Podcasts about msi h

Dear Colleagues,Welcome to the OncoAlert Weekly Round up Covering the TOP News and Trials THIS WEEK in Oncology. This week:Prognostic implications of risk definitions from the monarchE and NATALEE trialhttps://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djaf031/8002826?login=false#google_vignetteEvaluating the impact of histological vs. nuclear grading on CPS + EG Score for HR + /HER2-early breast cancerhttps://link.springer.com/article/10.1007/s10549-025-07685-8?utm_content=buffer1d9c4&utm_medium=social&utm_source=twitter.com&utm_campaign=bufferFDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancerhttps://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancerCirculating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: 5-year outcomes of the randomized DYNAMIC trialhttps://www.nature.com/articles/s41591-025-03579-wAssessment of a Polygenic Risk Score in Screening for Prostate Cancer (BARCODE1) https://nejm.org/doi/full/10.1056/NEJMoa2407934Neoadjuvant Aumolertinib for unresectable stage III EGFR-mutant non-small cell lung cancerhttps://www.nature.com/articles/s41467-025-58435-9Circulating tumor DNA Clearance as a Predictive Biomarker of Pathologic Complete Response in Patients with Solid Tumors Treated with Neoadjuvant Immune-Checkpoint Inhibitors: a Systematic Review and Meta-Analysishttps://www.annalsofoncology.org/article/S0923-7534(25)00130-9/abstract

CME credits: 1.25 Valid until: 30-12-2025 Claim your CME credit at https://reachmd.com/programs/cme/applying-current-guidelines-in-the-first-line-treatment-of-msi-hdmmr-mcrca-case-discussion/29852/ The NCCN Clinical Practice Guidelines are crucial tool in the treatment of cancer and provide detailed recommendations for treatment selection. The guidelines are regularly updated as new therapies are approved or as drugs received expanded indications. Moreover, data are constantly evolving regarding the role of biomarkers and treatment choice. This activity has been designed to provide an overview of the NCCN guidelines for gastric, colorectal, and hepatocellular cancers and the optimal application of these recommendations to clinical practice.

CME credits: 1.25 Valid until: 30-12-2025 Claim your CME credit at https://reachmd.com/programs/cme/first-line-treatment-of-msi-hdmmr-mcrc-the-role-of-immunotherapy/29850/ The NCCN Clinical Practice Guidelines are crucial tool in the treatment of cancer and provide detailed recommendations for treatment selection. The guidelines are regularly updated as new therapies are approved or as drugs received expanded indications. Moreover, data are constantly evolving regarding the role of biomarkers and treatment choice. This activity has been designed to provide an overview of the NCCN guidelines for gastric, colorectal, and hepatocellular cancers and the optimal application of these recommendations to clinical practice.

Host: Charles Turck, PharmD, BCPS, BCCCP Guest: Steven Maron, MD, MSc Given the recent identification of actionable biomarkers like PD-L1 and MSI-H,1-3 it's important to test patients with gastroesophageal cancer for these biomarkers as they may provide insights into options for a patient's treatment plan.4,5 To learn more about how we can detect biomarkers and other key considerations for biomarker screening in gastroesophageal cancer, Dr. Charles Turck speaks with Dr. Steven Maron, a gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center in New York. References: The Cancer Genome Atlas Network. Nature. 2014;513:202-209. Fontana E, et al. Ther Adv Med Oncol. 2016;8:113-125. Yang B, et al. J Exp Clin Cancer Res. 2019;38:283. American Cancer Society. https://www.fightcancer.org/sites/default/files/Improving%20Access%20to%20Biomarker%20Testing_FINAL.pdf. Accessed July 20, 2024. Catenacci DVT, et al. Future Oncol. 2019;15:2073-2082. ©2024 Amgen Inc. All rights reserved. USA-OCF-82400 9/24

CancerNetwork® spoke with Ritu Salani, MD, about the expanded FDA approval of dostarlimab-gxly (Jemperli) in combination with carboplatin/paclitaxel for patients with primary advanced or recurrent endometrial cancer.1  Salani, a board-certified gynecologic oncologist and director of Gynecologic Oncology at the University of California, Los Angeles Health, discussed the clinical benefit the dostarlimab combination showed for patients with endometrial cancer, particularly those with mismatch repair-deficient (dMMR) tumors, in the phase 3 RUBY trial (NCT03981796). Data leading to the approval showed a statically significant progression-free survival (PFS) and overall survival (OS) benefit in patients with dMMR or microsatellite-instability high (MSI-H) endometrial cancer, as well as for those across the overall population. Noting the significant impact dostarlimab had on survival benefit without significant added toxicity, which investigators reported as early as March 2023, Salani said it was “wonderful” to have a relatively short turnaround time in making the combination therapy available for patients with primary advanced or recurrent endometrial cancer. Beyond the particular benefit among patients with dMMR tumors, she expressed the need to improve outcomes for patients with mismatch repair-proficient (pMMR) or microsatellite stable (MSS) tumors, who did not experience as much of a pronounced benefit from treatment with dostarlimab. Salani also addressed the role of immunotherapy in subsequent lines of treatment following frontline therapy. Being thoughtful about sequencing agents in this setting may be an optimal strategy to give patients the greatest survivability and quality of life. She also considered alternative treatment strategies for certain patients, such as those with pMMR tumors.  “The thing that is interesting is the study highlighted patients who had residual disease or measurable disease present when they were getting this therapy, and that seems to be where the most significant impact [is],” Salani said. “Seeing more data on the right selection of patients will be really important. There are other avenues of treatment for these patient populations, particularly the pMMR population, where you might see some other therapies that may have an equally profound impact as immunotherapy. Maybe that will lend itself to leading immunotherapy for second-line treatment, if needed.” Reference FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. News release. FDA. August 1, 2024. Accessed August 15, 2024. https://tinyurl.com/mtr6tpyp

