scores and all that. Prostate cancer has lagged a little bit behind in that regard, despite the fact that it's such a common cancer that affects so many people across the country and across the world. So, we do have risk stratification schemes for prostate cancer. These are based off clinical and pathologic variables, like the level of PSA, the size of the tumor on digital rectal examination, now, we're incorporating MRI imaging as well, and then what the cancer looks like under the microscope, the Gleason score. And now there have been revisions to the Gleason score, but it's really kind of the architecture, what the biopsy looks like. And this was kind of developed many, many years ago by Donald Gleason, a pathologist at the VA. What we're not necessarily taking into account routinely is kind of the biology of the cancer per se. You know, what are the molecular drivers? How could that influence ultimate outcome? And that's very important because we have these risk groups, low risk, very low risk, favorable intermediate risk, unfavorable intermediate risk, high risk, very high risk. But within each of those groups, based on the clinical kind of pathological characteristics, there's a huge heterogeneity in outpatients too, and our treatments are effective, but they can be morbid. Putting someone on hormone therapy for an extended period of time has a lot of side effects. Dose escalating radiotherapy or doing surgery and then radiation afterwards, these are big things that have a big impact on the patient, and I think we really need better risk stratification tools to understand who needs intensification and who we can de-escalate treatment for. Dr. Rafeh Naqash: I think those are absolutely valid points, perhaps not just for prostate cancer, more so for all cancers that we currently treat, especially in the current day and age, where we have a tendency to add more and more therapies, combination therapies for patients, and as you mentioned, risk stratification to help identify high risk versus low risk, where you can de intensify treatment, is of high value from a patient standpoint as well as from a financial toxicity standpoint. So then, going to this next part of the approach that you used, and from what I understand in this paper, you had the radiological aspect, which is the PSMA PET, which we'll talk about. Then you had the genomic aspect, where you did some genomic risk-based stratification. Then you had the transcriptomic score based on the Decipher score. So, could you go into some of the details, first, for the PSMA PET, when is it used? What is the utilization? What is it based on, the science behind the PSMA PET? And then we can talk about some of the other genomic transcriptomic predictors that you use in this study. Dr. Amar Kishan: Sure. Absolutely. So, a PSMA PET is an advanced molecular imaging tool. PSMA stands for prostate specific membrane antigen. It's a membrane protein that is expressed on the surface of prostate cancer cells. It is expressed elsewhere in the body as well. The utilization of this for imaging has been a revolution in the staging of prostate cancer, both upfront and in the recurrent setting. We basically had fairly recent approval for PSMA PET being used more routinely in upfront staging and recurrent staging in 2022. Essentially, what this is it gives us an ability to detect whether prostate cancer has spread at a time of diagnosis or try to localize the recurrence. Now, no imaging test is perfect, of course, and a PET has a resolution of about 3 mm. There are questions about the sensitivity of the PET. You get it on a patient with high-risk disease, the PET is negative; you do surgery, there are positive lymph nodes. That can happen, but it's far superior to the tools that we have had before. For instance, beforehand, all we would have is a contrast enhanced CT, bone scan, and MRI. And the sensitivity of those is far below that of a PSMA PET. And that has actually been shown in a randomized trial called the ProPSMA trial out of Australia, where they compared conventional upfront imaging versus PSMA upfront imaging with a crossover design, and there was better detection of disease with the PSMA PET. So that's been a revolution in how we stage prostate cancer. But I'm sure many of your listeners and others are aware of the concerns. When you get a new test and you're detecting disease that's extra prostatic, for instance, are you seeing truly significant new disease that we do need to change our management for, or are we just seeing stuff that wasn't there before that actually wouldn't impact anything? And what I mean by that is, let's say you're seeing things that would never have made a difference to the patient, but now you're saying they have metastatic disease. You're changing their entire treatment paradigm, all kinds of things like that. There's implications to this that hasn't been fully fleshed out. But very recently, like we're talking in July of 2024, essentially, there was a Lancet Oncology paper that looked at the long-term prognosis of patients who had extra prostatic disease on PSMA PET, judged by something called a PROMISE score, kind of gives a quantification on the volume of disease, the brightness of disease, and they correlated that with long term outcomes. And that was really the first time that we have long term follow up data that this extra prostatic disease on PSMA PET actually is prognostically important. So, we're getting there. I mean, now that it's approved and, in some sense, the cat is out of the bag, patients are coming in asking for a PSMA PET, etc. I'm sure everyone has experienced that, but I think we now do have good evidence that it actually is prognostically important as well. Dr. Rafeh Naqash: Thank you for that explanation. And again, to put this into context for things that I've seen and that might also help the listeners in other tumors, so, for example, melanoma surveillance tends to be or while on treatment, patients tend to have more PET scans than what you see, maybe in individuals with lung cancer, where you get a baseline PET and then you have follow up CT scan based imaging is that something that you guys have shifted from in the prostate cancer space with the approval for PSMA PET, where follow up imaging, whether patient is on treatment or surveillance imaging, is PSMA PET based? Dr. Amar Kishan: Yeah, that's a good question. I think there's actually less robust data to support it as a means of treatment response. But in terms of evaluating a recurrence, then, yes, that has become kind of a standard tool. It's very complicated because all of the metrics that we have for, say, a treatment failing are based on conventionally detected metastases or something that shows up on a CT or bone scan. So, again, that question arises if someone is on systemic therapy and then you see something on a PSMA PET, are you going to abandon the therapy that you're on? It technically would be earlier than you would otherwise have done that, or what are you going to do? So, that hasn't been fully fleshed out, but it is used in that circumstance. So, I'd say less for treatment monitoring and more for evaluation of suspected recurrence. Dr. Rafeh Naqash: Understood. And I'm guessing, as a futuristic approach, somebody out there may perhaps do a trial using PSMA PET based imaging to decide whether treatment change needs to be made or does not need to be made. Dr. Amar Kishan: Yeah. It is being incorporated into trials as we speak, I think. Dr. Rafeh Naqash: Now, going to the second part of this paper is the Decipher score. Could you explain what the score is, what its components are, how it's calculated? Is it DNA, is it RNA, is it both combined? Is it tissue based; is it blood based? Dr. Amar Kishan: Yeah. So, the Decipher is also an approved test now, was approved in 2018. What it is, essentially, and how it's derived is based on the idea originally that patients might have a recurrence after surgery for prostate cancer. And it's just a PSA recurrence. It's this way. It's literally what we call a biochemical recurrence. That patient might not have any problems, whereas other patients with a recurrence might go on to develop metastatic disease. And we didn't have a good way of determining which patient is which. Get back to that prognostic problem that we have. So, some investigators, they looked at men that had radical prostatectomy from 1987 to 2001 at the Mayo Clinic that had archived tissue. They looked at FFPE, or basically paraffin embedded tissue. They extracted the RNA and then did a microarray analysis and looked at transcriptomic signatures and wanted to see, could this discern the patients who had mets, who had clinically significant recurrences from those that didn't? And out of that exercise came the Decipher Genomic Classifier, which basically is based on 22 genes. These are involved with cell proliferation, etc., but it's an RNA-based, tissue-based assay. So, if you wanted to order a Decipher on somebody, you would need to use a biopsy or prostatectomy specimen to do so. Essentially, that the samples, they would take the highest grade, highest Gleason grade specimen, send it to their lab. Their main lab is in California. The company is called Veracyte. And then they will do this RNA express analysis with a microarray and then return a score. The score is 0 to 1. Basically, 0 is the lowest, one is the highest, and it is a way of prognosticating the risk of metastasis. Originally, when you get a Decipher report, it actually will tell you the 5 and 10-year risks of distant metastasis, and we'll quantify that. Dr. Rafeh Naqash: And you said this is approved or has been approved in 2018. So, is this insurance reimbursable at this point? Dr. Amar Kishan: Most insurances do, not all, and the criteria for getting it can vary, so we can talk about it, but it was initially developed in this post-op setting. On the basis of a significant amount of validation studies, it has been moved to being used in the upfront setting as well. So, if you look at some of the ongoing NRG trials, for instance, they are stratifying patients based off the upfront Decipher score. And this is based off of validation studies that have been conducted looking at past RTOG trials and other trials. That said, sometimes it is not approved by commercial insurances in the upfront setting, because that wasn't where it was initially validated and derived. But honestly, here in 2024, that's very uncommon. It's much more common that it's approved. Dr. Rafeh Naqash: Understood. And in your practice, or the medical oncologist practice at your institution or other institutions, is this something that is commonly used for some sort of treatment decision making that you've seen? Dr. Amar Kishan: Yeah. So, as a radiation oncologist, I do think it's a useful test, because my approach is, if we're talking about adding hormone therapy, for instance, which is oftentimes dominating the conversation, we know that it offers a relative benefit to a lot of patients. We've published on this; others have published on it. Let's say it reduces the chance of metastasis by about 40%. 10-year risk of metastasis has a ratio of 0.6. So, 40% reduction. But if your risk of metastasis is 2%, that benefit is not that much in absolute terms. And we don't historically have a great way of saying, what is your absolute risk of metastasis? And I think Decipher is one tool that does tell us that - it literally gives it on the report. Now, is that a holy grail? Is it 100% accurate? Nothing is 100% accurate. But it does give us some quantification. Then I can go back to the patient and say, yes, you will get a benefit from adding hormone therapy, but you're talking about going from 2% to 1%, and so they can decide if that's worth it to them. Conversely, it could be a situation where they really don't want hormone therapy, but it comes back that their risk of metastasis is 20%, and then there's actually a big absolute benefit. So that's how I use it as a radiation oncologist, and we would use it upfront. Now surgeons, and if I was consulting on a post operative patient, maybe it plays more of a role. And do we need to do post operative radiotherapy on this patient, or do we need to add hormone therapy in the postoperative situation? From the medical oncology perspective, there are emerging data that may be useful in the choice of systemic therapy for metastatic disease, but that is a little bit earlier in the investigational stage, I would say. So, when I'm working with medical oncologists, it's often still in this localized setting, and typically, do we add hormone therapy or not, and that type of thing. Dr. Rafeh Naqash: Understood. And from a reporting standpoint, so the Decipher score, I'm guessing it's some sort of a report that comes back to the ordering physician and you basically see the score, it gives you a potential recurrence free survival percentage or a metastasis percentage of what is your risk for having metastasis in the next five years - is that how they generally do it? Because I've personally never seen one, so I'm just curious. Dr. Amar Kishan: Yeah, essentially, it comes back with a score, a numerical score, again, from 0 to 1, and it will basically give you the five-year risk of distant metastasis. The ten-year risk of distant metastasis. You can request an extended report that provides additional, not as well supported signatures that are out there, like ADT response signature, etc. But those maybe may have been published, but are not clinically validated as much, but the actual Decipher report, which goes to patients too, just has this kind of 5,10-year risk of distant metastasis. They have some estimations on prostate cancer specific mortality as well. Dr. Rafeh Naqash: Sure. Now, the third part of this project, and correct me if I'm wrong, the grid database of the 265 genomic signature score. From what I understood, this is a different component than the Decipher score. Is that a fair statement? Dr. Amar Kishan: Yeah. No, that's exactly correct. And that was an exploratory part of this analysis, to be honest. Basically, I think our main focus in the paper was those advances that we've talked about PSMA and Decipher, those happened concurrently. People started developing PSMA PET, people started developing Decipher. And so, what we wanted to understand was, if you have a patient that has extra prosthetic disease on PSMA PET, are those biologically more aggressive cancers, is their Decipher score going to be higher? What can we learn about the biology of this? And we were the first, to my knowledge, where we actually had a large data set of patients that actually received PSMA PETs and Decipher. And that's kind of the gist of the paper. We have patients in the upfront setting, patients in the post radical prostatectomy setting, and we're essentially showing that there is this correlation. In the upfront setting, the odds of extra prosthetic disease are higher for higher Decipher scores, which is kind of maybe validating that this biology is capturing something that's akin to this ability to spread. And in the post-op setting, because we have time to failure, technically, we can calculate a hazard ratio rather than odds ratio. So, we have a hazard ratio that's significantly associated with an increased risk of spread for patients with higher Decipher. The grid portion, which is the genomic resource information database, was more of an exploratory part where I mentioned the Decipher score is based off this microarray, they're looking at 1.4 million transcripts. Only 22 are part of the Decipher, but you can request the rest of the signature data as well. And so, we wanted to look at other pathways, other signatures that have been published, like looking at DNA repair, neuroendocrine pathway, just to see if we could see any correlations there that's not necessarily as clinically actionable. These are more exploratory. But again, we were trying to just look at whether patients who had non localized disease on their PSMA PET, whether their primary had more aggressive biology. We did see that. So that's kind of loosely speaking things like PTEN loss, androgen receptor, DNA repair, metabolism, neuroendocrine signaling, which are thought to be portenders of aggressive disease. Those pathways were upregulated at the RNA level in patients who had non-localized disease. And that's kind of the take home from that. But I wouldn't say any of that is clinically actionable at this point. It's more kind of defining biology. Dr. Rafeh Naqash: Some of the interesting correlations that you make here, at least in the figures that we see, you're looking at different local occurrences, nodal metastases, M1A and M1B disease. And one thing that I'm a little curious about is the Decipher score seems to be lower in pelvic nodal metastasis, that is, PSMA PET positive versus local recurrence, which has a slightly higher Decipher score. Is that just because of a sample size difference, or is there a biologically different explanation for that? Dr. Amar Kishan: Yeah, that's a good point. I would assume that's probably because of a sample size in this case, and it's a little bit complicated. It wasn't statistically different. And it was 0.76 on average for patients with local recurrence and 0.7 for patients with a pelvic nodal metastasis. Well, what I think is interesting is we can maybe think that in this post-op setting the time to failure could have been long in some of these cases. So, it is conceivable that an isolated nodal recurrence 10 years after the surgery, for instance, is not as aggressive a cancer as a local recurrence in a short time after the surgery. And that's not taken into account when you're just looking at median scores like we are in this fox and whiskers plot. But overall, I think what it's suggesting is that there are patients who have more indolent disease. That's actually pretty widespread there. There are pretty indolent cases that have these nodal metastases. So just because you have a nodal metastasis doesn't mean it's an incredibly aggressive cancer, biologically. Dr. Rafeh Naqash: Now, the exploratory component, as you mentioned, is the grid part where you do look at TP53, which is a cell cycle gene, and higher TP53 associated with worse recurrences, from what I understand. Do you see that just from a cell cycle standpoint? Because from what I, again, see in the paper, there's a couple of other cell cycle related signatures that you're using. Is that just a surrogate for potential Gleason score? Have you guys done any correlations where higher Gleason score is associated with maybe higher cell cycle checkpoint, pathway related alterations and replication stress and DNA damage and perhaps more aggressive cancers? Dr. Amar Kishan: Yeah, that's a great question. We haven't done that in this paper, but it has been published before that there is this correlation loosely between grade and some of these parameters - so repair, metabolism, androgen receptor signaling. However, it's a very great point that you bring up, which is that it's pretty heterogeneous and that's why we need something like this as opposed to Gleason score. So, you can have Gleason 10 cancer. I mean, that would be pretty uncommon. But within the Gleason 9, at least, which we have published on and looked at, there's a heterogeneity. There are some that are biologically not that aggressive. And the converse Gleason 7, you can have some that are actually biologically aggressive. That's why it may be useful to move away from just the pathological architecture and get a little bit more into some of these pathways. Dr. Rafeh Naqash: What's the next step here? I know this perhaps isn't ready for primetime. How would you try to emphasize the message in a way that makes it interesting and clinically applicable for your colleagues in the GU community? Dr. Amar Kishan: Yeah. I think for me, what I would try to emphasize here and what I think is the main takeaway is this is kind of a validation that having extra prostatic disease on PSMA PET is likely suggestive of a more aggressive disease biology. And I think what this stresses to me is the importance of getting a PSMA PET, particularly in patients with high-risk prostate cancer. This isn't always happening. And I think if we see things on a PSMA PET, we really need to consider systemic therapy intensification. And what do I mean by that as a practical point? You have a high-risk prostate cancer patient. You get a PSMA PET, you see an isolated pelvic lymph node. If we believe the results of the study, that's a more aggressive biology likely. Whether we have the Decipher or whether we have genomic signatures, which we may or may not have, maybe that patient should get treated with something like an androgen receptor signaling inhibitor in addition to ADT, more akin to a clinically node positive case. So, intensify the systemic therapy, more aggressive disease. That's how I would incorporate it practically into my practice, that really what we're seeing on the PSMA PET is real. It's a reflection of biology that's aggressive. It's not just some Will Rogers effect where you're upstaging stuff needlessly. I think this is telling us some true biology. So that's kind of what my takeaway would be. I think future areas of investigation would be, honestly, to try to have a better idea of what's going on in these metastases. So, if you could design a study potentially, where your biopsy some of these and actually do sequencing and understand a little bit more of that. And so, we're looking into stuff like that. But my takeaway for like the everyday clinician would be to try to get a PSMA PET, if you can, and to intensify therapy on the basis of that, or at least consider it, discuss it in a multidisciplinary setting. Dr. Rafeh Naqash: And I'm guessing somebody out there, perhaps even you, are thinking or planning on doing a ctDNA MRD based correlation here, since that's up and coming in this space. Dr. Amar Kishan: That is up and coming, I think one of the challenges in prostate cancer is the amount of ctDNA can be low. But yes, you're right, that's certainly things that a lot of us are looking at, too. Dr. Rafeh Naqash: Excellent. Well, thank you for the science discussion, Dr. Kishan, could you tell us a little bit about yourself, your career trajectory, where you started, what you're doing, and perhaps some advice for early career junior investigators, trainees, things that might have worked for you, that could also work for them as they are progressing in their careers. Dr. Amar Kishan: Sure. So, yeah, I'm a radiation oncologist at UCLA. I run the prostate cancer radiation program. Clinically. I'm also heavily involved in our research enterprise, so I kind of oversee the clinical and translational research aspect. That's what I do currently. So, I did my residency in radiation oncology at UCLA. Just on a personal note, my wife is from LA, her parents live in LA. We really wanted to stay in LA, so I was fortunate to be able to join the faculty here. I always liked GU oncology, so that was kind of a natural thing for me to kind of go into this position here and try to build the GU program. I've been very fortunate to have great collaborators. My message to students and trainees is to try to reach outside your department for mentorship as well. It's important to have people inside your department who can mentor you. But as a radiation oncologist, I work so closely with urology, so closely with medical oncology that I'm very fortunate to have individuals in those departments who have a vested interest in me and my success as well. I like working with them. It's important to be a team player. If they need help, you help them. If you need help, you ask for help from them. So, I think that's the single biggest thing that I would say to any trainee is don't be intimidated. Please reach outside of your department. Lots of people are willing to help and provide mentorship, and it's helpful to have that perspective. We are in a very multidisciplinary environment and era of practicing medicine. Dr. Rafeh Naqash: Well, thank you again for those personal insights and especially for submitting your work to JCO PO. And we hope to see more of this work perhaps in the subsequent sessions for JCO PO, and maybe we'll bring you back again. And at that point, the Decipher and the PSMA PET scan will have more data, more implementation in the clinically relevant real-world setting. Dr. Amar Kishan: Thank you very much. And if I could just give one quick shout out. The first author of this work, which I presented, was Dr. John Nikitas, who is a trainee that works with me here at UCLA a PGY5 resident. So, I do want to give credit to him as well. Dr. Rafeh Naqash: And John, if you're listening to this hopefully, it's always great to get a shout out from your mentor. Thank you both again for putting in the work and effort to submit this manuscript. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.   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.    Disclosures  Dr. Kishan Honoraria Company: Varian Medical Systems, Boston Scientific,  Janssen Oncology  Consulting or Advisory Role Company: Janssen, Boston Scientific, Lantheus  Research Funding Company: Janssen , Point Biopharma

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Dr. Diwakar Davar and Dr. Jason Luke discuss key abstracts from the 2024 ASCO Annual Meeting that explore triplet therapy in advanced melanoma, TIL cell therapy in immune checkpoint inhibitor–naive patients, and other novel approaches that could shape the future of immunotherapy in melanoma and beyond.  TRANSCRIPT Dr. Diwakar Davar: Hello and welcome to the ASCO Daily News Podcast. I am your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to have my friend and colleague, Dr. Jason Luke, on the podcast today to discuss key abstracts in melanoma and immunotherapy that will be featured and highlighted at the 2024 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the director of the Cancer Immunotherapeutic Center, as well as the associate director for clinical research at the University of Pittsburgh's Hillman Cancer Center.  You will find our full disclosures in the transcript of this episode.  Jason, as always, it's a pleasure to have you on this podcast to hear your key insights on trials in the immunotherapy space and melanoma development paradigm, and to have you back on this podcast to highlight some of this work.  Dr. Jason Luke: Thanks so much for the opportunity to participate. I always enjoy this heading into ASCO.  Dr. Diwakar Davar: We're going to go ahead and talk about three abstracts in the melanoma space, and we will be starting with Abstract 9504. Abstract 9504 essentially is the RELATIVITY-048 study. It describes the efficacy and safety of the triplet nivolumab, relatlimab, and ipilimumab regimen in advanced PD-1 naive melanoma. So in this abstract highlighted by Dr. Ascierto and colleagues, they report on the results of this phase 2 trial in this setting. By way of background, PD-1 inhibitors and immune checkpoint inhibitors starting in PD-1 and CTLA-4, as well as PD-1 and LAG-3, are all FDA-approved on the basis of several pivotal phase 3 trials, including KEYNOTE-006, CheckMate-066, CheckMate-067, and most recently, RELATIVITY-047. Jason, can you briefly summarize for this audience what we know about each of these drugs, at least the two combinations that we have at this time?  Dr. Jason Luke: For sure. And of course, these anti PD-1 agents, became a backbone in oncology and in melanoma dating back to more than 10 years ago now, that response rates in the treatment-naive setting to anti PD-1 with either pembrolizumab or nivolumab are roughly in the range of mid-30s to high-40s. And we've seen clinical trials adding on second agents. You alluded to them with the seminal study being CheckMate-067, where we combined a PD-1 antibody and CTLA-4 antibody or nivo + ipi. And there the response rate was increased to approximately 56%. And more recently, we have data combining PD-1 inhibitors with anti-LAG-3. So that's nivolumab and relatlimab. Now, in that trial, RELATIVITY-047, the overall response rate was described as 43%. And so that sounds, on a first pass, like a lower number, of course, than what we heard for nivolumab and ipilimumab. We have to be cautious, however, that the cross-trial comparison between those studies is somewhat fraught due to different patient populations and different study design. So I think most of us think that the response rate or the long-term outcomes between PD-1, CTLA-4, and PD-1 LAG-3 are probably roughly similar, albeit that, of course, we have much better or much longer follow up for the nivo + ipi combo.  The one other caveat to this, of course then, is that the side effect profile of these two combinations is distinct, where the incidence of high-grade immune-related adverse events is going to be roughly half with nivolumab and relatlimab, a combination of what you would see with the nivolumab and ipilimumab. So that has caused a lot of us to try to think about where we would use these different combinations. But we do see that all of these treatments can land a durable long-term response in the subset of patients that do have an initial treatment benefit. The landmark, I think, for the field has been the 7-and-a-half-year median overall survival that we've seen with PD-1 plus CTLA-4, nivo + ipi; of course, we don't have such long-term follow up for PD-1 and LAG-3. But I think that's the setting for thinking about the rationale for combining a triplet regimen of PD-1, CTLA-4, and LAG-3. Dr. Diwakar Davar: So, Jason, in your mind, given the difference in the disparity and durability of the responses for the 067 regimen of nivo-ipi, and the RELATIVITY-047 regiment of nivo-rela, what is the standard of care in the U.S., and how does it change in the rest of the world, knowing that nivo-rela is not necessarily approved in all jurisdictions? Dr. Jason Luke: So this is a major complication in our field, is that there is perhaps not complete agreement across the world in terms of what the frontline standard of care should be. I think most United States investigators, or those of us that really treat melanoma most of the time, would suggest that a combination regimen, given the enhanced response rate and longer-term outcomes, should be the consideration for the majority of patients. In fact, in my practice, it's hard to think of who I would treat with a monotherapy PD-1 approach in the PD-1 naive setting. So either nivo + ipi or nivo + rela. As you alluded to however, in other regulatory settings throughout the world, combinations might not actually even be approved at this point. So PD-1 monotherapy would be the backbone of that setting. It does set up some complications when you think about a comparator arm; say you were going to look at various combinations, probably PD-1 monotherapy would be the worldwide comparator. You have to understand though, in the United States, I think that that's a less attractive option. Dr. Diwakar Davar: So in RELATIVITY-047, Dr. Ascierto and his colleagues are looking at generating a triplet. And in this case, they looked at this in the context of frontline metastatic melanoma, 46 patients. Very interestingly, the dose of ipilimumab studied here was 1 mg/kg through 8 weeks, not the 3 mg/kg every three weeks times four doses using 067, or even the low dose ipilimumab regimen that you studied in the second line setting, which was 1 mg/kg every 3 weeks for 4 doses. So let's talk about the results and specifically the implications of potentially studying lower doses of ipi. Dr. Jason Luke: I appreciate you raising that point. I think it's really important as we think about this dataset because this triplet regimen is not by any means the only version of a triplet that could be developed using these agents. So just to give the high-level numbers from the abstract, we see from these data that the overall response rate is described as 59% and 78%, a disease control rate with patients having an unreached link. So duration of response of unreached, and then the progression-free survival at about 5 months. So those are really interesting data. But as was alluded to, it's not totally clear to me that that's the best that we could do with this regimen.   Now, you alluded to this low-dose ipilimumab schedule at 1 mg/kg every 8 weeks, and it's really important to note that we have no benchmark for that regimen in melanoma oncology. And in fact, the one study that used that regimen, which was the adjuvant study of nivolumab and ipilimumab, known as CheckMate915, is in fact the only immune checkpoint inhibitor study in melanoma oncology that was actually negative. That study noted no benefit to adding ipilimumab at 1 mg/kg every 8 weeks on top of nivolumab, again, the adjuvant setting. So it's a little bit curious to then understand what it means in this study to have that amount of ipilimumab added to the rela-nivo backbone. And that manifests in a few different ways. We see the response rate here at 59%. Again, if you compare that just against the standard nivo + ipi dosing schedule, it's about the same. So is that really an advantage to having the triplet as compared to just doing standard nivo + ipi?   We do see that it manifests in a slightly lower rate of grade 3/4 immune-related adverse events, at 39%. That's a little bit lower than what we'd expect for standard nivo + ipi. But again, I think that that emphasizes to me the possibility that some efficacy was left on the table by using this very low dose ipilimumab regimen. I think that's really a concern. It's not clear to me that these triplet data really differentiate from what we'd expect with the already approved regimen of nivo + ipi. Therefore, it makes it difficult to think about how would we really want to move this regimen forward, or should there be more work done about dose and schedule to optimize how we might want to do this?  Dr. Diwakar Davar: As far as triplet therapy in the context of frontline metastatic melanoma, meaning triplet immune therapy, because there are at least several targeted therapy triplets that are FDA-approved, [but] not necessarily widely utilized. How would you summarize the future for triplet therapy? Do you think it's potentially attractive? Do you think it's very attractive with some caveats? Dr. Jason Luke: Well, I think it's attractive, and we have 3 independently active agents. And so I do think it's a priority for the field to try to figure out how we could optimize the therapy. We've had such a revolution in melanoma oncology, talking about 7.5-year median survival from CheckMate-067, but that still implies that 7.5 years, half the patients have passed away. There's more to do here. And so I do think it should be a priority to sort this out. I guess I would be cautious, though, about advancing this regimen directly to a phase 3 trial because it doesn't seem clear to me that this is optimized in terms of what the outcome could be. If we're willing to tolerate higher rates of toxicity from other dose schedules of nivo-ipi alone, then I think we should do a little bit more here to potentially explore the space that might be possible to increase that overall response rate a little more without getting into a completely exaggerated toxicity profile that would be unacceptable. So, I do think it's exciting, but there's possibly more to do before really think about going big time with this. Dr. Diwakar Davar: Great. So now we'll switch gears and move from frontline metastatic melanoma to the second line and beyond looking at a new agent and contextualizing the effects of that actually in the frontline settings. So Abstract 9505 describes the efficacy and safety of lifileucel, which is essentially autologous tumor-infiltrating lymphocyte cell therapies, also known as TIL, in combination with pembrolizumab in patients with ICI naive, so not necessarily pretreated, but ICI naive metastatic or unresectable melanoma. This is data from the IOV-COM-202 Cohort 1A oral abstract presented by Dr. Thomas and colleagues. In this abstract, Dr. Thomas and colleagues are presenting data from the 1A cohort, which is the phase 2 portion of the frontline trial that is evaluating autologous TIL with pembro in checkpoint inhibited naive metastatic melanoma.  By way of background, TIL is FDA approved on the basis of several cohorts from a phase 2 trial. The data has been presented multiple times now by Drs. Sarli, Chesney, and multiple colleagues of ours. And essentially autologous TIL, which is generated from a surgical procedure in which a patient undergoes a surgery to extract a tumor from which T cells are then grown after ex vivo expansion and rapid expansion protocol. The entire procedure was essentially pioneered by several colleagues at the NCI, primarily Dr. Steve Rosenberg, and this approach produces objective response rates of approximately 31% to 36%. And the most recent publication demonstrated that at median follow up of approximately 2 years, the median duration of response was not reached. The median OS was about 14 months and PFS was about 4 months or so. So, can you contextualize the results of the abstract in the frontline setting? And then we'll talk a little bit about where we think this is going to go. Dr. Jason Luke: So I think this is a timely study given the recent approval. And in the abstract presented here, we see an early data cut from the PD-1 naive study, as you alluded to. So here we had 22 patients and distributed across various states of advanced melanoma. Ten out of the 22 had M1C, but there also were smatterings of earlier M1A and M1B at 18.2% and 9.1%. So this is important, as we think who the treatment population is that's going to be optimized with a TIL procedure. The median sum of diameters, meaning how much tumor burden the patients have, was about 5.5cm, and I'll note that that's a relatively modest amount of tumor burden, albeit not that unusual for an early-stage trial. So of the patients that participated, 8 had BRAF mutations so that's 36%. That's not that high, but it's reasonable. And I think the important overlying number, the response rate so far in the study, with about 17 months of follow up, was 63.6%, and that includes 22% or 23% having complete response. So those are interesting data.  And another point that was made in the abstract, which we've all seen, is that responses to TIL, all of immunotherapy but especially TIL, do seem to mature over time, meaning they deepen over time. So it's possible the response rate could go up some extent as we watch this study advance. So I think these are exciting data on some level. Also, a 63.6% response rate sounds pretty impressive, but we do have to put that in the context of a double checkpoint blockade, which we just got done discussing, gives you almost a 60% response rate, 59% response rate. So then the question really is: Is it worth the amount of effort that we could go into generating a TIL product in a treatment naive patient, and put them through the lymphodepletion that is associated with TIL and the high dose interleukin 2 treatment that accompanies the reinfusion of the TIL, if you're going to get a response rate that's roughly the same as what you would get if you gave them off the shelf nivo plus ipilimumab?  At this point it's a little bit hard to know the answer to that question. I think it could be possible that the answer is yes, because we don't know exactly which populations or patients are most likely to benefit from each of these therapies. And if it could be teased out who's not going to benefit to nivo + ipi from the get-go, then of course, we would want to offer them a therapy that has that frontline potential, durable, long-term response. But I have to say, on a one-to-one with TIL therapy, you get a lot of toxicity initially with the treatment; with nivo + ipi on the back end, you get a fair amount of toxicity with the treatment. How are we going to judge those two things? And I think we probably need a larger dataset to really have a good handle on that.  So these are interesting early data, but it's not totally clear to me that even if this holds up all the way through the trial, and we're going to talk about the design of the registration trial here in a second, a 60% response rate on its own without further biomarker stratification is a little bit hard for me to see in clinical practice why we would want to do that, given we can already just go off the shelf and give checkpoint inhibitors. Dr. Diwakar Davar: So that brings us to TILVANCE-301. So TILVANCE is a phase 3 trial. It's a registration intent trial by our Iovance colleagues evaluating the pembro-TIL regimen versus pembrolizumab alone. So in this phase 3 trial, approximately 670 patients will be randomized to either arm A, which is lifileucel + pembro. And in this arm A, patients are going to be getting lifileucel with the tumor resection, non-myeloablative lymphoid depletion, the lifileucel and abbreviated course of high-dose IL-2, and thereafter, continued pembro for the study mandated duration versus arm B, where patients will be getting just pembrolizumab monotherapy per label. Arm B patients, per the design, may cross over to receive TIL monotherapy at the time of central-blinded, radiology-confirmed disease progression.   The study design otherwise is fairly routine and, per most of our registration trials these days, patients have actually been permitted to receive neoadjuvant and adjuvant therapy, including checkpoint inhibitors, as long as the receipt of the therapy was more than 6 months prior to the inclusion of the patient in that registration trial. The dual primary efficacy endpoints as stated are BICR-assessed objective response rate as well as PFS, and the key secondary endpoint is overall survival.   So Jason, what are your thoughts on the study design and potentially the regulatory implications, particularly given, one, the control arm of pembro monotherapy, and two, the role of TIL crossover to receive TIL monotherapy at the time of BICR mandated progression for arm B? Dr. Jason Luke: So this goes to a few points that we've touched on already in the discussion here. When we think about the primary endpoints for this study, with one of them being overall response rate, one has to assume that that's a given that they would get that. I feel like that's a low bar. And we go back to that cross-trial comparison. If their results end up being that the response rates are about 60%, I don't know that that differentiates necessarily from what's already available in the field with combination immune checkpoint blockade. For the purposes of the study that would mean it's a positive study, so I think that would probably be good. But again, the comparator to pembrolizumab monotherapy, I think some of us would argue, isn't really consistent with what we would do with a patient in our clinic. So it's not that it's bad per se, but I think there's going to be a whole lot of cross-trial comparison. So if the study is positive, that would be good for getting the drug available. It's still a bit hard though, based on the preliminary data that I've seen, to imagine how this would have uptake in terms of utilization as a frontline therapy.  You alluded to the crossover, and I think there, the assumption is that patients who get TIL therapy as a second line perhaps would have an attenuated benefit. But I'm not sure that's really true. It certainly looks from the data that we have, like the patients who benefit most from TIL are going to be those who didn't respond to anti PD-1 in the front line. So I'm not sure how much difference there's going to be between first- and second-line TIL therapy, but those data will kind of wait to be seen. So I think it's an important study. Of course, the accelerated approval of TIL as a later line therapy is dependent on this trial being positive. So there is some risk that if this trial ended up not being positive, that that could have regulatory implications on the utility or availability of TILs, a subsequent line therapy. But all of these, I guess we'll have to wait to see the results. We do hope for a positive trial here, although I think it'll be nuanced to sort of interpret those data given that pembrolizumab monotherapy control arm.  Dr. Diwakar Davar: Fantastic. So we've learned a lot about TIL, both its use in the second-line setting and this very exciting but potentially risky frontline trial that is ongoing at some centers in the United States and certainly a lot of ex-U.S. enrollment.   So we'll now pivot to a related product which actually belongs to a much larger class of agents that are antigen specific T-cell therapies in a variety of different formats. And that is Abstract 9507, which is the “Phase 1 safety and efficacy of IMC-F106C, a PRAME × CD3 ImmTAC bispecific, in post-checkpoint cutaneous melanoma (CM).” Now, in this abstract, Dr. Omid Hamid and colleagues reported the results of this phase 1 trial. As a disclosure, I'm an investigator and the last author on this manuscript. Jason, it would be important for our audience, for us to maybe firstly, outline the PRAME as a target, and then the ImmTAC as a platform prior to discussing these results. So let's start with the target PRAME, which I think is a target that you know well. So why don't you start with the target and we'll talk a little bit about that and then the platform? Dr. Jason Luke: Yeah, so I think for the audience, being aware of PRAME, or the Preferentially Expressed Antigen in Melanoma, is going to be quite important moving into the future. So PRAME as a therapeutic target is a cancer testis antigen that's overexpressed in tumor tissues. And of course the name has melanoma in it, but it's not uniquely present in melanoma. So the expression patterns of PRAME as a target are very high in melanoma. So in cutaneous disease, this is upwards of almost 100%, somewhere between 95% and 100%, in metastatic melanoma tissues. And PRAME has several different roles on a molecular level, although I don't think for our purposes here, it's so much important to be aware of them, but rather that this is a very highly expressed target, which then can make it attractive for using T cell receptor-based therapies. And so in the case we're talking about here on the ImmTAC platform, that's a CD3 PRAME×CD3 bispecific approach. But of course there are other approaches that can also be taken, such as TCR T cells that directly go after PRAME itself. Dr. Diwakar Davar: Let's now talk about the platform and how it differs from some of the other antigen targeting platforms that you have just alluded to. I think the Immtac platform is basically a fusion protein comprising engineered TCRs with a CD3 specific short chain variable fragment. And then the engineered TCR therefore binds antigens in an HLA dependent fashion. But you know quite a lot about some of these alternative platforms, and I think it'll be important to contextualize for the audience the difference between ImmTAC, which is a prototype drug that is already approved in the context of tebentafusp. But how does this differ from some of the other more nuanced platforms, such as the Immatics TCR or TCR platform and TScan TCRT nanoplasmonic platform.  Dr. Jason Luke: Right. So the ImmTAC platform as alluded to is already approved on the market with tebentafusp, which is the gp100-CD3 bispecific molecule. And the advantage of that approach is infusion off the shelf of a drug. The downside of it is that it is a weekly dosing strategy as it stands now. And there are some complicated disease kinetics associated with treatment response, which we'll come back to in the context of the PRAME bispecific. Those are, in contrast with T-cell receptor-transduced T cells, as an alternative strategy, which is a form of adopted cell transfer. So we just got done talking about TIL therapy, which of course, is trying to take lymphocytes out of the tumor and grow them up and then give them back. Here with TCR-transduced T cells, we're talking about taking leukopak from the blood and then using different transfection approaches to try to insert into the lymphocytes of the patient a T cell receptor that recognizes to a certain cancer antigen, in this case, PRAME.  So you alluded to a couple of different companies that have different platforms to do this. Immatics has a molecule called IMA 203, for which there have been data disclosed in the past year, again showing some very interesting responses in patients who have highly refractory melanoma. That process, though, again, does require lymphodepletion before you reinfuse the cells. Again, in contrast, the ImmTAC, which is an off the shelf revenue administer, there you have to make the product and then bring the patient back, lymphodeplete, and give the cells back. Immatics platform uses a viral transfection vector. The T scan approach that you alluded to before uses an approach of a mixed system on multiple HLA backgrounds to try to get past HLA-A*02:01 only, and in this case, uses a plasmid-based transfection syndrome that perhaps can be more broadly utilized given the lack of a lentiviral vector.   So this is a complicated area of technology that starts to get into immune engineering, and I think for the purposes of this discussion, we don't want to belabor it. But both of these technologies, talking about the CD3 bispecific with the off the shelf aspect of it and the adoptive cell transfer, each of these using a T cell receptor-based therapy to try to go after PRAME, I think have very high upsides, and I think we'll initially see it in melanoma over the next year or so. But this is likely to be relevant to multiple tumor types beyond melanoma.  Dr. Diwakar Davar: So let's discuss the results of this phase 1 trial. IMC-F106C, like all other ImmTAC, is administered intravenously and does require step-up dosing. You alluded to the fact that the tebentafusp was approved, and it's one of those drugs that is fortunately otherwise administered weekly, which can be difficult for the patient and requires at least the patient spend the first 3 doses overnight under some kind of monitoring, whether it's in the hospital or extended outpatient monitoring, for at least 23 hours. The efficacy of this agent and this platform appears to be surprising in that you tend to see a relatively low RECIST response rate. We'll have you comment a little bit on why that is the case and what may be the role of ctDNA, as opposed to conventional RECIST in assessing response.   At least in this trial, they mandated pre-testing, but did not require it for study enrollment. And pre-positivity was defined using immunohistochemistry with a relatively low H-score of 1%. And the molecular response definition was a 0.5 log or a 68% ctDNA reduction just prior to the first imaging assessment. So how do you contextualize the results? But maybe before you talk a little bit about the results, the ctDNA aspect, that was a recent publication by Drs. Rich Carvajal, Alex Shoushtari, and I think you are also involved in that.  Dr. Jason Luke: So, I think an interesting observation around tebentafusp has been that ctDNA may be a better predictor of long-term outcomes. And how you define ctDNA response is still something that the field is grappling with, albeit that I think is going to be an important consideration as we think about these novel therapies, these ImmTACs and other CD3 engagers moving into the future. But for the purposes of the abstract here, we see that in the population of patients treated, there were 46 patients with cutaneous melanoma. The majority got monotherapy with IMC-F106C, and that's the PRAME bispecific. So 40 patients that got monotherapy and six who got a combination with checkpoint inhibitor. All these patients had prior treatment with immunotherapy, and most of them had PD-1 and CTLA-4 antibody with a small spanner that also had BRAF inhibitors.  In terms of that PRAME testing that you alluded to, based on the immunohistochemistry H-score greater than 1%, 35 out of 40 patients were positive, so they defined 5 as negative. And we could come back if we have time, but there are other ways to do PRAME testing as well that I think may become unique for different agents, maybe an important biomarker. In the data, 31 out of the 46 patients were RECIST evaluable. The outcomes of those patients were to note that the response rate was 13%, which was four partial responses. But 35% of patients had tumor regression with a disease control rate at 65%. It was clear that there was an enrichment by PRAME positivity for both progression free and overall survival. So those patients who had obvious positivity essentially had a doubling of the PFS and more than the doubling of the OS, 2.1 to 4.1 months for TFS and landmark OS, 40% to 94%. So I think these are quite intriguing data.  It does suggest that for the vast majority of patients, we do see some induction of the antitumor effect, albeit that RECIST might undercall the effect. And so this may become another area where the ctDNA monitoring might be able to help us to understand who is likely to have really long-term benefit from this therapy. And given the number of emerging treatments that we have for melanoma, we might be able to really focus in on that group of patients in terms of optimizing how we would use this drug moving into the future. Dr. Diwakar Davar: So you talked about a response rate, and at first glance, this response rate is a little underwhelming. We're talking about 4 out of 31 RECIST evaluable patients, 13%. So it's in the double digits, but barely. So how enthusiastic are you about the results? How does it contrast with at least the publicly known data from other brain targeting approaches, such as the IMA203 agent, understanding that while they may be all targeting somewhat the same target, they are actually extraordinarily different platforms. One's off the shelf, one's highly customized. How do you contextualize the results? How would it contrast with other cellular approaches?  Dr. Jason Luke: I think it's important, again, to emphasize the point you made, which is that they're very different kinds of treatments. So even though they both target PRAME, they're going to be differently useful, and they could be quite useful for different groups of patients. And so here we see that there is a subfraction of patients who are deriving long-term benefit. And we commonly have an argument in our field about, is overall response rate really a useful monitor that describes a patient-centric outcome? While, of course, patients like to know their tumors are shrinking, what they want the most is for the tumors not to get worse and for them not to pass away from cancer. So I think I'm enthusiastic about these results, but emphasizing the point that we need to better understand who is going to benefit the most from this CD3 bispecific PRAME approach and how we're going to be able to harness that into long term benefit for patients because there's no doubt that an off the shelf therapy has a high degree of value relative to adoptive cell transfer, which sort of requires a big wind up.   So when you say, what does it contrast with? Well, the data for IMA203 has shown more than a 50% response rate in patients with more than 5 lines of therapy for metastatic disease. That really looks quite exciting. And several of those patients are now out for quite an extended period, meaning 2 years or more given only a single dose of IMA203. But again, the caveat being, you have to make the cell product for the patient, and that takes time. You lymphodeplete the patient, not all patients can tolerate that in the refractory disease setting, and then they have to be able to tolerate the reinfusion of the cells. And so this drug, IMC-F106C, looks very promising. Moving into the earlier phase trial that we'll talk about, I think the TCR T cell program has a lot of upsides for patients, especially with refractory disease. And so I think these two different approaches are really on parallel tracks. They both target PRAME, but I don't think they necessarily need to be compared one to one, as if they're going to go head-to-head with each other. Dr. Diwakar Davar: So now we'll talk a little bit about the frontline setting, because on the basis of some of these results, Immunocore is now exploring IMC-F106C frontline melanoma. This trial is actually being presented as a trial in progress at this meeting by Georgina Long and colleagues. Some of us are co-authors in that abstract. And in this study, HLA-A*02:01 positive patients with advanced unresectable melanoma will be randomized one to one to the combination of IMC-F106C, which actually, I think after this meeting will be known as bre-ni in combination with nivolumab versus nivolumab regimens, which will either be nivo or nivo-rela, investigators choice and likely dependent on region. So what do you think of the challenge of this trial? We talked about some of the challenges of the TILVANCE trial earlier. But what is going to be the challenge of this trial and in this setting, particularly given the response rates that we've seen so far? Dr. Jason Luke: Yeah, so, similar to comments we had before, thinking about what the optimal control arm is for a study like this is difficult, and so that'll be important as we think about interpreting the results. One has to assume for the purpose of this conversation that it is a positive trial, and that adding the PRAME bispecific theory does lead to an improvement in progression free survival relative to those in checkpoint alone approaches. And I think the magnitude of that difference is going to be of some relevance. And then I think importantly, also figure out who needs this treatment and who's going to benefit long term are going to be really important considerations.  We alluded to how this drug requires an intensive dosing period at the get go, and so telling patients that they need to come in weekly or bi-weekly initially for some number of weeks before they switch to a longer-term intermittent regimen, that comes with real world considerations for patients, their families, their finances, etc. So the benefit has to be clearly obvious that makes it worthwhile doing that, again, because a default could be giving drugs that we've had for 10 years with the nivolumab and ipilimumab. So there's going to be a lot of cross-trial comparison that is going to necessarily have to take place here to think about what these results really mean in the context of other available therapies.  I think the study is reasonable to do. I think this is a very active agent. There's no doubt there's a subset of patients who seem to benefit a lot from it. And I would just emphasize the point that that's probably going to be the most important thing to really drill down on is under the assumption there's a positive trial, we need to know who those people are so we could optimize giving this kind of a treatment to them. Dr. Diwakar Davar: I guess one important point to underscore what Jason said about potential predictive biomarkers, I think as part of the presentation, Dr. Hamid and colleagues will be talking about a candidate predictive biomarker of this agent, which is potentially class specific and not necessarily agent specific of a T cell signature that potentially could define patients who are more likely to benefit from this agent.  So, Jason, as always, thank you for sharing your expertise and insights with the team today. We certainly look forward to catching up again for our wrap up episode after the annual meeting where we'll talk about some of the data that we could not talk about, particularly the late breaking abstracts and other key advances that will shape the future of, certainly the field of immunotherapy and melanoma, potentially the field of cancer immunotherapy at large. Dr. Jason Luke: Oh, thanks very much for the opportunity. Dr. Diwakar Davar: And thank you to our listeners today. You'll find the links to the abstracts discussed today 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 podcast. So thank you, and we'll see you soon.   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      