La Dra. Julieta Gómez Avalos, oncóloga médica egresada del CMN "20 de Noviembre" del ISSSTE en la Ciudad de México y actualmente en entrenamiento en Oncología Gastrointestinal en el Hospital Clínico Universitario en Valencia, España, comparte los aspectos más destacados del Congreso de ESMO sobre tumores gastrointestinales realizado este año en Alemania del 26 al 29 de junio. TARZAN: evalúa la combinación de radioterapia, atezolizumab y bevacizumab en pacientes con cáncer de recto en etapas tempranas e intermedias, con el fin de evitar la cirugía radical y mejorar las tasas de preservación de órganos. El objetivo primario es evaluar la respuesta clínica completa a las 12 semanas mediante endoscopia y resonancia magnética, buscando una tasa superior al 25%. Los objetivos secundarios abarcan la respuesta patológica, la tasa de preservación de órganos, la seguridad del tratamiento y la supervivencia libre de recurrencia. NEST-1: estudio de un solo brazo que investiga el uso neoadyuvante de botensilimab, un inhibidor de CTLA-4 mejorado con Fc, junto con balstilimab, un inhibidor de PD-1, en pacientes con cáncer colorrectal resecable, tanto con microsatélite estables como con alta inestabilidad de microsatélites (MSI-H). El objetivo es evaluar la viabilidad, seguridad y eficacia de la combinación para un estudio más amplio. ECOG-ACRIN EA220: estudio fase II, de un solo brazo, que investiga el uso de nivolumab e ipilimumab, combinados con radioterapia de corto curso, seguidos de cirugía en pacientes con cáncer de recto localmente avanzado con MSI-H o dMMR (reparación deficiente por desajuste). El objetivo primario es evaluar la tasa de respuesta patológica completa después del tratamiento, con la posibilidad de incluir la respuesta clínica completa en un análisis combinado si la tasa de excisión mesorrectal total es menor de lo esperado. Abstract 7MO: el estudio analizó el ADN tumoral circulante y el ImmunoScore® en pacientes con cáncer de colon resecado en estadio III, utilizando datos post hoc de los estudios IDEA-France y HORG. El objetivo es evaluar el valor pronóstico de ambos elementos para mejorar la predicción y personalización de los tratamientos adyuvantes en estos pacientes. Fecha de grabación: 5 de julio de 2024               Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

Our 2024 ASCO epic trundles onto its next generation, advanced colorectal cancer. Over the last 10 years, treatment in this area has made incremental progress through the discovery of the clinically meaningful KRAS and BRAF mutation pathways and most recently with the potential for immunotherapy in the deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H) subgroups. In this episode, Josh and Michael examine studies looking at KRAS G12C-mutated, HER2-positive and dMMR colorectal cancer, as well as a very exciting study examining the utility of transplantation in patients with liver-only colorectal metastases.Links to studies discussed in this episode (subscription may be required): CODEBREAK300: https://meetings.asco.org/2024-asco-annual-meeting/15829?presentation=234200%23234200 MOUNTAINEER: https://meetings.asco.org/2024-asco-annual-meeting/15829?presentation=231646%23231646 CHECKMATE 8HW: https://meetings.asco.org/2024-asco-annual-meeting/15828?presentation=231645%23231645TRANSMET: https://meetings.asco.org/2024-asco-annual-meeting/15828?presentation=231641%23231641For more episodes, resources and blog posts, visit www.inquisitiveonc.comPlease find us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comOncology for the Inquisitive Mind is recorded with the support of education grants from Pfizer, Gilead Pharmaceuticals and Merck Pharmaceuticals. Our partners have no editorial rights or early previews, and they have access to the episode at the same time you do.Art courtesy of Taryn SilverMusic courtesy of AlisiaBeats: https://pixabay.com/users/alisiabeats-39461785/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice. Hosted on Acast. See acast.com/privacy for more information.

I sit down with Dr Asaf Maoz, Medical Oncologist at Dana Farber Cancer Institute, who I recently saw at the LynkedIn and Scientific Symposium.  We discussed what brought Dr Maoz to this point, discussing immunology, T-cells, receptors and targets.  Dr Maoz confirmed that not all Lynch cancers are MSI-H.  This year, for the 5 year anniversary of the patient LynkedIn conference, they had the scientific symposium the day before.  Dr Michael Foote from MSK presented some data on cancer risk after immunotherapy.  I appreciate the debates and conversations that take place at the symposiums, and how data will continue to drive innovation, but like anything, until you generate the data you can't hypothesize and stratify.  Of course we ventured into the cancer vaccine space and the unique molecular features of Lynch Syndrome and the potential to prevent cancer in the future.  Takeaway is to keep up with screening regardless.  We also discussed language barriers to healthcare overall, not just Lynch Syndrome, including how AI is being looked at in order to potentially find tidbits that are missed.  

El Dr. Jorge Gallardo, oncólogo médico, Coordinador de Oncología Médica en la Clínica INDISA en Providencia, Santiago de Chile junto con la Dra. Marytere Herrera Martínez, oncóloga médica adscrita a la Unidad de Tumores Gastrointestinales del Instituto Nacional de Cancerología, en la Ciudad de México, México nos hablan sobre los estudios más relevantes presentados durante el Simposio de Cánceres Gastrointestinales 2024 :   Tubo digestivo KEYNOTE 590: resultado a 5 años del estudio fase III, aleatorizado, doble ciego, que evaluó el uso de pembrolizumab en combinación con quimioterapia (QT) con cisplatino y 5-fluorouracilo vs. placebo + QT como tratamiento de primera línea en pacientes con cáncer esofágico avanzado metastásico. MATTERHORN: estudio fase III, aleatorizado, doble ciego que evaluó el tratamiento de durvalumab o placebo neoadyuvante-adyuvante y QT FLOT (fluorouracilo + leucovorina + oxaliplatino + docetaxel) seguido de durvalumab o placebo adyuvante en pacientes con cáncer resecable de la unión gástrica y gastroesofágica. KEYNOTE 585: estudio fase III, aleatorizado, doble ciego, el cual comparó pembrolizumab perioperatorio más QT vs. placebo perioperatorio más QT en pacientes con cáncer en la unión gástrica o gastroesofágica localmente avanzada. Cabe destacar que se realizó una cohorte en donde se evaluó pembrolizumab + FLOT y los resultados mostraron un aumento en las respuestas patológicas completas con pembrolizumab perioperatorio más FLOT vs. FLOT solo. Tumores neuroendocrinos NETTER-2: estudio fase III, multicéntrico, aleatorizado y abierto que evaluó la eficacia y seguridad de Lu-177 dotatate en combinación con octreótido en pacientes con tumores neuroendocrinos gastroenteropancreáticos (TNE-GEP) con altas tasas de proliferación (G2 y G3). Se observaron mejoras significativas en la supervivencia libre de progresión con la combinación vs. octreótido en dosis elevadas. Carcinoma hepatocelular EMERALD-1: estudio fase III, global, aleatorizado, doble ciego, controlado con placebo que evaluó el uso de durvalumab + quimioembolización transarterial (TACE, por sus siglas en inglés) concurrente, seguido de durvalumab con o sin bevacizumab hasta la progresión, en comparación con TACE solo en pacientes con carcinoma hepatocelular (CHC) irresecable elegibles para embolización. Cáncer colorrectal CheckMate-8HW: estudio fase III, abierto, en el cual se observó una mejora en el objetivo primario de supervivencia libre de progresión (SLP) con la combinación de nivolumab + ipilimumab vs. la QT elegida por el investigador (mFOLFOX-6 o FOLFIRI con o sin bevacizumab/cetuximab) en el tratamiento de 1L para los pacientes con cáncer colorrectal metastásico (CCRm) con inestabilidad de microsatélites alta (MSI-H, por sus siglas en inglés) o deficiencia en la reparación de emparejamiento (dMMR, por sus siglas en inglés). BESPOKE: estudio de cohorte observacional, prospectivo y multicéntrico en el cual se inscribió un total de 2000 pacientes en etapa I-IV y se realizó un seguimiento de los mismos durante un máximo de 2 años con análisis seriados de ctDNA programados con las visitas de atención estándar. Fecha de grabación: 24 de enero de 2024.               Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

Meet Dr. Ulka Vaishampayan* – an oncologist and leading expert in treating people with kidney cancer, including renal cell carcinoma (RCC) which is the most common type of kidney cancer in adults. She understands all too well how scary and overwhelming hearing the words “you have cancer” can be for anyone – especially when facing an advanced diagnosis in RCC. In these cases, Dr. Vaishampayan believes that information is power and people can feel better prepared to move forward if they have a support system and strong patient-doctor communication.  On today's episode of the Cancer Horizons podcast, Dr. Vaishampayan shares information that's important to understand about RCC and navigating a diagnosis, key questions patients and caregivers should ask their doctor, and insights into a potential dual immunotherapy treatment option for certain patients. When it comes to making a treatment plan, Dr. Vaishampayan believes in involving her patients closely in the process. “In my practice I tend to explain what options are available to someone, including the pros and cons of each, and I sometimes make a recommendation about a treatment approach if I feel that's appropriate in their case,” she explains. “I would still explain the reasons for my choice. My intention is that either way it's a discussion, as it should be a joint or shared decision-making process.” Terry Broussard**, a man who was diagnosed with advanced RCC, also shares advice from his experience. In Terry's case, his doctor recommended the dual immunotherapy treatment combination Opdivo® (nivolumab) plus Yervoy® (ipilimumab), which is approved by the U.S. Food and Drug Administration for certain newly diagnosed adults whose kidney cancer has spread (advanced renal cell carcinoma) and have not already had treatment for advanced RCC. It is the first and only combination of two immunotherapies of its kind approved to treat advanced kidney cancer, or RCC. To learn more, listen to the podcast, visit www.Opdivo.com and see below for Important Safety Information. *Dr. Vaishampayan is a paid consultant of Bristol Myers Squibb. Dr. Vaishampayan's statements/opinions are those solely of Dr. Vaishampayan and are not necessarily those of Bristol Myers Squibb. Individual results/experiences may vary. **Terry is an actual patient who has been compensated by Bristol Myers Squibb. Terry's results may not be typical. Medication may not work for everyone. Indication OPDIVO® (nivolumab) is a prescription medicine used in combination with YERVOY® (ipilimumab) to treat adults with kidney cancer in certain people when your cancer has spread (advanced renal cell carcinoma) and you have not already had treatment for your advanced RCC. It is not known if OPDIVO is safe and effective in children younger than 12 years of age with melanoma or MSI-H or dMMR metastatic colorectal cancer. It