Alien technology (might be fun at parties but probably won't solve anything).  While we're at it, Hostus Maximus Justin Fort revels in the old Party Point ‘Squatch Runs, Justmark's M1A, tales of cohosts like The Jaimz and Dirty Dave, crime versus law and order (and citizens living in an upside-down world that makes the Second Amendment even more important), Uncle Doug's Northstar-powered Caddy versus Dad's Lincoln, and what it means for a tire to actually work in sheddy snowy situations.  There's also a lot of red meat in this episode for Jeep haters, bureaucratic fakers, tire deflators and Eurocrat takers. More more more:  Foghat, Deep Purple, Get Shorty, Dennis Farina and John Travolta, plus Ryan's whiskey, Leslie's Miata and Churchill's quote.

Alien technology (might be fun at parties but probably won't solve anything).  While we're at it, Hostus Maximus Justin Fort revels in the old Party Point ‘Squatch Runs, Justmark's M1A, tales of cohosts like The Jaimz and Dirty Dave, crime versus law and order (and citizens living in an upside-down world that makes the Second Amendment even more important), Uncle Doug's Northstar-powered Caddy versus Dad's Lincoln, and what it means for a tire to actually work in sheddy snowy situations.  There's also a lot of red meat in this episode for Jeep haters, bureaucratic fakers, tire deflators and Eurocrat takers. More more more:  Foghat, Deep Purple, Get Shorty, Dennis Farina and John Travolta, plus Ryan's whiskey, Leslie's Miata and Churchill's quote.

So much junk in this trunk… Zippos and hippos and chrome-plated nipples, plus a fancy Luftkraft shift knob cohost PK Caleb (ala EAS) bought for the Porsche he hasn't yet.  Hostus Maximus Justin Fort's reports from the Tanner Gun Show illuminated more than overprices ammo (unless you're willing to bundle bullets) - yes, used and new pew-pews are starting to act affordably again (so don't sit on your hands).  He also picked up a neato flexy Bad Ass (straight out'a Texas) IWB holster for one of the compacts, which iridium 192-soaked cohost Isotope of Mark immediatedly coveted, but he managed to slake his thirst with a scouterized M1A he built for why nots…  Hey, it's the Garage Hour - because why not is why enough. Whyle we're at it:  proprietary Japanese rounds, the NRA has been DeWayned (probably should'a mentioned that sooner), Norma's making a .22LR that'll drop squirrels at 500 yards, and shotguns for Caleb, R.L.O. Custom Leather for Mark and risotto for Justin.  Hell yes, we're awesome.

So much junk in this trunk… Zippos and hippos and chrome-plated nipples, plus a fancy Luftkraft shift knob cohost PK Caleb (ala EAS) bought for the Porsche he hasn't yet.  Hostus Maximus Justin Fort's reports from the Tanner Gun Show illuminated more than overprices ammo (unless you're willing to bundle bullets) - yes, used and new pew-pews are starting to act affordably again (so don't sit on your hands).  He also picked up a neato flexy Bad Ass (straight out'a Texas) IWB holster for one of the compacts, which iridium 192-soaked cohost Isotope of Mark immediatedly coveted, but he managed to slake his thirst with a scouterized M1A he built for why nots…  Hey, it's the Garage Hour - because why not is why enough. Whyle we're at it:  proprietary Japanese rounds, the NRA has been DeWayned (probably should'a mentioned that sooner), Norma's making a .22LR that'll drop squirrels at 500 yards, and shotguns for Caleb, R.L.O. Custom Leather for Mark and risotto for Justin.  Hell yes, we're awesome.