is not known if OPDIVO is safe and effective in children for the treatment of any other cancers. OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous (IV) use. Important Safety Information for OPDIVO® (nivolumab) + YERVOY® (ipilimumab) What is the most important information I should know about OPDIVO + YERVOY? OPDIVO and YERVOY are medicines that may treat certain cancers by working with your immune system. OPDIVO and YERVOY can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. These problems may happen anytime during treatment or even after your treatment has ended. You may have more than one of these problems at the same time. Some of these problems may happen more often when OPDIVO is used in combination with another therapy. Call or see your healthcare provider right away if you develop any new or worse signs or symptoms, including: Lung problems: new or worsening cough; shortness of breath; chest pain Intestinal problems: diarrhea (loose stools) or more frequent bowel movements than usual; stools that are black, tarry, sticky, or have blood or mucus; severe stomach-area (abdominal) pain or tenderness Liver problems: yellowing of your skin or the whites of your eyes; severe nausea or vomiting; pain on the right side of your stomach area (abdomen); dark urine (tea colored); bleeding or bruising more easily than normal Hormone gland problems: headaches that will not go away or unusual headaches; eye sensitivity to light; eye problems; rapid heart beat; increased sweating; extreme tiredness; weight gain or weight loss; feeling more hungry or thirsty than usual; urinating more often than usual; hair loss; feeling cold; constipation; your voice gets deeper; dizziness or fainting; changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness Kidney problems: decrease in your amount of urine; blood in your urine; swelling in your ankles; loss of appetite Skin problems: rash; itching; skin blistering or peeling; painful sores or ulcers in the mouth or nose, throat, or genital area Eye problems: blurry vision, double vision, or other vision problems; eye pain or redness. Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with OPDIVO and YERVOY. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include: Chest pain; irregular heartbeat; shortness of breath; swelling of ankles Confusion; sleepiness; memory problems; changes in mood or behavior; stiff neck; balance problems; tingling or numbness of the arms or legs Double vision; blurry vision; sensitivity to light; eye pain; changes in eye sight Persistent or severe muscle pain or weakness; muscle cramps Low red blood cells; bruising Getting medical help right away may help keep these problems from becoming more serious. Your healthcare team will check you for these problems during treatment and may treat you with corticosteroid or hormone replacement medicines. Your healthcare team may also need to delay or completely stop your treatment if you have severe side effects. Possible side effects of OPDIVO + YERVOY OPDIVO and OPDIVO + YERVOY can cause serious side effects, including: See “What is the most important information I should know about OPDIVO + YERVOY?” Severe infusion reactions. Tell your healthcare team right away if you get these symptoms during an infusion of OPDIVO or YERVOY: chills or shaking; itching or rash; flushing; shortness of breath or wheezing; dizziness; feel like passing out; fever; back or neck pain Complications, including graft-versus-host disease (GVHD), of bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be severe and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with OPDIVO or YERVOY. Your healthcare provider will monitor you for these complications. The most common side effects of OPDIVO, when used in combination with YERVOY, include: feeling tired; diarrhea; rash; itching; nausea; pain in muscles, bones, and joints; fever; cough; decreased appetite; vomiting; stomach-area (abdominal) pain; shortness of breath; upper respiratory tract infection; headache; low thyroid hormone levels (hypothyroidism); constipation; decreased weight; and dizziness. These are not all the possible side effects. For more information, ask your healthcare provider or pharmacist. You are encouraged to report side effects of prescription drugs to the FDA. Call 1-800-FDA-1088. Before receiving OPDIVO or YERVOY, tell your healthcare provider about all of your medical conditions, including if you: have immune system problems such as Crohn's disease, ulcerative colitis, or lupus have received an organ transplant have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic) have received radiation treatment to your chest area in the past and have received other medicines that are like OPDIVO have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome are pregnant or plan to become pregnant. OPDIVO and YERVOY can harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if OPDIVO or YERVOY passes into your breast milk. Do not breastfeed during treatment with OPDIVO or YERVOY and for 5 months after the last dose of OPDIVO or YERVOY. Females who are able to become pregnant: Your healthcare provider should do a pregnancy test before you start receiving OPDIVO or YERVOY. You should use an effective method of birth control during your treatment and for 5 months after the last dose of OPDIVO or YERVOY. Talk to your healthcare provider about birth control methods that you can use during this time. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with OPDIVO or YERVOY. You or your healthcare provider should contact Bristol-Myers Squibb at 1- 844-593-7869 as soon as you become aware of a pregnancy. Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements. Please see U.S. Full Prescribing Information and Medication Guide for OPDIVO and YERVOY.

Dr Mirza discusses the FDA approval of dostarlimab plus chemotherapy in patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer; key efficacy and safety findings from the RUBY trial, and ongoing research investigating the role of frontline immune checkpoint inhibitors in patients with endometrial cancer.

Featuring perspectives from Dr Michael J Overman, including the following topics: Introduction (0:00) Case: A woman in her mid 40s with microsatellite instability-high (MSI-H) colorectal adenocarcinoma metastatic to the brain receives pembrolizumab; KRAS G13D and somatic BRCA exon 11 mutations — Warren S Brenner, MD (16:27) Case: A woman in her late 50s with MSI-H Stage IIIB adenocarcinoma of the colon, BRAF V600E mutation — Eric H Lee, MD, PhD (23:20) Case: A woman in her early 70s with past medical history of diverticulitis and partial colectomy diagnosed with T1, microsatellite stable (MSS) cecal colon adenocarcinoma, minimum residual disease-negative after resection — Farshid Dayyani, MD, PhD (32:37) Case: A woman in her late 60s with past medical history of hypothyroidism has mass in right lung consistent with colorectal adenocarcinoma but no evidence of primary or other distant disease — Swati Vishwanathan, MD (42:58) Case: A woman in her mid 60s with multiregimen-relapsed RAS wild-type, HER2-positive metastatic rectal cancer, now receiving trastuzumab/tucatinib — Sunil Gandhi, MD (46:51) Case: A man in his mid 60s with MSS metastatic cecal adenocarcinoma and progressive disease on FOLFIRINOX/bevacizumab and capecitabine/bevacizumab maintenance — Dr Brenner (50:13) Case: A woman in her mid 60s with metastatic BRAF V600E-mutant colorectal adenocarcinoma, with circulating tumor DNA positivity after FOLFOX, heated intraperitoneal chemotherapy and colectomy/debulking surgery — Jeremy Lorber, MD (54:31) CME information and select publications

Dr. Mohamed Salem, Dr. Myriam Chalabi, and Dr. Andrea Cercek discuss pivotal neoadjuvant immunotherapy clinical trials for patients with MSI-H/dMMR colorectal cancer, focusing on the development of active therapies in the neoadjuvant setting—where patients are treated without surgery, radiation, or chemotherapy—and the importance of patient selection in finding the right target and treatment to improve outcomes. TRANSCRIPT Dr. Mohamed Salem: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host today, Dr. Mohamed Salem. I'm a GI oncologist at the Levine Cancer Institute at Atrium Health. Today, we will be discussing very promising advancements in the neoadjuvant immunotherapy for patients with MSI-H/dMMR colorectal cancer. And I'm very delighted to welcome two world-renowned oncologists whose research has tremendously helped shape the treatment landscape of colorectal cancer. Dr. Myriam Chalabi is a GI medical oncologist at the Netherlands Cancer Institute, and Dr. Andrea Cercek is a medical oncologist at Memorial Sloan Kettering in the United States.  Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod.  Dr. Chalabi and Dr. Cercek, welcome to the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you for having me. Dr. Andrea Cercek: Thank you very much for having me. Dr. Mohamed Salem: It's a pleasure to have two world-renowned stars like you. Thank you for taking the time.  So, before we start going deep into the topic, obviously, now we are seeing emerging data in CRC using immunotherapy as the neoadjuvant approach, which actually can reduce or even eliminate some of the other treatment modalities and potentially save patients from toxicities. Both of you led what I think are landmark studies in this field. I wanted to give you the chance to tell our audience about your studies and why you think they're important. Dr. Cercek? Dr. Andrea Cercek: Sure. Thank you so much. So, our study was a neoadjuvant study in early-stage, locally advanced rectal cancer with tumors that were mismatch repair-deficient or MSI-H. And rectal cancer normally is treated with chemotherapy, chemoradiation, and surgery. And the goal of the trial was to utilize PD-1 blockade alone in this subpopulation and evaluate the response.  Patients received six months of dostarlimab, which is a PD-1 blocking agent, and then were evaluated for response. If there was no residual disease, they were able to avoid radiation and surgery. And what we've seen thus far in the presentation at GI ASCO in 2022 was that all patients who received six months of dostarlimab had a clinical complete response, so no residual tumor, and were able to avoid chemotherapy, radiation, and surgery and are on observation. And the study is ongoing and actively accruing patients. Dr. Mohamed Salem: All of us were very excited seeing that presentation at ASCO. And when we came back to the clinic everyone was talking about it, including patients, obviously. Thank you for this, Dr. Cercek. Dr. Chalabi, you also led a similar study that was actually presented in ESMO in 2022. Can you please give us, like, a brief description of that trial? Dr. Myriam Chalabi: Yeah, sure. So, this is the NICHE trial, and actually the NICHE trial has been ongoing for quite some time now. We recently presented a larger NICHE-2 study, but basically– so what we started out by doing in NICHE is giving patients what we considered back then a window of opportunity study. We treated patients with MMR-deficient tumors, which I'll be focusing on for now, with two cycles of nivolumab and one single cycle of low-dose ipilimumab. And patients all undergo surgery within six weeks of registration within the study. And back in 2020, we published the first data of NICHE-1 showing 100% pathologic responses with 60% pathologic complete responses and decided that this should definitely be a treatment that we need to explore in a larger group of patients. And that's where NICHE-2 was born, which we presented at ESMO last year, where we treated over 100 patients with this neoadjuvant approach of two cycles nivolumab, one single cycle ipilimumab, showing 99% pathologic responses, including 95% major pathologic responses and 67% pathologic complete responses. And this was all within five and a half weeks of the first treatment with immunotherapy, so a very short treatment duration with dual checkpoint blockade. Dr. Mohamed Salem: Amazing results, too. And I know you had a standing ovation when you presented the outcome of the study. And again, congratulations to you, your investigator, and also all the patients participated. Dr. Myriam Chalabi: Thank you so much.  Dr. Mohamed Salem: I guess the first question that comes to my mind - we have two trials, obviously, now we're moving from one size fits all to precision therapy, like getting actually the right treatment for the right patient. But in the NICHE study, it was a checkpoint inhibitor, and the rectal study was a single agent. I want to start with you, Dr. Chalabi. In your opinion, when should we use single agent or double blockade immunotherapy? Dr. Myriam Chalabi: That is a great question. I'm going to start off by saying that I don't know the exact answer. I don't think we know that answer. And Dr. Cercek is going to share also her thoughts on this because we're seeing, of course, fantastic responses with monotherapy as well in Dr. Cercek's study. And we've also seen that in a study by Dr. Overman with monotherapy. So that may suffice in some patients, although what we're seeing is that you need to treat patients longer, probably to achieve that response, at least clinically. And I think that is the difference with dual checkpoint blockade, that we're giving in NICHE where we're seeing these very deep responses in just under six weeks' time.  