Episode Summary This week on Live Like the World is Dying, we have a short story about prepping called "Blood, Soil, & Frozen TV Dinners" by Matthew Dougal. It's a parody about two right-wing preppers who are faced with a collapse in society. After the story, there's an interview with the author about prepping mentalities and writing. This episode was reposted from the Strangers in a Tangled Wilderness podcast. The story can be read at tangledwilderness.org. Host Info Inmn can be found on Instagram @shadowtail.artificery Reader The Reader is Bea Flowers. If you would like to hear Bea narrate other things, or would like to get them to read things for you check them out at https://voicebea.wixsite.com/website Publisher Info This show is published by Strangers in A Tangled Wilderness. We can be found at www.tangledwilderness.org, or on Twitter @TangledWild and Instagram @Tangled_Wilderness. You can support the show on Patreon at www.patreon.com/strangersinatangledwilderness. Theme music The theme song was written and performed by Margaret Killjoy. You can find her at http://birdsbeforethestorm.net or on twitter @magpiekilljoy Transcript Live Like the World is Dying: “Blood, Soil, & Frozen TV Dinners” with Matthew Dougal **Inmn ** 00:16  Hello, and welcome to Live Like the World is Dying, your podcast for what feels like the end times. I'm your host today, Inmn Neruin, and today we have something a little different. I host another podcast called Strangers in a Tangled Wilderness where every month we take a zine that Strangers puts out and turn it into an audio feature and do an interview with the author. We had a two-part feature called Blood, Soil, and Frozen TV Dinners by Matthew Dougal, and it is a short story about prepping from a very strange perspective, that of two right-wing preppers facing a mysterious collapse of society. This short story is a parody and I promise that the two main pov characters are not the heroes of the tale. It's a fun story and I do an interview with Matthew afterward about prepping mentalities, fiction, and other neat stuff. If you like this episode, check out my other podcast that this is featured from. I did not re-record the outro, so you'll get a little taste of Margaret playing the piano, because she wrote the theme music for the Strangers podcast. You'll also get to hear our wonderful reader, Bea Flowers narrate the story. Follow along with the transcript or at Tangledwilderness.org where you can read all of our featured zines for free. But before all of that, we are a member of the Channel Zero Network of anarchist podcasts and here's a jingle from another show on that network.  [sings a simple melody] **Bea ** 02:49 “Blood, Soil, & Frozen TV Dinners” by Matthew Dougal. Read by Bea Flowers. Published by Strangers in a Tangled Wilderness.  Katie sat, wide-eyed, beneath the kitchen table and hugged her knees to her chest. She was shaking, vibrating visibly. Tanner put his finger to his lips and prayed that her silent tears would remain just that. There was no time to stop and calm her down. Not again. He moved slowly around the kitchen, fumbling through cupboards and pulling out pre-wrapped packages of food. Always be prepared. Tanner had practiced this before things went dark, but it was different doing it for real. His hands hadn't been so shaky, back then.  A noise, on the porch. His body froze before his mind registered the sound. Tanner dropped into a crouch and crossed the room to the window, willing every cell in his body to radiate confidence toward his baby girl. His hand found the Glock 17 at his belt and he brought it up in front of him, the familiar feel of the grip reassuring. He took a breath, steadied himself, and raised his eyes to the level of the windowsill. The muscles in his thighs steeled and he remained, unblinking, utterly still, staring out into the darkness.  After thirty or forty nerve-twanging seconds, Tanner drew breath and relaxed. His quads were burning, and they thanked him as he straightened. He could hear the specter of his ex-wife in his head, telling him to lose some weight, exercise more… Well she'd left, and that was 135 pounds gone right there. She'd probably say that was a good start.   An unbearably loud ringing pierced the silence and sent him diving to the floor, landing awkwardly on his gun and sounding a crash through the kitchen. A keening whine came from under the table, Katie shaken from her silence.  The doorbell.  Feeling foolish, Tanner twisted over his shoulder and hissed at his daughter to be quiet. Still prone, he crawled toward the hallway in the most reassuring manner he could manage and pointed his Glock at the front door.  Footsteps outside, then a shadow appeared at the window. Tanner's heart pounded in his ears—more violent pulses of silence than sound—and his vision blurred as panic flooded his body. He'd heard the early reports of armed groups in the streets, some sort of fighting downtown, but he hadn't really believed they would come here. His legs were weak, and he silently thanked God that he was already on the floor. The shape at the window didn't move, frozen in the gloom, silhouetted by flickering light coming from the street. As Tanner's head cleared he tried to take stock of what was happening.  The apparition was vaguely man-shaped but shorter and slighter, an ethereal grace evident even in its stillness. A voice called out, muffled through the door, the guttural singsong completely at odds with the sleek form at the window. Tanner couldn't understand everything, but he thought he caught the words “little girl.” A second shape mounted the porch alongside the first, similarly short but squat and stocky, and grunted something to its companion in an alien tongue. Fluorescent light flooded the yard and the voices momentarily disappeared beneath the growl of an angry engine. Tanner's breath caught. His trembling finger hovered over the trigger and he willed the barrel to still its swaying dance. Two shots exploded outside—loud shots, from a much bigger gun than his. The creatures spun to face this new threat, their chatter rising in pitch and speed. They sounded panicked.  “yalla! hawula' alnaas majnoon.” Tanner sensed his opportunity. He was forgotten. All those hours of training kicked in and muscle memory took over as he rose to one knee, took a two-handed grip, and unleashed a furious hail of fire at his front door.  “Keep your filthy hands off my daughter!” He fired until he felt the Glock stop kicking, the magazine spent. As the cacophony faded he realized he was screaming.  “Tanner! It's me, Blake. Stop shooting goddammit, they're gone.”  “Blake?” Tanner mechanically reloaded his gun. “Why…” His throat was raw, his voice barely audible even to him. He swallowed, fighting to control his breath, and cleared his throat. “What are you doing here?”  “Come to see if you were okay. Figured you and the kid might need a hand.”  A stocky, heavily muscled figure wearing fatigues and a plate carrier stepped up to the porch, visible through the splintered ruins that had been the front door. A halogen glow lanced through the holes, like the brilliant aura of some kind of avenging eagle.  “When this shit spread across the river from the city we locked down. It was touch-and-go for a while, but things quieted down eventually. When they did, I came straight over. Good thing I got here when I did. The quick little fuckers ran for it, but I think you hit one of ‘em.”  The figure stopped, pulled down the red, white and blue bandana covering its mouth, and spat. Tanner had never been more relieved to see his buddy's foul-mouthed face. Or his M1A SOCOM 16 rifle.  “We're alright.” Tanner's voice was exhausted, his body shivering as the adrenaline fled. “Thank God I was prepared. Still, it's good to see you.”  “Prepared, shit.” His buddy grinned. “I been telling you for years to get something heavy duty.” Blake kicked the splintered remains of the door and his grin faded. “You can't stay here. Those things'll be back. Grab your girl and jump in the truck. Let's head to mine, she'll be safe there.” The grin returned.“Prepared, shit.”  An hour later they were sitting in “the Hole,” as Blake affectionately called it. The Hole was both name and description, although it perhaps undersold the amount of effort that had gone into its construction. Attached to the garage by a short, downward-sloping corridor, The Hole was a full-blown bunker that spread underneath almost the entirety of Blake's backyard. Tanner was sitting in the main chamber eating Top Ramen, chicken flavor.  They had made the half-mile journey in silence—lights down on the Tacoma, Tanner jumpy, Blake grim, Katie in a state of shock. The streets had looked completely foreign, the usual calming glow of LEDs replaced by the orange flicker of scattered flames. The familiar hum of traffic had been gone. Instead, gunfire had cracked in the distance.  Blake's wife Lauren had buzzed them inside after Blake confirmed his identity via video feed—three times: at the gate, the door, and the entrance to the Hole. The security was impressive. Lauren had ushered them inside, AR-15 at the ready. “This is prepared,” Blake was saying, as Katie stared blankly at her untouched ramen. “Old owners, they had this backyard full of fruit trees, vegetables, fuckin' kale and kohlrabi. What good is that gonna do, I said, you gonna hide in the pumpkin patch with a slingshot? Idiots.  “Anyhow me and Lauren, we wanted to be ready, so I been building this the last two years. Ain't no one knows about it, not even the contractors…” Blake sliced a finger across his throat, then laughed, “I'm joking, but they were from one of them Mexican countries. Had no idea what they were building. Good workers, though, came here the right way. And I did the security all myself.”  Tanner laughed too, but at what he didn't quite know. “You took this all real serious.”  “Yessir. You never really believed, but we did. Earl Swanson was right, this here's been a long time coming. It's just like he said, and we listened. And here we are, while you was laying on the floor waving round that little waterpistol of yours.”  Tanner had listened too, but apparently not well enough. There was only so much time he could watch an angry man on TV shouting about the state of the nation, no matter how prophetic he was turning out to be. Tanner tried to put up a strong front and flex his knowledge. He had listened, dammit.  “Is this it, then? The invasion? Earl said they've been preparing it for years, brainwashing people. Recruiting sympathizers and traitors…”  “It's worse than that. The invasion started way back, we just didn't notice. Well, most of us didn't. Earl did. He tried to warn us, that the aliens'd started infiltrating, landing in remote parts of the country, blending in, looking just like us…” Blake spat. “Well, not quite like us. But close e-fucking-nough, hiding out and biding their time.” “And now it's out in the open…” Tanner looked from his friend's face to his daughter's, scared and staring, and trailed off. He may have been listening, but he sure as hell didn't understand.  “What's happening?” Tanner asked. “We've been laying low at home, locked down and trying to wait out whatever this is. We haven't heard a thing since the power cut out three days back.”  He could feel a surge of emotion building, pent-up adrenaline and stress and fear and loneliness rolling over him in a wave as they were released. His stoicism wobbled.  “We're… Katie's scared and confused, and tired and sick of hiding and we're all alone! What is all this? What's happening?” Tanner realized he was shouting and stopped, taking a deep breath and lowering his voice. “Blake, man, what the hell is going on?” Blake never flinched, just ran his tongue over his teeth in thought while he watched Tanner's outburst through hooded eyes. “Naw, we don't know nothing for sure. Swanson's been off-air for two days, since just after shit started going down. Said he was right, that it sure as shit seemed like those aliens he'd been warning us about were making a move, and the whole fuckin' lot of us did nothing. Well, seems like it blew up in our face. Last thing he said was he's heading somewhere safe to keep broadcasting, and he'd let us know when he found out more,” Blake paused, sucked his teeth, “We've had the TV and radio on non-stop since then, since we fired the generator up. Nothing.”  Lauren lent forward. “There was something, couple days back…”  “Nothing useful,” Blake cut in. He spat. “Same old fuckin' commie stations, same old crap. They took over the channels, emergency broadcasting. Said there was a ‘protest.' Stay inside, all under control, daddy government's here, blah blah,” he laughed “Hell of a protest. More like an insurrection. Doublespeak bullshit.”  “So what's the plan? We hide out? Lay low? Wait for the military?”  “The troops ain't coming, chief.” Blake grimaced, “Alien tentacles go deep. Probably strolling around in general's stars by now, the politicians just handing over the keys. This President'll have us kissing their feet before dinner.  “Nah, if we wanna fight back we can't rely on that fuckin' bunch of secretaries and scribes. We hole up here, wait for instructions.” He laughed again, “Huh, hole up in the Hole. That's funny.”  That grin was starting to get on Tanner's nerves. “Instructions from who? How long is that gonna take? Who's gonna fight back against… this?” “I know some people, from back in the old days. Good people. There's still patriots out there who won't give up this country without a fight.”   Tanner still bristled with questions, but he was starting to feel relieved. There were people in charge, and they had a plan. That was something he could work with. “What if it takes weeks? Months? Do we have food for that long?” Blake settled further into his chair, grinned that cocky grin. “I do, don't know about you.” Before the words were even out of his mouth he was already raising his palms, “Chill out, I'm joking. I'll put it on your tab. You're a lawyer, I know you're good for it. Show him, babe.”  Lauren got up and went over to a large yellow flag hanging on the concrete wall, pulling it aside to reveal a long, narrow room that ended abruptly at a large steel door. She flicked on the light.  “Dry storage,” she said, gesturing at the shelves lining both walls. Packets of ramen, boxes of cereal, rows of whiskey, and gleaming stacks of cans stared down at Tanner. “And cold storage,” Lauren continued as she stepped over to the door, kicking aside two enormous tubs of supplements and pulling it open to reveal a walk-in freezer. Tanner followed her inside as she happily chatted away, showing everything off like a house-proud hen.  “We've got everything we need. Steaks, hotdogs, chili, hamburgers, mac and cheese, chicken parmesan, mashed potatoes--whatever you want. There's a well, too, over the other side, we had that dug last summer. Tastes a bit funny, but it won't hurt you.” Tanner was hardly listening. He had never seen anything like it, never imagined anything on this scale. Blake really had taken preparing for the end of the world seriously. The freezer room was filled, wall to wall, with a treasure trove of gourmet excess; thousands upon thousands of frozen TV dinners.  Tanner stared at his microwaved salmon filet, fries drooping from his fork. Out of habit he was eating in front of the TV with Katie, though the display hadn't changed in… however many days it had been. Just the red, white and blue logo, a tile flipping between ads for pillows, brain pills, and frozen food, and the same scrolling red banner:  Breaking: The United States of America is under attack. Stand by for updates.  Katie was poking at her food silently, barely eating. Still no appetite. Tanner had told her they were safe, told her he wasn't going to let anyone hurt her, told her a hundred times in different ways that she was his precious little girl and he would make sure she was okay. It had made no difference. She had just looked up at him with big, frightened eyes that pulled at Tanner's heart. The only time she had spoken in the past 24 hours was to ask why he had tried to shoot people. Of course she didn't understand. Maybe he should ask Lauren to talk to her.  The TV display glitched, blipped, flicked to static and then to black. Tanner shoveled the fries into his mouth and rubbed his eyes. He'd been staring at a blank TV for too long. He chewed and stretched, squeezing his eyes shut and trying to straighten out his aching back.  Earl Swanson was on TV. Tanner blinked a few times to make sure he was seeing straight. Swanson's shirt was wrinkled, his hair a mess and his signature bowtie slightly crooked, but his face wore that familiar expression of righteously indignant bewilderment. It was him.  “Blake. Blake, get in here!”  Swanson was in what looked like a large living room rather than his usual studio. Bookshelves and a TV cabinet were visible behind him. There were shadows under his eyes and his wrinkles were clearly visible without his usual TV makeup, but his eyes were as sharp as ever. There was a strength to them, piercing the screen, full of faith and fire. It felt like he was in the room. He looked like he'd been in a fight, and won. He was back.  “Good evening America, and welcome to Earl Swanson Tonight.” “Blake!” Blake stuck his head through the door.  “What? I'm working out, give me a…. No shit.” Blake stepped into the room. He was topless, breathing heavily. His stomach was shiny with sweat, pooling and running down the chiseled channels between his well-defined muscles before disappearing behind the low-riding waistband of his camo pants. Tanner realized he was staring and felt his cheeks flush as he snapped his eyes back to his friend's.  “Blake, it's--” “Shut up, I'm trying to listen.” The rebuke slapped Tanner back to the present and back to the TV. He surreptitiously sat a little straighter and sucked in his gut, trying to ignore the heat rising in his face. “...cities up and down the west coast. From Seattle to San Diego, the alien invaders and the traitors from among our own citizens have taken control, sowing chaos and destruction. Order has broken down, and anarchy rules in the streets. Yet we hear nothing but silence from the White House. The elites in Washington won't do anything about this -- they encouraged it. They caused it! “No, it is up to patriotic Americans to stop this existential threat. It is up to us, to you and me and the other patriots out there. If you value the American way of life, if you respect the principles that built the greatest nation ever imagined, if you care about your family and the future of your children, then the time has come to stand up. Your country needs you.  “I have been warning about this day on this very program for years. If you have been listening, you will be prepared for this betrayal. You know what to do. Find other true Americans who are ready to fight for our civilization and our culture. Defend our Western values against this attack by anarchists and aliens who wish to destroy us. They tried to take our guns from us, to disarm us, and failed -- now is the time to use them. Seek out the prepared, the militias, the heroes. Fight back. Show them that we will not allow it. “I will be moving to an undisclosed safe location so I can keep you informed. You know your job. I am doing my part, will you do yours?” Swanson sat erect and defiant, no less commanding for his disheveled appearance. His willpower flowed from the screen in waves, washing over the watchers. It was compelling. It was urgent. It was the only option.  The screen went black.  Swanson's gaze bored into Tanner long after the TV went dark, burning with righteous fire, lip curling with fury. The heat in Tanner's cheeks sharpened, focused, began to spread into his chest and throughout his body. There was only one thought in his mind. “We gotta go.” It took him a second to realize that Blake had spoken the words out loud.  “We do. But where? I don't know anyone like that.” “You know me, and I know people. Don't worry about that. We gotta go to Baker City. I talked to one of my buddies from the marines this morning, he's headed to join one of the militias out east. They might not be big, but they're hard. They're something.” Tanner looked at Blake blankly, unable to quite comprehend what he was being told. Days of no news, no action, now everything all at once.  “But what's in Baker City? Don't you know anyone here? This is where we live, where we have the Hole, where we have a safe base.”  Blake was clearly agitated, shifting from foot to foot.  “It's not safe. Weren't you listening? It's fallen. The military ain't doing jack, like I fuckin' told you they wouldn't.” Blake stopped bouncing and steadied himself. “But my buddy said the boys in Baker held out. It was bloody, but they held strong. If we can get there in a hurry, we can join a caravan heading for Boise.”  “Baker… Boise? What the… Boise?! Surely it's safer in Texas, or… or…”  “Texas? And how far away is that? Look, I don't know nothing about nothing, but I know I ain't looking for safer. All I know is I got buddies in Baker, and they say Boise, and they are the fuckin' resistance. We got our orders, soldier. “The west had been invaded. Destroyed. Gone. You heard Swanson, same as me. Grids are down, water's down, TV's down--mostly, anyway. Sky's half full of fire and smoke, gangs roaming the streets, traitors and aliens taking or breaking whatever they can get their thieving hands on.” Tears came to Blake's eyes.  “It's a fucking mess out there, buddy. Anarchy. They've burned the lot.” It was a lot to chew on. Tanner put a piece of salmon in his mouth.  “I'm not gonna let some filthy aliens take my home, fuck my wife, invade my country, and steal the god damn US of A! The fight is right there, and I'm gonna fight it. Are you?”  Tanner's brain was spinning, but his blood was still hot from Swanson's speech. Blake's fire, delivered standing there half-naked like a Steven Seagal action figure, was rousing something inside him. His country needed him, and he felt the call in his bones. He put down his fork. He swallowed. He rose.  “Of course I'll fight. I'll put a bullet in every alien who steps foot on American soil. I'll put every collaborator in the dirt.” He saw himself, next to Blake, riding shotgun as they made a fighting escape through the streets. He saw a heroic journey to Baker City, filled with danger and righteous violence. He saw a triumphant return, at the head of an army, cleansing his city with purifying flame. And he saw Katie, small and fragile and beautiful. Perfect, and terrified. The flame wavered.  “But I'm fighting for her,” Tanner gestured, “I got my little girl, and I'm not so red-hot on riding out guns blazing to meet these savages with her hanging off my arm. She's the future of this country, and that's a future we have to protect.”  To Tanner's surprise, Blake took a half step back.  “Shit. I know, man. Katie and Lauren, the innocent and the pure. I'm thinking of them, too.” He dropped his shoulders, but held Tanner's gaze. “But it's not safe for them here neither. We're on our own, and all hell has broken loose up top. We fight for them, and they are the reason we have to fight.” Tanner paused, then nodded. He reached out and placed his hand on his friend's shoulder, fingers gripping the sweaty skin.  “Let's go pack the truck.”  As the sun set and twilight brought a low fog creeping across the city, they piled into the Tacoma with as many frozen dinners as they could carry.  Tanner rode in back. Lauren was up front, AR at the ready, while Blake drove, M1A by his side and his Glock taped to the dash. Katie was at Tanner's side, curled up below the window and hidden from view, and Tanner watched over her with his own Glock and a borrowed Remington 870. They were all a little jumpy. He and Lauren had wanted to maintain a shoot-on-sight policy. Blake had been more cautious. According to Swanson, there would be plenty of people collaborating with the aliens. Lights out, engine low, and hopefully they could slip right on by.  No one knew what to expect—Tanner suspected they were all terrified. He certainly was. Even Blake had swapped out his flag bandana for a more understated camo print. He had stashed the red, white and blue fabric in the bed of the truck with the rest of their gear.     They pulled out into streets Tanner knew, but didn't. He had driven them every day, on the way to work, to Katie's school, to church, to the mall. The streets were as familiar as a cold Coke, yet now, in some important way, they were… different. As they left the Hole and drove through the suburb he couldn't quite put his finger on it, but once Blake reached the main street and turned past the bars and shops and take-out joints, it hit him.  The streets were dead. The cars were gone. The steady flow of traffic, of people living their lives, had stopped. The parking lot in front of the drug store was empty; so was the one behind the bar. The convenience store, normally ticking over with a steady stream of customers buying cigarettes and beer, was dark behind its windows. Unintelligible graffiti in some alien script covered the ads for energy drinks, an expression of mindless violence across someone's hard work.  A light rain had started, misting around them and adding to the dreariness. A billboard loomed overhead, the lights that illuminated the Colgate-bright smiles of the models now permanently dark. Tanner was glad—the gloom obscured the flame-scarred destruction streaking the toothpaste company's perfect white message. “Disgusting,” Blake spat. He looked like he wanted to say more but pulled up short, shocked at the sudden sound of his own voice. His eyes focused back on the road and he fell into uneasy silence. The truck continued its crawl down the deserted street, barely clocking 20 miles an hour. Even at that speed, the low growl of the engine seemed unbearably loud as it reverberated among the carcasses of commerce and ricocheted down abandoned side streets.  They kept driving, and nothing kept happening. It was torturous. Every minute of unbroken inactivity twisted the crank on the tension in the car, until the unceasing hum of the engine began to seep into Tanner's brain. Every muscle in his arms and legs, primed and waiting and ready to spring, began to tremble, and his eyes focused and unfocused on nothing at all.  His frantic heartbeat messed with his breathing, a powerful panicked thud that matched the rumble of the pistons.  Overall, he was relieved when the road curved and they entered a strip of restaurants to see signs of life among the debris littered across the street in the distance.  It wasn't immediately clear through the gloom what was happening. Blake slowed the truck, now rolling along at barely more than walking pace, and they crept closer. The scene was illuminated by the flickering light of small fires and backlit by a pair of enormous floodlights, creating a glowing aura in the surrounding mist. Images began to resolve, ghostly figures flitting in and out of view and the harsh geometric shapes—not of debris, but of hastily manufactured barricades—throwing long shadows that lanced through the air around them as they approached.  All eyes were fixed on the barricades as they pulled within shouting distance, and Tanner nearly pissed himself when someone knocked on his window. He yelped, Blake swore, and Lauren's weapon x-rayed Tanner's head and pointed at the intruder. Tanner followed her lead and jerked his gun up to aim in the general direction of the window and for ten, twenty heartbeats nothing moved. Then another knock, and Blake hissed at them: “Put those things away you idiots, we're the good guys here. Whatever side that guy is on, so are we.”  Tanner slowly lowered the gun, then the window.  “Hey folks, no cars through here.” The man was clad head to toe in black—black jeans, black hoodie, black gloves, black bandana covering his face, black curly hair running with rainwater. No wonder they hadn't seen him. The stranger spotted their guns.  “Oh, nothing like that,” he added, catching the nervous energy in the truck, “You're a bit late to the party. No trouble ‘round here, this area's been cleaned out for days.” He chuckled, sending a shiver through Tanner.  “Some folks messed up the cop shop a while back, it was a bit of a fight. Streets were all blocked up anyway, so we set up a little kitchen here. Been feeding some folks. Symbolic, like, new world in the ruin of the old and all that.” The smile fell from his face as he took in the scene in the truck.  “Everything alright? Is she okay?”  He gestured at Katie, curled up and quivering silently beside Tanner. Tanner opened his mouth to respond, but Blake was quicker. “Sure, probably just spooked by that fucking mask. Look, we don't mean to bother you people. Just heading east, trying to cross the river. We'll go around you and your little kitchen.”  If the man took issue with Blake's tone, it didn't show.  “Bridge is a no-go, I'm afraid. Pigs blew the cables as they pulled out, some of it collapsed. It's way too unstable to cross.” He scratched at his temple. “What d'you want out that way, anyway? There's dangerous people out there, not exactly safe for… families.”  “We're heading for, uh, Hood River,” Tanner spoke up, “Taking supplies out to the girl's grandparents.”  “Indians,” Blake chimed in, “they need the help.” He winked at Tanner.  The stranger turned to Blake and met his eyes, holding his gaze for an unnerving moment. Then he seemed to resolve some internal discussion, relaxing his shoulders. “Well, you might be able to get across up St. Johns, last I heard the bridge was still intact. There's some folks in the park up there, you can ask them.”  “St. Johns? That's the wrong fucking way!”  “A bridge is a bridge. It's that or swim, champ.” “Can you at least call the, uh, your boss? Tell him you checked us out, ask if we can get across?”  The man smiled, but something hardened behind his eyes.  “My boss? Sure, sure. Look, I think it's time you moved on. Head on up there and tell ‘em what you told me, they'll let you out. There's a bunch of poor Indians waiting for their dinner.”  There was something strange about the way the man said “Indians,” but he patted the hood of the truck and turned away, waving them down a side street away from the barricade. As Blake slowly drove off, Tanner collapsed back into his seat and quickly rolled up the window. His underarms were cold with sweat, and he relaxed muscles he hadn't known were clenched.  Blake took the turn the stranger indicated, muttering that if he heard anyone say “folks” again he would hit them. Tanner stared out the window at the “little kitchen” as they passed. There must have been a couple hundred people, milling around a dozen or so small fires. They were all loosely centered around a large tent directly in front of the scorched skeleton of the precinct. Laughter and music drifted through the open window, and Tanner closed it. He didn't think he could see any aliens, but it was difficult to tell in the dark.  “Collaborators. Must be a ration station or something,” he muttered, mostly to himself.  Lauren heard him. “No, this has been going on much longer than that, it just wasn't so out in the open. Swanson warned us about it. He said they lure hungry people in with food.”  “Yeah,” cut in Blake, “this is how they recruit ‘em. Set up a kitchen, give ‘em food, homeless and crackheads and queers, mostly. Drugs too, probably, and spewing their propaganda. That guy was probably one of the junkies. Sure as shit looked like it, you see the way he stared at me?”  Tanner shuddered. A junkie. He had an overwhelming urge to wash his hands. He remembered the way the man had talked about the police station, his manic laugh in the face of such violence, and glanced back at the quickly fading light. And saw a small figure, tottering at the edge of the firelight. A child.  “Disgusting,” he said out loud.  “Yeah, disgusting. It's like Earl said,” Blake continued, “they been feeding people right under our fucking noses.”  They drove on toward the bridge. The streets were more cluttered here, both with people and the remnants of the riots, and they could only manage a slow pace as they picked their way through the destruction. Blake had to swerve to the wrong side of the road to avoid a group of people carrying trash bags, picking through the rubble.  “Looking for something to eat,” he grunted, and locked the doors.  Signs of violence were everywhere. Tanner's chest tightened as they drove past the law firm where he had started his career—the job that had brought him to the city after he finished college, working for his father's best friend and learning his profession. Inside the shattered windows it was nothing but a shell, the desks overturned and the computers gone. No one would be working there any more.  The destruction was completely random. Violence for its own sake. Beside the firm was a pawn shop, covered in graffiti and looted. Next to that, a Vietnamese restaurant, completely unharmed except for ‘Delicious, 5 stars' sprayed on the pavement outside. Across the road was an untouched convenience store and a bookshop with its doors wide open, light flooding out and people crowding the entrance. A donut shop and an Apple store destroyed, a mechanic and a bar looking like they had simply closed for the night. There was absolutely no pattern or reason to it.  They saw a Fred Meyers with every window broken, the front door jammed open with a twisted shopping cart. A movement caught Tanner's eye and he saw someone leaving from a side door, carrying a huge bag of stolen food. He hoped Blake didn't see—he might do something stupid, and Tanner didn't want to stop. It wasn't safe.  They made it a few more blocks when Lauren gasped and grabbed Blake's arm, making him brake. She gestured across the intersection to a KFC. Half the building had collapsed in what must have been an enormous fire; the half that still stood had been savagely attacked. She pointed to the entrance with a shaking finger. Someone—or something—had toppled the giant bucket sign and sent it crashing through the ceiling of the kitchen. Above the door, someone had scrawled a message in red spray paint:  FUCK YOU SANDERS OUR SECRET SPICES NOW There were more barricades set up near the bridge. Where the others had been makeshift, marking a boundary, these were more serious. They were to stop people getting through. Blake slowed before they got too close to the blockade, which they could now see was lined by shapes that very much suggested people. On both sides of the road the land fell away into darkness, sloping down to become a park that ran beneath the bridge.  The park itself, a rare green space normally dotted with dog walkers and children, was transformed. The once-quiet lawns were a mass of tents and makeshift structures, stages and bars and sound systems, the proud trees now decked out with effigies and lights. Fires burned everywhere, and the distant space was carpeted with a swarming mass of humanity, undulating to a throbbing cacophony of noise.  “This doesn't look good,” said Blake. He pulled over, a hundred yards or so short of the bridge.  “That guy said they would let us through,” said Tanner, “if we stick to our story.”  “He was a junkie,” scoffed Lauren.  “But he thought we were working with them,” said Tanner, “he had no reason to lie to us.”  “I guess it's worth a try. Anyway, they ain't gonna try anything against this much firepower.” Blake grunted. “Too late to change our minds now. They've seen us.”  He nodded at the barricade, where two shapes had detached from the mass. They moved toward the Tacoma, and Blake responded by flicking the lights to high beam and heading to meet them. As Blake swung back out into the road the beams cut through the darkness to illuminate the figures, throwing wild shadows from the two shapes until the truck steadied course and they coalesced into recognisable forms. One was a large man, white, with a nose ring and a loosely-tied blond ponytail. He was wearing a plaid shirt and carrying a large rifle. The other—Tanner's throat caught—the other looked like one of the aliens.  “Shit,” said Blake, as the headlights picked out at least half a dozen more shapes along the barricade, several with big guns visible. “Fuck.” He stopped the truck and rolled down the window, then cursed again and threw open the door.  “I'll be fucked if I'm gonna sit here and be pulled over like some criminal. Tanner, you're with me—let's go meet them man to man.” Tanner scrabbled for the door handle and chased after Blake, half-skipping to catch up. They pulled up a few paces before colliding with the approaching party. The blond man stepped forward.  “How's it going, dude?” he said.  “We need to get to Hood River,” said Blake, “we're trying—” “Yeah, we heard.” The man cut him off. “Bridge is closed to traffic, unfortunately. You wanna cross, you'll have to walk.”  Blake bristled. “Are you joking? We need to bring all this stuff. It's… important,” he objected. “You can't just keep people here!”  “We could,” said the blond man, calmly. He sounded confident in his assertion. Looking at the line of men—and women, Tanner realized—standing along the barricade, he agreed.  “But we're not,” the man continued. “You can go wherever you want. Take your shit, cross the bridge. Some folks have organized buses up the river, they'll take you. But the truck stays.”  “But that's my fucking truck!” Blake squealed. The man's eyebrows shot up and Tanner laid a hand on Blake's shoulder, squeezing it and hoping he got the message. The stranger paused, then sighed.  “Look, I'm sorry dude. I love my truck, too. But there was an attack at another camp last night by these so-called freedom fighters,” he grimaced. “Militia wackjobs, really. Word is they are gathering across the river, and we can't risk weapons and vehicles falling into the wrong hands. Especially not an arsenal like you folks got here.”  The alien stepped forward and, much to Tanner's surprise, spoke in perfect American English.  “Don't worry, it'll be here when you get back. We'll take real good care of it for you. They will appreciate the help guarding the buses and I'm sure they'll be more than happy to help you move these… important supplies.”  They signaled to the group at the barricade and two more figures made their way into the light of the truck's high beams. The first was a slim Black man in fatigues, wearing a red beret at a jaunty angle and carrying a AR-style rifle in one hand. The other was a woman, tall and imposing. She wore a leather jacket over a long black dress, which was slit to the thigh to reveal hints of slim, bare legs that stretched from the pavement to the heavens. Tanner blinked rapidly and swallowed. He had always had a soft spot for long legs in thigh-slit dresses.  As they came closer the man nodded at Tanner and Blake, but he was not what held their attention. The woman with the legs from God was also rocking a luxurious mustache that would have put Teddy Roosevelt to shame. As Tanner's eyes bulged, she caught his gaze and winked.  “Hello, boys. I'm Sunshine, they/them. I'll be with you on the bus.”  Tanner didn't know how to react. A fuzzy memory bounced around in the back of his head. “An investigation on college campuses found that increasing numbers of American citizens are using pronouns.” Earl's bewildered face frowned, then puckered. “These ‘theys' and ‘thems' are making a mockery of the American tradition, seeking to spread their insidious ideology among good, hard-working citizens, brainwashing young Americans into adopting these ‘pronouns.' What's next, people identifying a different age? A different race? We need to speak out against this perverse trend and most importantly, keep them away from our children.” _ That was it. These were the pronouns Swanson had warned them about. He gripped his gun and glanced at Blake, trying to get his mental footing.  Blake looked shocked, too, but quickly pulled himself together. He threw Tanner a sly look, one that hinted at an idea. “Give us a minute,” he snapped, and pulled away from Tanner, back to the truck. When they were both inside he turned on the occupants with a spark in his eyes.  “They must be talking about my boys, alive and kicking,” the old grin was back, his excitement barely contained. “Must have set up in the woods. We'll head over and find ‘em. Maybe they got word from Earl. If they're here, and they're fighting, maybe we don't have to go all the way to Boise after all.” “What's going on?” Lauren looked confused.  “We're leaving the truck. Grab the shit, cross the bridge, hijack their fucking commie-wagon and strike out east. Either we find them in Baker, or our boys find us first.”  Tanner was still coming to grips with the situation. “What about… them?” he said.  “Who?” “They… them. In the dress, with the pronouns!”  “And what are they going to do, stop us? You ever tried to fight wearing something like that? No. The four of us, across the bridge, grab the bus, easy.” “Katie's not hijacking any bus. She's eight, for God's sake. Maybe she and Lauren should stay here…”  “You stay here with Katie,” Lauren snapped, cutting Tanner off. “If you think it's safer, if you're looking for safer, you take her for a nice walk in the park down there. I'll be with my husband, taking my country back from these freaks.”  “I know you want to keep Katie safe,” Blake added, almost apologetically, “but you saw what it's like out there. You heard Swanson's warnings. These aren't people, they're animals, aliens. She's your baby fuckin' girl, man. You do what you're at peace with, but my wife sure as shit ain't staying here to get felt up by some dick in a dress.”  Tanner looked at Lauren. “But she's just a kid! What if she gets hurt.”  “What if she gets hurt _here? So you look after her. Be a man,” Lauren spat back.    Blake clapped Tanner on the shoulder and held his gaze. “It's do or die time, soldier. Let's get the fuck outta here, hook up with the resistance, then bring back the fury of God and freedom and the USA to take back this city and liberate my God damn truck!” Tanner looked at Katie, curled up in the footwell, and wanted to object. He wanted to take her somewhere safe, back to the Hole, where it was warm and they could hide from the aliens and the bad people and they had all the food they could need and they could wait for this all to be over.  But the fire in his belly wouldn't let him. He knew Blake was right, he knew that he should be ashamed of his moments of weakness. He saw Lauren gripping her rifle and staring at Blake with faith and devotion in her eyes and he knew that was the kind of man he wanted to be. Tanner breathed a silent promise to keep Katie safe, no matter the cost.  “Let's do it.” Blake pulled the truck up to the group of guards and they all piled out, Tanner standing straight and feeling tall, Blake's words ringing in his ears. It's do or die time. _ Two of the barricade guards came over to help them unload while the others stood around and watched, their mustachioed escort who made Tanner's skin crawl and the large blond man. Traitor. They stripped off the tray covering and began shifting gear, Blake and blondie up above handing packages down to everyone else. Tanner heard the guards muttering to each other.  “Holy shit, that's a lot of firepower.” The blond man snorted. “And a lot of nasty-ass TV dinners. Important supplies, my ass.”  Sunshine shrugged. “Folks eat what they eat. Not everyone lives in a Whole Foods and learned to make Tom Yum on their gap year,” they rebuked him. The man grimaced and scratched his jaw. “Yeah, right. That was unfair of me. Well, Thai cooking workshop tomorrow and I'll make a big pot, so at least folks here don't have to eat that frozen stuff… unless they want to.” They busied themselves unloading, bundling food and weapons into bags or tying them together for ease of carrying. Tanner was tying the straps of his backpack and settling it on his back when he heard a curse from the back of the truck. He glanced up, and, frozen in time, watched the next few seconds helplessly.  The blond man had pulled out one of the last few satchels, the one containing all their spare clothes. He was standing upright, arms held out, nose ring quivering in silent outrage. In his left hand he had Blake's flag bandana; in his right, Blake's spare jacket, rebel flag patch sitting proudly on the shoulder.  Blake reacted fastest. He dropped the food he was holding, raised his Glock, and with a vengeful crack the blond ponytail exploded in a spray of red.  The man in the beret raised his rifle and fired two shots into Blake's chest, sending him flying from the tray. A scream burst from Lauren as she reached for her gun, but the alien matched the sound and met her with a powerful tackle, sending both of them crashing into a pile of frozen hamburgers. Sunshine reached out and grabbed Tanner's arm. Time snapped back into motion for Tanner. He instinctively pulled away and shook his arm free of the grasping fingers. Stepping back, he spun and swung his fist in a wild roundhouse. It connected with Sunshine's jaw as they overbalanced toward him. Tanner watched them collapse in a heap. His gaze danced over the chaos unfolding around him, frantically searching for Katie. _There. Tanner picked her up and ran.  They plunged off the road and into the darkness. There was only one thought in his mind: get Katie across that bridge. She was sobbing, shaking in his grasp, and Tanner made what he hoped were comforting shushing noises as he ran. He knew this park—there was a staircase inside one of the support towers that rose from the park to the bridge overhead. That was his way out. Holding Katie tightly, breath ragged, he ran toward the orgy of light and noise pulsating below.  The two escapees burst into the mass of people. Tanner looked around, eyes darting, taking in the madness and trying to get his bearings. The sensory assault was overwhelming, but he slowly made out patterns in the polyrhythmic press. What had looked from above like a continuous swell of humanity was actually a hundred, a thousand separate groups and camps and parties. People flowed freely between them, groups forming and merging and coming apart in a chaotic, everchanging anarchy. A makeshift stage to his left throbbed with bass, colliding with the bone-jarring screams and guitars of a group of punks. Tanner found himself surrounded by ecstatic dancers, while a group almost under his feet sat staring into a campfire, oblivious to the rest of the world. He crashed through their doped-out reverie and bounced off two men, locked in a hungry embrace.  Tanner recoiled and turned away, shielding Katie with his body, searching desperately for the tower that would lead him out of this nightmare. Lights flashed, blinding, creating a sort of slideshow of horror as Tanner scanned the crowd. There. He found it. His escape from this festival of the damned. He soldiered on, caught up in a whirl of half-naked dancers, men, women, and everyone else, mindless of the frigid air as they span and writhed in rapture.  Tanner spotted an exit, an island of calm, and dove for it. He exploded from the throng, gasping for air, and breathed in the relative silence. Collecting himself, he was faced with rows of bodies, still, staring at something unseen up ahead, the very air trembling with collective anticipation.  A voice shattered his uneasy reprieve, loud and bombastic and dripping with drama.  “And now, my darlings, it is time for these fuckers to do what I do best—go down!” Tanner dashed through the crowd as they roared and surged into motion, and caught a glimpse of the scene ahead: two lines of people, straining on thick ropes, as a woman in lingerie and feathers pranced like a princess of hell before them. The ropes led upwards, where they were tied around the necks of two enormous metal figures. Lewis and Clark.  Tanner broke into a full sprint, shouldering bodies aside. He was almost there. Up ahead, rising from the chaos, was his stairway to the heavens. His legs trembled and his breath came in ragged sobs, but he couldn't slow down. Not when he was so close. He tore out of the crowd and into the comforting darkness of the spaces in between. His hysterical panic began to subside. One foot in front of the other. Keep running. They were going to make it. As he neared the tower a figure came into view at the base, looming from the shadows of the doorway, staring into the blackness beyond. A stocky, muscled figure wearing fatigues and a plate carrier. It couldn't be… “Blake! Blake, thank God.” Tears welled in Tanner's eyes as he reached his friend. Lauren was nowhere to be seen, but right now Tanner couldn't think about her. He had survived, and he had brought Katie through. His heartbeat was still frantic, but from exertion rather than fear. They were here. He, Katie, and Blake. Emotionally exhausted, physically spent, battered and terrified, but alive. They were going to be okay. He reached out to his friend. Blake turned—No, not Blake. A thick black beard engulfed the shadowy face, momentarily lit by the glowing ember of a huge cigar. The eyes were deep-set and dark, the skin weathered, wrinkled, brown. The face of an illegal alien.  Tanner's throat betrayed him. He squeaked, and nothing more would come out. His knees wobbled and threatened to give way, his feet froze in place. He wavered. He whimpered.  Puffing on the cigar, the alien took in his terrified face and the little girl slung over his shoulder. He gestured toward the doorway and blew out an enormous plume of smoke.  “Go, gringo.”  It was well past midnight when Katie ran into the side of a tent, fell on her bottom, and started crying. They had crossed the bridge, left the highway, and headed for the safety of the forest. Since then they had been wandering among the trees for hours, directionless, driven by fear, then by hope, then exhausted aimlessness. Tanner wasn't going anywhere except away from that park. He had briefly entertained the image of finding a group of militia, sitting around a fire, eating and laughing and, maybe, swapping stories with their old friend Blake. That was hours ago. Visions were fleeting in the fever dream of the forest. Since then, they had walked because they didn't know what else to do. Tanner stumbled over to Katie and collapsed beside her, holding her close and hushing her. He felt like crying too.  A flashlight clicked on inside the tent and a dreadlocked head poked out of the flap.  “Hey, there's someone here!” Rustling erupted from all around and more faces appeared. “Wasn't someone keeping watch?” “I thought you were.” “Doesn't matter, doesn't matter. Someone's crying.” “You folks okay?” Tanner and Katie were soon surrounded by a small group of people. He looked up at them. “Are you the militia?” “No, don't worry. You're safe here. We're friends.” “Although I guess we are a militia if you think about it. Sort of.”  “Shh, don't confuse the poor people. They're terrified.”  “Sorry. No, no militia. Someone get them a blanket and something to drink.” Minutes later, Tanner and Katie were wrapped in sleeping bags, sipping on hot cocoa. It was scalding and familiar and Tanner felt the tension of the past day fading, leaving bone-deep exhaustion in its place.  “Are you okay? What happened?” “Thank you. We were… we just need to sleep.”  “And you? What's your name? Are you alright?” Katie looked at her dad, then stared up from her tin mug. “I'm Katie. I'm scared.” “You're safe now. We'll help you. Look, we'll get you somewhere to sleep.” The first face they had seen rummaged around in a tent and brought out a bag. “Lucky we have a spare tent. I'll just put it up, won't be a second.” The tent was almost up by the time Tanner and Katie finished their drinks, and they got up and walked over, sleeping bags over their shoulders, holding hands. “Hey, thanks,” Tanner said. “I would have helped but I don't really know how. Never had much call for camping. I am, uh, was a lawyer,” he glanced around, “not criminal, uh… intellectual property. Copyright.”  “No problem, of course. Here, it's not hard. I'm just clipping the…” “This isn't the time for camping lessons, Jacob. Anyway, you'll scare the man, sharing information for free like that. They've been through enough already.”  “Sorry, yeah. Look, slide in. Take these sleeping mats. It'll do for tonight, I'll teach you tomorrow.”  Tanner and Katie squeezed into the tent, sleeping bags huddled together on the cold, hard ground, and slept. THE END **Inmn ** 1:03:01 Hello, and welcome to the show. Thank you so much for coming on today. Could you introduce yourself with your name, pronouns, and just a little bit about what you do in the world? **Matt ** 1:03:15 Yeah, hi, I'm Matt. He/him pronouns. And I'm a student again, after a really long time, actually, which is why I've just moved to where I'm living now. But I like to write, you know, mostly for me, and this is the first first thing I've published but I enjoy it. And yeah, I'm really grateful that you've taken an interest in it. **Inmn ** 1:03:37 Yeah, totally. I love the story. So we just listened to the second half of your story, Blood, Soil and Frozen TV Dinners and even though listeners just heard...just heard the whole story, I'm wondering if you could just kind of like walk us through the story in your--you know, from the mouth of the author--what is this story about? **Matt ** 1:04:01 So the story, for me, was about, to some extent, seeing yourself in some ways or, you know, people like you, through the eyes of...through the eyes of someone else, I guess, someone who's very different and might see things in a different way. So I always find it interesting to play with different perspectives or different characters instead of telling the story from a heroic perspective or something. And I wondered what a pathway to a better world might look like from someone who didn't necessarily want that to happen. So we have these, you know, preppers who--call them you want, right-wing conservatives, something like this--and what they might think, given the knowledge that they receive about the world, what they might think is happening when something happens that a lot of the rest of us might want. **Inmn ** 1:05:00 Yeah, totally. I really like how you put that. What was it, like, "a better world that they don't necessarily want?" [both laugh] Okay, well, how did this, how did this story kind of...like how did it come to be? What inspiration did you kind of draw from to craft this situation or these like personalities from Tanner and Blake or Earl Swanson? 1:05:35 Yeah, the story itself, there was a discussion last Halloween, I believe it was, on Coffee With Comrades, there was a interview with Pearson and Margaret Killjoy, talking about the discussion of the monster in literature, which is where I first took the idea that they were talking about seeing yourself as the monster in this idea and sometimes reveling in that or perhaps enjoying it. And that was where the first idea came from. And then the most specific layout of the story or main theme, I guess, was, I was doing something on the US Tax Office website. And there's this whole section for aliens, right, if you're an alien in the U.S., these are the tax rules you need to follow. And I just thought it was a funny word. You know, I'd seen it on Fox News or something before but it just struck me as really weird in such an official position. Yeah, and I just was playing with the ideas of this and, you know, I like thinking about utopias and things. And this is where the like the main shape of the story had come from, just the idea of seeing the monster, seeing the alien from there. And then specific characters, I mean, some of them are just kind of people that I've met, you know, Tanner and Blake, specifically, and I think Earl Swanson's character, I mean--I don't know it's possibly libelous--but we can probably figure out who that's meant to be, right? I think it's reasonably obvious. **Inmn ** 1:07:09 Totally, totally. Yeah. Yeah. No, that's super interesting. Yeah, it's funny, I was rereading the story today to prepare for this interview and I realized that the first time that I was reading it, because of this perspective of the.... I'm like, okay, I know, these are some, you know, at least center-right, far-right preppers and they're using the word "alien" and I don't actually know what they mean by this, which was, you know, maybe a purposeful being vague about it, but I was like, I don't know if they think that it's, you know, illegal aliens or undocumented  migrants or whatever or if they mean, like, literal from outer space aliens. And, yeah, I was like, I don't know what they mean by what they're talking about. And maybe they don't either.   1:08:20 This was part of the conceit, right, was setting it up like it's a pretend big reveal, I think, that it's a twist in the story that at some point gets revealed, but that's not really the point. It's not really meant to be a big trick or something like this, you know? I think in discussions in the editing, we talked about in the first page or so when they speaking Arabic, and it's reasonably obvious to anyone that knows Arabic who these people are, you know, it's not hidden, but this was the idea, that they may have meant illegal alien all along, was, you know, the way they we're using the term, but that they weren't necessarily drawing so much of a distinction between the two uses of the word alien, that in their minds a, sort of, invasion by one was the same as the invasion by the other to some extent. **Inmn ** 1:09:10 Yeah, which, you know, I actually really love that from the perspective of.... It's like maybe an interesting twist. I didn't listen to that interview with Pearson and Margaret, so I'm not sure what they talked about, but there's this kind of idea in a lot of spaces that I've been part of,you know, when people talk about things like assimilation or something, especially in queer spaces, of like, "We have to seem harmless to them. We have to seem innocent. We have to seem like we just want to be part of the group," you know, and then this other side that's like, "No, we want to be unknowable. We are claiming the monstrosity that they are putting on us," and I'm like, yeah, we're fucking.... I don't know, anarchists are kind of aliens, like, in an entirely other way of thinking, you know? 1:10:09 Yeah, and just considering some social norms is completely irrelevant or harmful or repressive and other things that other people would consider, perhaps, violent or something seem completely okay to other people. There is a complete sort of alienation of perspective from broader society, I think. And yeah, it is, there's a tension between sometimes wanting to go unnoticed, or, as you say, like assimilate, and even, for me, walking around, you know, sometimes you want to look like an anarchist and sometimes you don't. It's an interesting dynamic, I guess, that you can switch sometimes day-to-day. **Inmn ** 1:10:54 Yeah, yeah. Have you read much of--you know, love talking about this person on the show--have you read much of Ursula Le Guin's Hainish Cycle? 1:11:08 I've read only "The Dispossessed" and "The Left Hand of Darkness".  **Inmn ** 1:11:16 Great examples. I think "The Left Hand of Darkness," kind of brings out this idea of where the reader is going to maybe most identify with the alien, or whatever, in "The Left Hand of Darkness" being not the not the Gethens--or I don't remember what they're called. But then it's like, the more that we're reading the book... or there's some times where I'm this alien or, you know, our perspective person just doesn't understand this culture. And that's really painful. And then there are other times when I'm like, I don't know, maybe the alien's perspectives on the world are far more dissimilar to what a normal person on like our planet Earth would think, because they're advocating for a better world that is very alien to people on this planet. Does that make sense? **Matt ** 1:12:24 Yeah, I mean, in "The Dispossessed," I think it's the same dynamic with Shevak coming back to Earth and presenting the perspective, both ways that it seems incredibly alien to him and then the other way around to everyone else that's there, to the general culture there. Yeah. I think it's an interesting literary device to present the outsider point of view, I think, which I mean, is quite the opposite of what I did in this story, I presented the more mainstream point of view, I guess, but from the circles that we're in, it's funny to see from the outside what that looks like. **Inmn ** 1:13:02 Yeah, yeah, I had this very silly idea once for...I don't know if it was gonna be a short story or what but kind of, using that "alien" trope or like "Stranger in a Strange Land" trope as a way to talk to my parents about anarchism or about radical queer spheres. **Matt ** 1:13:27 Yeah, I mean, that's about as alien as it can get for a lot of people's parents, right. **Inmn ** 1:13:31 Totally. But just as some funny little zine that's like an introduction to the punk house, you know? **Matt ** 1:13:44 Yeah, viewed as some sort of interesting zoo creatures. **Inmn ** 1:13:46 Yeah. I was wondering if you could talk a little bit about the kind of political renderings of Tanner and Blake or ,rather, their differences in how they perceive or interact with either preparedness or this new world that they're encountering? **Matt ** 1:14:14 Yeah, I think that Blake's character is a lot.... He knows what he's doing, right? It's a lot more intentional and more--I guess educated is maybe not quite the right word--but a lot more of an actually constructed ideology, whereas for Tanner it's very much received. He's not so keen, not so entirely sold on the idea or doesn't necessarily know the idea. It feels like it's like lost and failing a lot of the time and I think that's why I found him a much more interesting character because that's how I feel a lot of people that I know and talk to and family members and friends and things or friends of people I know get pulled into a lot of these, you know, reactionary ideologies is kind of by accident a lot of the time, right? Because it's what's presented and what they're drawn into by someone who has a lot more investment in it than they do. And they just kind of bumble into it almost by accident. Yeah. **Inmn ** 1:15:20 Because it's what they're seeing on TV. People who are deeper into that philosophy are like.... It's like the people that they're around who are their own little echo chambers of, "Oh, okay, there's this thing happening. Not sure how I feel about it. But I'm being like, fed this perspective on it." **Matt ** 1:15:46 Yeah, and a lot of the social or interpersonal issues that draw people in as well, I think. I tried to make it seem relatively obvious that Tanner is envious of Blake in a lot of ways, right? He is, you know, hotter than him and he is cooler than him and he knows more than him and he's always trying to, like, live up to this ideal that he has just completely interpersonally with no politics or anything in it. And he just wants to live up to what he thinks Blake wants him to be, which it turns out, is a bad thing. I mean, I'm not trying to excuse Tanner's character too much here. But yeah, I think this is what's really dangerous a lot of the time actually, for people who don't necessarily have a fully formed belief in all of these philosophical systems or something that then puts them on the wrong side not by...not necessarily out of evil intention. **Inmn ** 1:16:54 Yeah. No, that's very true. And it's interesting talking about not excusing Tanner's character too much, but as I was reading the story I found myself like, not necessarily rooting for Tanner and Bl