So, I think it may be more of a question of how long we want to treat patients for to achieve the endpoint that we're aiming for. And, of course, there may be, at some point, patients that need dual checkpoint blockade, but so far, we're seeing great responses in both of our studies. So I think we need more patients, more data to see whether we're going to see non-responders. And hopefully, the studies that are ongoing in the metastatic disease setting will give us at least a little bit of insight into what the differences are in response to mono and dual checkpoint blockade and whether we can tell which patients might benefit more from the combination. But I think there's still a lot of work to be done in that field. Dr. Mohamed Salem: I totally agree. Dr. Cercek, same question to you. What do you think?  Dr. Andrea Cercek: Dr. Chalabi answered beautifully and very comprehensively. I agree completely with what she said. It's hard to argue with the responses that we're seeing with PD-1 blockade alone. But then again, dual checkpoint inhibitors in the NICHE study with just one month of therapy had phenomenal responses as well. So I think it's a question of duration of therapy and, really importantly, what we're trying to achieve. If our goal is organ preservation, then perhaps longer duration is better. The question then becomes, can we do, should we do longer duration with dual checkpoint inhibitors versus single agent? So I think, as she concluded, I couldn't agree more that we just need more information, we need more work to do, basically to answer this question for our patients. Dr. Mohamed Salem: More to come and more studies, which is fascinating.  So, Dr. Chalabi, you created actually a new term on Twitter called ‘Chalabi Plot'. It was amazing to see such a response. But we're curious, among those patients who achieved complete response so far, did you see any relapse? Dr. Myriam Chalabi: Short answer, no.  we're waiting, of course on the disease-free survival data, the three-year DFS data for NICHE-2, and we hope to have that by the end of this year, beginning of next year. But as of now, we showed that data, and so far, we haven't seen any recurrences in, actually, any of the patients treated in NICHE-2. Dr. Mohamed Salem: Fantastic. Dr. Cercek. So I think your slide -- I remember clearly from the ASCO presentation -- was all complete response, every single patient.  Same question, did you see any relapse so far? Dr. Andrea Cercek: So far, no, we have not. Dr. Mohamed Salem: Amazing. So, Dr. Cercek, as you know, and obviously, this is metastatic disease, but in KEYNOTE-177, as you know, about 30% of patients with MSI-high tumors did not respond to checkpoint inhibitors. So that makes some of us feel nervous about using checkpoint inhibitors alone in colorectal cancer, even with MSI-high status. I was curious if you can comment on this and if there is a way we can perhaps sort out who actually is likely to respond and who is likely not going to respond. Dr. Andrea Cercek: I think that's a really important question and an excellent point. And we believe that the difference lies in the fact that in KEYNOTE-177, the patients had metastatic disease, whereas in our neoadjuvant studies that we're discussing, they have early-stage disease. And whether that has to do with the tumor differences, young tumors versus older tumors once they become metastatic, or the microenvironment, remains to be determined. But certainly, there is this pattern of incredible responses with checkpoint inhibitors in early-stage dMMR tumors. And in KEYNOTE-177, as you mentioned, about 30% of patients progressed. And I think we don't know why that is. We are seeing this, about a third of progressors repeatedly in the metastatic setting with checkpoint inhibitors. And so perhaps there is a population. But whether this is driven by genomics or something else, we don't know. Dr. Mohamed Salem: Great. So, along the same lines, especially rectal cancer, obviously, because surgical resection is a key component in the treatment paradigm, do you feel patients who achieve pathological complete response should still go under surgical resection or should go under the ‘watch and wait' approach? Dr. Andrea Cercek: In general, I'm a fan of organ preservation. I think in rectal cancer, the reasons are obvious. It's a challenging surgery. It's very toxic to the patients. It changes their lives forever. In survivorship, 30% of them require a permanent colostomy because of the location of the tumor. So there, the field of rectal cancer, in general, is moving towards non-operative management, even in the MSI-proficient patients, by trying to optimize therapy to increase clinical complete responses and therefore omit surgery. So that's the difference with rectal cancer. In colon cancer, it's a different discussion. I think for many patients, surgery is very straightforward. It's a hemicolectomy. It doesn't alter lifestyle in survivorship, so it's not as morbid as it is in rectal cancer. Of course, I think if a patient is older with MSI-deficient tumor perhaps can undergo surgery, then clinical complete responses become critical because then we can monitor them after just checkpoint blockade, and they don't need surgery.  The challenge there, and I would love to hear Dr. Chalabi's comments on this, too, is just that imaging is challenging. We have a hard time in colon cancer determining whether someone has a clinical complete response or not. It seems to be very different than in rectal cancer, where with endoscopy and with the rectal MRI, we really can't tell whether the tumor is still present or not. This remains a challenge in colon cancer. Dr. Mohamed Salem: Dr. Chalabi, I would like to hear your thoughts and also how you practice in Europe. I don't know if it's the same like here in US or different. Dr. Myriam Chalabi: I completely agree with Dr. Cercek. Well, if we look at the rectal cancer patients, I think this is fantastic. That even though this is a small population achieving this high clinical complete response rate, not having to operate or even give any chemotherapy or radiation therapy to these patients, it is extremely important both in the short term but also in terms of long-term complications and morbidity. When it comes to the colon cancer responses that we're seeing in NICHE, those are all pathologic responses, of course. And we have been evaluating also preoperatively using scans to see whether we can assess these complete responses based on imaging. That doesn't seem to be the case. We do see responses in all patients, so we see these are all very large bulky tumors that we're treating in NICHE-2. And we do see responses in almost all of these patients, but it's not close to complete responses, definitely not in all of the complete responders that we're seeing. So that makes it difficult.  