Dr. Shannon Westin and her guests, Dr. Michael Atkins, Dr. Adil Daud, and Dr. Gary Schwartz, discuss a definitive work: The DREAMseq Trial. TRANSCRIPT The guests on this podcast episode have no disclosures to declare.     Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast that gets in-depth on articles that have been published in the Journal of Clinical Oncology. And it is my great pleasure to be your host. I'm Shannon Westin, GYN oncology, and I serve as the social media editor for the Journal of Clinical Oncology.   Today, we're going to be discussing a very exciting article describing “The DREAMseq Trial—ECOG-ACRIN EA6134, Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma.” This article was published in the JCO on January 10th, 2023.   And I am joined today by the lead author, Dr. Michael Atkins, who is Deputy Director, Georgetown Lombardi University Hospital, and Scholl Professor and Vice Chair of Oncology at Georgetown University Medical Center. Welcome.   Dr. Michael Atkins: Thank you. Nice to be here.   Dr. Shannon Westin: In addition, we are also accompanied by two experts in the field, Dr. Adil Daud, Professor in the Department of Medicine at the University of California San Francisco, and Director of Melanoma Clinical Research at UCSF Helen Diller Family Comprehensive Cancer Center. Welcome, Dr. Daud.   Dr. Adil Daud: Hi, great to be here.   Dr. Shannon Westin: And with Dr. Daud is Dr. Gary Schwartz, the Division Chief of Hematology Oncology and Deputy Director of the Herbert Irving Comprehensive Cancer Center in Columbia, New York. Thank you for being here.   Dr. Gary Schwartz: Delighted to be here.   Dr. Shannon Westin: So I'm surrounded by experts, and I'm very excited as a GYN oncologist to hear all of what you all have learned in melanoma because we're always excited to take that back into our field. So I think first, though, for those of us that aren't melanoma experts, Dr. Atkins, can you just level set for us and tell us what was the standard of care for melanoma when you began this study?   Dr. Michael Atkins: Sure. Well, first of all, this was a study for patients with BRAF V600 driver mutations in their melanoma, which represents about 50% of the patients with metastatic melanoma. And at the time the study was launched in 2015, two BRAF/MEK inhibitor combinations were FDA approved and shown to produce significant progression-free survival and overall survival benefits relative to BRAF inhibitor monotherapy. In addition, combination checkpoint inhibitor therapy with nivolumab and ipilimumab was shown to be superior to ipilimumab and, in particular in patients with BRAF-mutant melanoma, also to nivolumab monotherapy based on the results of the CheckMate 067 study, leading to its FDA approval. So we had these two regimens there that were approved. Of note, despite the many debates and attempts to garner real-world evidence at the time—the study actually reported out in 2021—marketing data showed that half of all patients in the US with metastatic BRAF-mutant melanoma were receiving BRAF/MEK inhibitors, and only one-quarter received nivo-ipi as initial therapy. So there remained a confusion throughout the course of the study as to which regimen was best in the US and around the world.   Dr. Shannon Westin: Tell me, what led to the current study? Was it really trying to drive at that very question?   Dr. Michael Atkins: These were the best treatment available at the time. And they really had changed melanoma patient outcomes in ways that we could have only dreamed about just five to 10 years prior, when median survival for patients with metastatic melanoma was six to nine months. Hence, the DREAMseq trial, this doublet, randomized evaluation of advanced melanoma sequencing, was really an apt acronym for the trial. But we had these two regimens of BRAF/MEK inhibitors tending to display the overall survival curve, while immunotherapy tended to raise the tail. And at the time the study was launched, it was really unclear which treatment was preferred in general or for particular subsets of patients. And given that patients would likely have the option to receive both approaches, was there a preferred sequence? So the DREAMseq trial was a launch to address these questions.   Dr. Gary Schwartz: I can echo Michael's statement about that. There was also—having been at the beginning of immunotherapy and targeted drug therapy, the transformation of cancer medicine in melanoma was extraordinary. Over a very short amount of time, we transformed a disease that's incurable to curable. And I don't think anybody, at least not in my lifetime, that ever think we'd ever see—or I'd see that type of transformation. But the debate in the community was what should be the first therapy. Should it be a targeted drug combination targeting RAF and MEK for BRAF-mutant melanoma, or should it be immunotherapy? And actually, there was a trend favoring immunotherapy, I think, at the time of the start of the study. It was actually an unresolved issue that many of us were continuing to debate up to the publication of this data, which certainly has now solidified the role of immunotherapy as a starting point for patients with BRAF-mutant melanoma.   Dr. Michael Atkins: Thanks, Gary.   Dr. Shannon Westin: I would love for you—because it is a complex design, and I feel like a lot of times, as drug developers, we're often discouraged to do too many lines in a row. And I was just so intrigued at how well this was laid out to really understand those very questions of superiority as well as sequence, which we don't often assess. Dr. Atkins, will you just summarize the design so that all of the very smart researchers on the line can utilize that for their own cancer types?   Dr. Michael Atkins: Yeah, it was complicated to execute, but the design was pretty simple. Patients with treatment-naive BRAF-mutant metastatic melanoma were stratified according to ECOG performance status and LDH normal and high and randomized in step 1 to receive either combination nivo-ipi induction for 12 weeks, followed by nivo monotherapy maintenance for up to 72 weeks—that was arm A, and that was standard of care for that regimen—or dabrafenib-trametinib continuously, and that was arm B. And if patients experienced disease progression and met the step 2 eligibility criteria, they were able to cross over to the alternative sequence: arm C, dabrafenib-trametinib, or arm D, nivo-ipi. And we followed the patients and chose two-year overall survival as the primary endpoint.   Dr. Shannon Westin: And we kind of got a little hint. So what was the primary finding?   Dr. Michael Atkins: Yes, because of the anticipated distinct shapes of the overall survival curves, with the BRAF/MEK inhibitors tending to have their benefit early and the immunotherapies tending to raise the tail of the curve, we thought there'd be non-proportional hazards and that the overall survival curves might cross. And therefore, we chose as a primary endpoint two-year landmark overall survival, with an estimate that the nivo-ipi first sequence would have a 70% overall survival rate compared to 50% for the dab-tram first sequence. And with 300 patients enrolled and 270 evaluable, there was about a 90% power to show this difference in two-year overall survival rate, with a two-sided type one error rate of 0.05.   Dr. Shannon Westin: And it met its primary endpoint?   Dr. Shannon Westin: Yes, the study was opened in July of 2015, and it was set up that there would be Data Safety Monitoring Committee meetings after the first 100 patients were accrued every six months and that the data cutoff used for the fourth interim Data Safety Monitoring Committee meeting, which was a median follow-up of a little over two years, 265 patients had enrolled in step 1—those were evenly split between the two arms—and 73 had enrolled in step 2, with nearly two-thirds of those being on arm D, second-line nivo/ipi. And the two initial arms were balanced for most of the characteristics and was randomized for the important characteristics.   And from an efficacy standpoint, once again, we chose landmark two-year overall survival as a primary endpoint. And the overall survival curves for the combined sequences showed the anticipated biphasic pattern; they actually crossed around 10 months, and 100 patients had died, with 62 of them on the sequence beginning with dab-tram. And the two-year overall survival rate was 72% for patients who started on nivo/ipi and 52% for those who started on dab-tram. And that was a pretty significant difference; P equals about 0.01 by log-rank test. And so this 95% repeated confidence intervals, along with the 20% difference in overall survival, ranged from 3% to 38%, and the O'Brien-Fleming boundary had been crossed based on this estimate. Interesting, as we published, the three-year overall survival difference was even greater, approaching 24%. So that was the main study endpoint. And because the Data Safety Monitoring Committee felt that that difference was clinically significant even though we had only had about 59% information, they recommended at that point that the study be closed early and that patients who were on arm B, dabrafenib-trametinib, be given the option to cross over to immunotherapy before disease progression.   So that was the primary endpoint. I'm going to pause there. There were some secondary endpoints that I think were interesting, but maybe Gary or Adil have comments about this.   Dr. Shannon Westin: I hope they do, yeah. I'm going to give over my podcast hosting to you.   Dr. Adil Daud: Mike, congratulations on that study. I mean, that's transformative. I mean, I think there was a feeling, like Gary was saying, that immunotherapy might be better in the long term. But I remember a lot of discussions, and I think you answered them in 2015 or 2014 and 2013 because you've been working on this design for a while, that the people who were treated with BRAF inhibitor therapy were just different. And a lot of people would say that when somebody walks into the clinic, the folks who are BRAF-mutant, they just have rapidly progressive disease, like something really bad is going on. And that's why the results on BRAF/MEK inhibitor therapy just looked different than immunotherapy. Immunotherapy was for slower-growing tumors, and I think your study kind of puts maybe a different spin on that, basically suggesting differently. Would you comment on that?   Dr. Michael Atkins: Yeah. So, Adil, I think early on, people thought that the BRAF/MEK inhibitor was for patients who had rapidly progressive disease, and you needed to get a response to get the disease under control. But over time, as those studies were followed out, it appeared that the BRAF/MEK inhibitors tended to work best in patients who had less aggressive disease—performance status 0, M1a or b disease, and normal LDH. And so it was still confusing as to who should get which therapies. And when you compared the results using retrospective data between those who got immunotherapy and those who got targeted therapy, it was really difficult to be sure that these were the same patient population. So the only way you could really know whether immunotherapy was truly better was to do prospectively randomized studies where the two arms were balanced, which is what we set out to do in DREAMseq.   Dr. Adil Daud: Yeah, I think there's a lot of areas in oncology where people think whether you should give somebody a CAR T-cell or whether you should give somebody myeloma therapy or—people think, well, these are just totally different. Or in melanoma, I think, the TIL therapy, there's this question about, can you really compare that to anything else? And I think your study, which perhaps wouldn't be done by a pharmaceutical company and perhaps wouldn't be— outside of the cooperative groups, I feel that it's hard to really do a study of that type.   Dr. Michael Atkins: I agree.   Dr. Gary Schwartz: Yeah. First, I want to say congratulations on really an extraordinary study, Michael. I think it really answers some critical clinical and biological questions that have been subject to debate in the melanoma and the medical oncology community for the last five or more years.   There were a couple of things that surprised me. One was the fact that patients that started on dab-trame, when crossed over to immunotherapy, the outcomes were pretty poor. And that was a biological outcome, I guess, we kind of thought about. But this study certainly suggests that there's something about prior targeted drug therapy that may affect outcome and immunotherapy. And also, the other thing that was surprising was the number of dropouts that developed and couldn't cross over because of the rapid progression on the first-line study. Do you want to comment on both of those points and maybe share some thoughts about what that means for the medical care of patients who get this type of treatment?   Dr. Michael Atkins: Sure. First of all, response rates were similar between the step 1 regimen and for dab-tram, whether used in step 1 or step 2. In contrast, as you said, nivo-ipi appeared to be less effective after progression on dab-tram than in the first line. It was like a 46% response rate in the first line, and about 30% in the second line. The median PFS in the first line was about 11+ months, and in the second line, was only about three months. And I think there was some feeling in the community—probably wishful thinking and also based on what I think are some flawed preclinical and translational studies—that BRAF/MEK inhibitors might cause some immunogenic cell death and cause new antigens to be expressed and activate the immune system, be synergistic with immunotherapy given afterwards, while I think other data suggested that the resistance mechanism to the dabrafenib-trametinib was immunosuppressive, leading to upregulation of VEGF and things like that.   So this result suggested that immunotherapy didn't work as well in the second line. There are probably several reasons for that. It could be biologic changes, which I think we don't pay enough attention to when we think about what we're doing in the first and the second line. But also the type of patients who progressed on BRAF/MEK inhibitors. when you stop those drugs, the disease tends to accelerate. Many of them probably had subclinical CNS disease, and it was just not a good time for them to be going on immunotherapy, while in the front line, you didn't have to deal with those type of issues. And with regard to crossover, one of the things that we looked at as a secondary endpoint in this study was feasibility of doing the crossover. Because in clinical practice, we found that if you waited until disease progression on BRAF/MEK inhibitors and then tried to cross them over, oftentimes, patients progressed really rapidly, and you weren't able to get the immunotherapy in to large degree, while in patients who got immunotherapy, they had a lot of toxicity often, which caused them to stop therapy. And if they had toxicity at the time they were progressing, it might be complicated to add new drugs in.   And so I think the community was a bit surprised that only about half the patients were able to successfully cross over. But I think that's reality, that if you use these drugs to progression and then have eligibility criteria, which you have to have in a clinical trial for patients to go on the second-line treatment, you're going to have a lot of dropouts. One of the major reasons for dropouts on dab-tram was progression in the CNS, and dabrafenib-trametinib doesn't work as well in the CNS as it does systemically, while immune therapy actually appears to work as well for patients with asymptomatic or undetected CNS metastases as it does systemically. And I think that was an important reason why immunotherapy was better.   Dr. Gary Schwartz: I've looked at your paper now multiple times, Michael, and I can't think of any reason why anybody would want to start a targeted therapy for BRAF-mutant melanoma. I mean, I think this really becomes a definitive study declaring that immunotherapy is where all medical oncology should begin in the treatment of BRAF metastatic melanoma. Is that too much of a statement to make, or would you agree with that as well? I've been trying to think of all the reasons why not to give immunotherapy first. I can't think of one now, after your paper, that would suggest otherwise.   Dr. Michael Atkins: Well, I've been chastened by a lot of reviewers, as you know, to say that these results only definitively apply to the patients who were eligible for this study. And patients who had poor performance status or active brain mets or who required steroids and needed to be in the hospital or had to have a response were not eligible for this study. And so I think there are some patients where the disease is just on fire, where you may need to give BRAF/MEK inhibitors to try to cool it off before you start immunotherapy, particularly if patients need to be on immunosuppressive drugs to control edema in their brain, or because of bone mets pressing on the spinal cord or things like that, I think that it's important to have that other option. But as soon as you can, as soon as you've created enough window to get patients off immunosuppressive drugs or improve their performance status enough so that they can be an outpatient, you probably should switch to immunotherapy and give them the chance for a long-term benefit.   Dr. Adil Daud: I have doctors call me outside of academia and say, “Hey, I've got a patient walking in. I'm trying to decide, should I do the triple therapy, or should I do…”—which triple therapy in melanoma refers to dabrafenib plus trametinib plus a PD-1 drug like pembrolizumab or, in some cases, like a PDL-1 inhibitor—and they're questioning whether that's an appropriate place to start. Or sometimes people say, “Well, what about doing a sandwich regimen where we start off with dabrafenib-trametinib and then switch over to something else without waiting for progression just to give people…” And I give a long-winded answer to that, but I'm curious to hear what you think, what you both think.   Dr. Michael Atkins: So my view is—I've always thought, based on some of our early translational studies, which were presented at ASCO and hopefully we'll be able to publish soon, that the BRAF/MEK inhibitor data that showed that there was an influx of immune cells and potential synergy was actually an artifact, that it was not increasing immune cells in the tumor microenvironment, but actually loss of tumor cell in the tumor microenvironment that was causing the impression that the tumors were more inflamed. And I felt that when it came to immunotherapy, BRAF/MEK inhibitors were not ipilimumab and were not going to add to the benefit that we see with immunotherapy of durable responses the way you can see with nivo/ipi.   So I've stayed away from those triplet regimens, and I think we've seen with the studies that have been published so far that they tend to have sub-additive benefit when you add an anti-PD-1 to BRAF/MEK inhibitors. You see some prolongation of PFS, but you don't see the same tail of the survival curve. And even at two years, the tail of the survival curve for those triple regimens is below where it is for nivo/ipi in the BRAF-mutant population all the way out at five years. And the nivo/ipi population—I'm talking about the progression-free survival curve—and that nivo/ipi population can still get BRAF/MEK inhibitors if they progress. So I think that triple regimen, I can't think of a patient where I would use that. But the sandwich regimen, as I was just describing, may be useful in some patients who just aren't in appropriate shape to start with immunotherapy.   Dr. Gary Schwartz: Now, I would agree with Michael. I think the clinical trial data would really discourage the use of triplet therapy. They really lean—again, the benefit of triplet therapy for all the published papers we've seen so far in that area. But I guess you're right. The idea, if you have one of those patients that comes in and who's really on fire with rapidly progressive disease, on steroids, and needs a very quick benefit, perhaps initiating targeted therapy first for a short time would be reasonable in the treatment of those patients. But beyond that, I really think there probably are not going to be many exceptions to starting immunotherapy first because your data, to me, strongly would suggest that starting targeted therapy is going to diminish the benefits of immunotherapy to follow. And that, to me, is an important take-home point of the study and sort of validates some of the preclinical data. I mean, depends what you look at. But there is preclinical data suggesting that MEK inhibition will diminish T-cell responsiveness, and I think this supports that biological effect. So I think we have to be cautious about upfront targeted drug therapy now and have to find what are those opportunities where it may be appropriate. But I think they're really diminishingly few.   Dr. Michael Atkins: And I would just emphasize the flip side of that, which is that targeted therapy is equally effective in the second line for patients who don't respond to immunotherapy. And I think that was also a critical component of why the immunotherapy first sequence was better than the targeted therapy first sequences. You had better salvage.   Dr. Gary Schwartz: That's a very good point.   Dr. Shannon Westin: Well, I personally just want to thank the three of you. I learned a ton today, and I fully intend to take that back to the work that we're doing in gynecologic malignancies, combining immune therapies and targeted therapies, and I hope our listeners will do the same.   Further, I agree with you, Dr. Schwartz. I think this is a practice-changing study. I appreciate you, Dr. Atkins, in being a little cautious. I appreciate the editors that reviewed it as well. But this is as clear a definitive trial as we can get and a testament to your hard work through the cooperative groups, which we all know can be a struggle in itself to get this type of trial through. So congratulations again.   Dr. Gary Schwartz: And I think the lessons learned in melanoma are going to be applicable to all solid tumors. So melanoma is about so far ahead of many other tumors, but what we learned here isn't just impacting melanoma, but will impact all cancer medicine. And I think that what's so important about this trial is that lessons learned here really are broadly based and have clinical applications to many patients getting immunotherapy, targeted drug therapies today. So congratulations, Dr. Atkins. I think you hit a home run on this one. The medical oncology community is indebted to you and to your group to making this possible. And thank you for bringing it to JCO as well. I think that itself speaks to the success of the journal and the impact these types of studies have on reaching a large segment of the medical oncology community.   Dr. Michael Atkins: Well, thank you very much, Gary. I do want to emphasize the point you made, that I think this result does impact how we think about the use of targeted therapies or chemotherapies or antiangiogenic therapies in other tumors in coordination with immunotherapy. And I'm sort of on a mission to make the point that if you want to get the most benefit out of immunotherapy, you should give it first, and you should give it unencumbered by other things that might interfere with its activity.   Dr. Gary Schwartz: I think that's the last word, Shannon.   Dr. Shannon Westin: I believe it is. I believe it is. Thank you all so much for being here. And thank you to our listeners for being here for another episode of JCO After Hours. Again, we were discussing “Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial—ECOG-ACRIN EA6134,” published in January 10th, 2023, in the JCO.   Please do check out our other podcast offerings. You can check them out on the JCO website or anywhere you get your podcasts. Until next time, be well.     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.  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.25.525483v1?rss=1 Authors: Zhang, C., Yi, X., Hou, M., Li, Q., Li, X., Lu, L., Qi, E., Wu, M., Qi, L., Huan, J., Qi, Z., Lv, Y., Kong, X., Bi, M., Feng, S., Zhou, H. Abstract: Cerebral ischaemia-reperfusion injury, during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m1A) is an RNA modification that can affect gene expression and RNA stability. The m1A landscape and potential functions of m1A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m1A modification in normal and OGD/R-treated neurons and the effect of m1A on diverse RNAs. We investigated the m1A landscape in primary neurons, identified m1A-modified RNAs, and found that OGD/R increased the number of m1A RNAs. m1A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA-RBP interactions and circRNA translation. We showed that m1A modification mediates the circRNA/lncRNA-miRNA-mRNA ceRNA mechanism and that 3'UTR methylation of mRNAs can hinder miRNA-mRNA binding. Three methylation patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m1A-regulatory specificity. Systematic analysis of the m1A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA methylation and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology related diseases. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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We Like Shooting, episode 446.  This episode’s topics: Akdas AK12 UBS, CZ Scorpion, Tactical Lever Action with Chris Costa, 2A news and more! Welcome to the We Like Shooting Show, On episode 447 of WLS we're gonna talk about Air rifles, iguana hunting, Fenix lights, Nick's M1A, 2A news and more with your cast – … We Like Shooting 447 – Sir Nick the White Knight Read More »

We Like Shooting, episode 446.  This episode's topics: Akdas AK12 UBS, CZ Scorpion, Tactical Lever Action with Chris Costa, 2A news and more! Welcome to the We Like Shooting Show, On episode 447 of WLS we're gonna talk about Air rifles, iguana hunting, Fenix lights, Nick's M1A, 2A news and more with your cast – … We Like Shooting 447 – Sir Nick the White Knight Read More »

This episode explores what characteristics are paramount in a versatile self-defense firearm for survival situations. Based on a worst-case, apocalyptic scenario, it discusses rifles, shotguns, handguns, cartridges, and appropriate ammunition.  SHOW NOTES:  Characteristics of a great survival gun Reliability Portable and handy Firepower Accuracy Long-range capability Cartridge authority Appropriate bullets Specific recommended cartridges Crossover hunting tools Recommended firearm types and models Optimism... "Let not your heart be troubled" Preparedness is peace of mind ENJOY!    FRIENDS, PLEASE SUPPORT THE PODCAST!  Join the Backcountry Hunting Podcast tribe and get access to all our bonus material on www.patreon.com/backcountry   VISIT OUR SPONSORS HERE:  www.browning.com www.leupold.com www.silencercentral.com www.timneytriggers.com www.siembidacustomknives.com https://javelinbipod.com