And the question is, what if we would be waiting or treating longer because these bulky tumors need more time to disappear or to be cleared before you're going to see it on the imaging? So that is a question that I don't have an answer to just yet. We may be getting some more data on that with the currently ongoing trials. And as Dr. Cercek pointed out, the endoscopies when you have a right-sided colon tumor are different than doing just a sigmoidoscopy for a rectal tumor. So, we actually do have one patient who hasn't undergone surgery, and that is actually a patient with an MMR-proficient tumor within the NICHE trial who had a complete response. And that patient has a sigmoidal tumor, and he actually had toxicities which prevented him from undergoing timely surgery and now has a complete response after two years, both endoscopically and on imaging. So, he hasn't undergone surgery, and that is a great example of how we may be doing this in the future. It's an interesting case within the trial to follow and see how we can do it in the future. Dr. Mohamed Salem: That's fascinating news. So, was it MMR-proficient? Dr. Myriam Chalabi: Yes, this is an MMR-proficient tumor.  Dr. Mohamed Salem Wow. Any particular biomarkers that you think he or she had to predict that? Dr. Myriam Chalabi: We have treated more patients with MMR-proficient tumors. We have 31 patients, and we have seen actually responses in 9 out of 31 patients in the MMR-proficient tumors with the same combination of two doses of nivolumab and one of ipilimumab. We previously published on half of the cohort approximately on what the possible predictive biomarkers of response could be, and that was a costimulation for CD8 and PD-1. So PD-1 positive CD8 T cells. And we're currently doing the same work for the rest of the cohort. So hopefully, we'll be able to show that soon and see whether this still stands for the completed MMR-proficient cohort. But definitely also very exciting data for the MMR-proficient. Dr. Mohamed Salem: So, this is actually a very good segue to my next question because I know all of us are looking for this. Like, obviously, we're seeing a fascinating response in those patients with MSI-high tumors, but majority of colorectal cancer, as you know, they actually have MSS-proficient tumors. Any thoughts about how we can overcome the primary resistance for this tumor to checkpoint inhibitors? So let me start with you, Dr. Cercek.  Dr. Andrea Cercek: I'm very much looking forward to Dr. Chalabi's data on this because, honestly, we have not seen such amazing responses to immunotherapy in MSS tumors. The initial studies were complete flatline, no responses at all. And here, she just described a patient that had a complete response to just a month of checkpoint inhibitors. So that's phenomenal, and hopefully, we'll learn from the responders.  We believe that there is a subpopulation of MSS colorectal cancer that is more immune sensitive, immune hot, whichever term you like to use. And it's just a matter of appropriately identifying those patients. And personally, I think the answer lies in the neoadjuvant setting in early tumors where they're treatment-naive, not exposed to chemo, not exposed to radiation, younger, have their innate microenvironment. And so, I think it's likely a combination of the above. But obviously, the ultimate goal is to find out who those patients are and then potentially treat them just like this with immunotherapy. And that would be another nice chunk of the pie where we could utilize immunotherapy for our patients. Dr. Mohamed Salem: Very true. Dr. Chalabi, especially with your experience and just showing there is a chance for those people to respond, what are your thoughts about how we can overcome this primary resistance? Dr. Myriam Chalabi: It's great to be here with Dr. Cercek because, obviously, we have very similar interests but it's also good to see that we think the same way because I completely agree with what she just said in terms of neoadjuvant. I think that was one of the most important things that we did here, giving this neoadjuvant treatment in non-metastatic tumors. It's probably a very important driver in the responses that we're seeing. So, we've been seeing data now a bit more in the metastatic disease setting where MSS tumors seem to be responding to new generations of checkpoint blockade. And the question is how those would do in the neoadjuvant setting that would be even different than what we're seeing now. But there's definitely some proof of MSS tumors that can respond to immunotherapy. The question on how to overcome the primary resistance, I think that question is for us: Who are the patients with primary resistant tumors and why are they primarily resistant? And then we can think about how to change that and how to change them into the tumors that are responding. I think these types of data will be key to understand more and know; hopefully, even you said, in the metastatic disease setting, to make these tumors more pliable in response to immunotherapy. Dr. Mohamed Salem: I agree. So, both of you are leading us toward how to choose the right patient with the right target for the right treatment. That's an amazing journey you're taking all of us on.  So, Dr. Cercek, I have to admit that with your data, it created some problems for us in the clinic because all patients the following day came in asking for immunotherapy. We had a hard time trying to explain that maybe this is not the right treatment for them or, like, not the right platform. But I wanted to ask you, if we'll have a patient tomorrow in the clinic with localized rectal cancer and happen to have an MSI-high tumor, what would be your recommendation in terms of how to approach that patient? Dr. Andrea Cercek: I think, ideally, you would discuss clinical trials with the patient. We have opened the study now to not just rectal cancer but colon cancer and, in fact, all solid tumors that are mismatch repair-deficient. So I think at this time, the patients really should be treated on a clinical trial. As we learn more, in particular, until we are more comfortable assessing for a clinical complete response and follow-up. I think the surveillance piece will be critically important. In rectal cancer, it's well established, but it's not in the other tumor types. So my recommendation would be to enroll the patient on a trial. Dr. Mohamed Salem: Just to add to that too, obviously, as you know, there is now the cooperative group trial that's looking at that option and we obviously encourage all centers to participate and open that study to have this option for our patients. Dr. Chalabi, so what do you guys do in Europe for these patients? Dr. Myriam Chalabi: In Europe, it's a very different situation. I would have answered this question differently by saying, well, we don't have that option of treating patients outside of clinical trials. So basically, we have to make sure that we have clinical trials for these patients. And that's something that we've had for colon cancer patients. That is still the case. And we're getting rectal cancer trials also for patients with MMR deficient tumors and have those also for MMR proficient tumors. For us and I agree completely that we should be treating patients within clinical trials, we don't have another option. But still, even if we did, I think it's important to create data within clinical trials to be able to ultimately also show why this should be standard of care and how we can make it standard of care. Because if you're not accumulating that data, then it's going to become very difficult if accrual is lacking. Now, we treat patients either with standard-of-care treatments, but usually, we try to find something within clinical trials.  