Today we talk about the M1A platform, its history, its positive attributes and its shortcomings....yes, there are shortcomings. What makes the M1A a valid battle rifle? What are some myths floating around the gun community? The M1A has been around for a long time and many people have some opinions about it. We're going to look at some cold hard facts, and give our take on some data!

Ryan Gresham and Kevin "KJ" Jarnagin discuss the pros, cons, and what you need to know if you carry a handgun while hunting. Plus, an interesting night frog hunting with an M1A, bear scares, and hanging out in Alaska. Gun Talk Hunt is brought to you by Timney Triggers and Springfield Armory. Gun Talk Hunt 07.18.20

The boys are here to bring you the latest in the world of Tom Clancy games. We got some news for Rainbow Six, something big is happening there. Information on the M1A nerf in the Division and the latest patch for Ghost Recon. It's a fun time You can find our new website here Our Patreon here Our Merchandise store here Our twitch channel here And our Mixer channel here

Washington madness, Virginia Stand and Fight, New Colt Python woes, DSA Heavy Barrel FAL. M1A scope mounting, Are old guns dangerous?, Best Value bolt actions, greatest centerfire and rimfire handguns, Do business with??  

Last week the Air Force inadvertently tried to add their own kind of fireworks to the holiday festivities. Apparently, an A-10C Thunderbolt II out of Moody Air Force Base in Georgia dropped three 25-pound nonexplosive training bombs after an unlucky encounter with a bird. Fortunately, the rounds fell harmlessly just outside of Suwannee Springs in Northern Florida. Thus far the Air Force has failed to locate the shells. Fortunately, the jet wasn’t carrying its wartime payload of 500-pound M1a-82 bombs. The dummy rounds do carry a small pyrotechnic charge and could pose a slight danger to anyone who might try to handle them. Although this encounter had a minimal impact on the plane, its passengers and its surroundings, bird strikes are no joke in the aerospace industry.They first gained notoriety after an incident that became known as “The Miracle on the Hudson”, when Captain Chesley Sullenberger had to land his Airbus A320 on New York’s Hudson River after one of the engines was damaged by a flock of Canadian geese.According to a recent report on Business Insider, the Air Force has encountered more than 105,000 bird strikes since 1995. The 28th Bomb Wing Public Affairs office also attributes the deaths of nearly 40 airmen to bird strikes since 1985. These encounters with our winged friends have also generated more than $800 million in damages to jets and transport planes. The most recent being an F-35 stealth fighter that needed $2 million in repairs after encountering a bird during takeoff.

In this devotional you will hear J.'s story of how he became "book smart" about guns but had a funny but potentially serious run in with a cop. Support the show (https://www.c50hope.com/giving-info)

Jacob, Stephen, and Kaden talk about some of the history revolving around the AR platform, and why its still one of the most successful weapon platforms ever made. The guys dig deep into why its still at the top of the service rifle food chain, and why you should want to own one personally.

This week Marty, Tim, Gavin, and Andrew recap a load of current events. Marijuana being “legal” and some nonsense around the Ontario Cannabis Store. RCMP being unable to produce any data to support their statements that many illegal guns are acquired through straw purchases. A Canada Man that is out on bail following an assault at Medieval Times and swimming naked with the sharks at the Ripley's Aquarium in Toronto, twice. The ontario government is reviewing a private members bill to strip returning terrorists of access to provincial services, since the federal government is going out of its way to repatriate ISIS terrorists. Intro Hello to all you patriots out there in podcast land and welcome to Episode 155 of Canadian Patriot Podcast, the number one LIVE podcast in Canada. Recorded Monday October 22 2018. Marty - Hunter and sport shooter in rural southern Ontario Liberal Tim - Husband, father of 3, a sport shooter and the owner and operator of Tim’s Good T-Shirts, they’re quite good.  Also the proud descendant of immigrants. Gavin - Business Owner, Hunter, Atheist, Gun Enthusiast & CCFR Field Rep for the GTA Andrew - I’m a recovering libertarian, competitive shooter, and firearms instructor at Ragnarok Tactical   We’d love to hear your feedback about the show. Please visit  canadianpatriotpodcast.com/feedback/ or email us at feedback@canadianpatriotpodcast.com A version of the show is Available on Stitcher at and iTunes http://www.stitcher.com/s?fid=77508&refid=stpr and iTunes at https://itunes.apple.com/ca/podcast/canadian-patriot-podcast/id1067964521?mt=2   Check the podcast out on http://facebook.com/canadianpatriotpodcast and Instagram  https://www.instagram.com/canadianpatriotpodcast/   We need your help! To support the show visit https://www.patreon.com/cpp and become a patreon. You can get a better quality version of the show for just $1 per episode. The more you pledge the better the rewards are. Show you’re not a communist  buy a CPP T-Shirt, for just $19.99 + shipping and theft. Visit the http://canadianpatriotpodcast.com home page and follow the link on the right. Arrowhead Coffee Arrowhead Coffee is Owned and Operated by Canadian Armed Forces Veterans. They love our Country, the True North Strong and Free, their family and friends. Join Arrowhead Coffee on their hunt for the perfect brew to raise morale and bring that feeling of home to you, no matter where you are. A portion of all profits helps Canadian Armed Forces Members, Veterans and their Families. What Are We Drinking Andrew - Crown Royal Maple Marty - Oban 14 and Water Tim - 40 Creek Copper Pot with reverse osmosis water Gavin - Coors Banquet Upcoming Events Ragnarok Tactical is sponsoring a 22 Precision Rifle Match at Guelph Rod and Gun Club on October 27. Match fee is $40. 50 Rounds. 5 stages. Distances 0 to 100 yards. more than one magazine is an asset https://www.facebook.com/events/179053676251452/ https://practiscore.com/22-precision/register News Guns RCMP HAVE NO RECORDS TO SUPPORT CLAIMS OF ‘STRAW PURCHASES’ https://dennisryoung.ca/2018/09/13/no-records-to-support-rcmp-claims-of-straw-purchases/?fbclid=IwAR2GvBFFMMhWiUVXZxG9RFNnXuLOs9NzoLEaUxS6ghmKhPcBrZzn-fecP6Q Pot Kids will be able to possess weed under federal marijuana legislation https://leaderpost.com/news/saskatchewan/kids-will-be-able-to-possess-weed-under-federal-marijuana-legislation?fbclid=IwAR1hU7ypn_BwVBJuvqFqgJY7Y7f7kMszD5uOU_bJNr4OJCXSiL3nJ-EyXF0   https://www.facebook.com/JustinPJTrudeau/photos/a.101277015648/10157153125505649/?type=3&theater&ifg=1   Workers tied up during armed attack on legal cannabis grow-op https://www.ctvnews.ca/canada/workers-tied-up-during-armed-attack-on-legal-cannabis-grow-op-1.4141812?fbclid=IwAR2ESavSwZ4w-6UTO9773a1sE4ujtjKHZqhAvbTfQpshLOZtcKWK_LA8ow0 Ottawa moves to pardon Canadians convicted of pot possession as legalization takes effect https://www.thestar.com/news/cannabis/2018/10/16/ottawa-moves-to-pardon-canadians-convicted-of-pot-possession-as-legalization-takes-effect.html?fbclid=IwAR1FrHo-kh8USEWmOWsyOWkygQEG04OeZOKjf7yxQUsMuZPxv6sAyPqJZg0 Ontario Ontario bill aims to strip returning terrorists of provincial privilegeshttps://torontosun.com/news/provincial/ontario-bill-aims-to-strip-returning-terrorists-of-provincial-privileges?fbclid=IwAR1YNpodY2T06hJCJhdqjYo67mgV875uojYhMHziHwh2pKse049qm4b1XUA Canada Man Naked man who jumped in shark tank at Ripley's Aquarium wanted for assault at Medieval Times https://toronto.citynews.ca/2018/10/15/naked-man-jumps-into-shark-tank-at-torontos-ripleys-aquarium/?fbclid=IwAR2237uVkJhsheZwLEYV2kZ2BEoUM50cuFt2hzWkDOSuollxmEBYgPkOqkc   2 charged after they allegedly fed Timbits to bears along B.C.'s Alaska Highway https://www.cbc.ca/news/canada/british-columbia/2-charged-after-they-allegedly-fed-timbits-to-bears-along-b-c-s-alaska-highway-1.4867872?cmp=FB_Post_News&fbclid=IwAR2DR8Yge7LpapJaGYVGW5mB7C0DhTukFleXKGNq-aT8ZkVq_PVy12fltik Rapid Fire Feedback Email Subject: Catching up on older episodes I was listening to your older episodes on itunes, I got episode 65 (watching in reverse order). I could not stop laughing about  18:50 into the show, talking about sloppy rods on the M1A . Speaking of Garands, being french canadian myself I think I know some of the relatives, they did make shovels under a similar name and they did speak of a relative who got rich by selling his product to the united states and moving there. Alex Outro Andrew - https://ragnaroktactical.ca/ Visit us at www.canadianpatriotpodcast.com like us on Facebook at www.facebook.comcanadianpatriotpodcast We value your opinions so please visit www.canadianpatriotpodcast.com/feedback/ or email us at feedback@canadianpatriotpodcast.com and let us know what you think. Tim’s Good T-Shirts, facebook.com/timsgoodtshirts   and remember “You are the True North Strong and Free”   Music used under Creative Commons licenses The last ones by Jahzzar http://freemusicarchive.org/music/Jahzzar/Smoke_Factory/The_last_ones Epic by Bensound http://www.bensound.com/royalty-free-music/track/epic

On this week's episode, we discuss the M1A in 6.5 creedmoor, the Vudoo Ravage in .22lr, and a NXTGEN EZ 20 shotgun caddy. For all the show notes and back episodes, head over to firearmsradio.tv/gun-and-gear-review-podcast

On this week’s episode, we discuss the M1A in 6.5 creedmoor, the Vudoo Ravage in .22lr, and a NXTGEN EZ 20 shotgun caddy. For all the show notes and back episodes, head over to firearmsradio.tv/gun-and-gear-review-podcast

Sorry for the delay in getting this episode posted. We have been busy with opening day of gun season. In this weeks discussion freeze and I discuss: Opening Day of Gun Season is here. Freeze's father is very good with iron sights on his AR. After the Russian airliner bombing in Egypt, local security busted using fake metal detectors.  Hollywood news: Hillary Duff buys a Glock and a NCIS star is assaulted by a mentally ill man who should be locked up. But isn't. I think I broke my S&W 547 Revolver. ISIS fighters from West complaint about lack of Starbucks and other amenities in the caliphate.  No. The FBI has NOT selected the SIG P320 as the next service pistol. At least NOT YET! The internet is wrong. It's click bait! So stop! The M1A really does suck, Dude.  So...the indictments for the Waco biker shootout have been handed down. Where are all the apologists now? Oh that's right! It REALLY was about drugs after all! Shocker! Why Freeze isn't allowed to have a company credit card: He wants to buy a French Fighter Jet.    We appreciate all your support. The response has been overwhelming. Don't forget to leave feedback on iTunes. That really helps us get the word out.    Sincerely, Marky & Feeze www.tacticaltshirts.com "Shooting Guns & Having Fun"  

Grant extols the virtues of a Sssshhhteyr pistol, Ian discusses a muddy M1A and King Abdullah of Jordan shot at Gunsite!

Welcome to the We Like Shooting show, Episode 36.  This week we’ll talk about the Sphinx SDP Compact, Nordic mag extensions, fury tactical kuba kickz, budget shotguns, M1A optics aaaand the Wolf Arms VEPR 12.