Dr. Mohamed Salem: I totally agree. And as we always say, the standard of care should be a clinical trial participation. So, I must say, both of you, Dr. Cercek and Dr. Chalabi, you made 2022 a very exciting year for us in GI cancers. You really changed the way we look at how to treat these patients and give them a huge chance of, I would say, actually cure and obviously organ preservation. So, I'm very curious to know what you are both are working on now and what we should expect in 2023 and 2024.  Dr. Andrea Cercek: So, for me, the study is ongoing, as I mentioned, and we've expanded to all mismatch repair-deficient solid tumors with the same approach of six months of dostarlimab and then the option of nonoperative management. And I think that it'll be important for us to learn in terms of responses on the luminal versus some of the other tumor types, like, for example, pancreas cancer, where we don't see these robust responses in the metastatic setting, that will be important to do. We're doing some correlative analysis, as Dr. Chalabi described as well in our patients.  And then, I'm interested in optimizing neoadjuvant approaches to minimize therapy in rectal cancer specifically. So, we have a study now for HER-2 amplified RAS wild-type patients with locally advanced rectal cancer with a similar approach of utilizing HER-2 targeted therapy first and then in combination with chemotherapy. In our case, it's a combination of trastuzumab and tucatinib and then chemotherapy with CAPOX and assessing for response and potential omission of radiation and surgery depending on responders. So, I'm very excited that study is open and actively accruing, and hopefully, we can get similar responses that we did in the MSI population with PD-1 blockade. Dr. Mohamed Salem: Is that only available at MSK? Dr. Andrea Cercek: It is at this time. However, we will likely be expanding, so if there's any interest, let me know. Dr. Mohamed Salem: Great. I'm sure many centers will be. Great. What about you, Dr. Chalabi? Any sneak peek in the future? Dr. Myriam Chalabi: So many sneak peeks, where to begin? I think it's very exciting to be working in this space at this time, and we're very lucky to be in it. So, for NICHE, we're actually accruing now in new cohorts for both MMR-deficient and MMR-proficient tumors. For the patients with MMR-deficient tumors, we're actually testing a new combination of nivolumab plus relatlimab, so anti-LAG-3 plus anti-PD1. And we're testing the same co-formulation in patients with pMMR tumors. In addition to another cohort for the pMMR tumors with nivolumab, all within this window of opportunity, as we did previously in NICHE, and to see if we're going to see more responses if these are going to be different tumors than the ones responding to nivolumab and ipilimumab. And for the MMR deficient tumors, we're treating longer with this combination now. So, we're operating after eight weeks instead of six weeks. We're giving two cycles, four weekly cycles, to see whether we can even improve the PCR rates, even though this is, of course, a different combination treatment. So, very exciting times for NICHE, and we'll have the readout for the DFS at the end of this year, so that's also very exciting. And then, well, it's similar to Dr. Cercek. So again, we're on the same page when it comes to these neoadjuvant treatments. We have actually an ongoing trial for neoadjuvant treatment of patients with MMR proficient rectal cancers, and that is using a combination of radiation therapy followed by a combination of atezolizumab or anti-PDL1 with Bevacizumab with the aim of organ sparing approach in these patients. And we actually presented stage 1 of this trial as a poster at ASCO GI, showing that we achieved 56% complete or near complete responses clinically at 12 weeks. And after at least a year of follow-up for all patients, we have 50% organ preservation. So those are very exciting data as well. Also, in the MMR proficient tumors, I'm very excited to hear about the HER-2-positive tumors and Dr. Cercek's study. So there's definitely a lot going on that we hope to share as soon as the data are available. Dr. Mohamed Salem: We'll be looking forward to your next presentation and seeing that. So again, most of your work showed us that we really have to choose the right patient with the right target for the right treatment to achieve the best possible outcome. So we're getting short on time here. But before we conclude, ASCO Daily News Podcast has a huge audience of oncologists, I wanted to give you the chance to share anything you'd like to share with our audience today before we finish. Dr. Cercek? Dr. Andrea Cercek: I believe this is an incredibly exciting time in colorectal cancer. I think it's finally our turn, which feels really nice, and obviously, we have a lot more work that needs to be done. But my personal belief is to keep trying to chip away at the pie and identify responders and keep working to have better-targeted drugs and better treatment options that will improve responses and improve outcomes for our patients. But I certainly believe that we are well on our way there, and it's very exciting. Dr. Mohamed Salem: I totally agree. Dr. Chalabi, any thoughts? Dr. Myriam Chalabi: I think after 2022 and the data that we've been showing, I think it's important to– and I think by now, maybe it's not even necessary anymore to say it– but I think it's important to really look at the tumors and look at these MMR proteins or MSI, and to make sure that you're treating the patient in the right way, and to consider that. Before, it wasn't as important in the neoadjuvant setting or these localized tumors, but now it's becoming essential.  And I think if you would have looked five years ago and you would say, yeah, these MSI tumors are important to find, it's a very small proportion of patients, in rectal cancer even lower than in colon cancer. But still, it has such a huge impact on what you're doing in these patients and your chances of cure. So I think that would be my most important giveaway to test for MMR deficiency before deciding on a treatment for your patients. And we're working on trials with neoadjuvant immunotherapy. Also in other tumor types, Dr. Cercek is also doing the same. I think those will be very important also outside of the GI field to see whether this approach works for a much larger patient population, despite the low incidence.  Dr. Andrea Cercek: Dr. Chalabi just made a critical point that that is most important is to remember that we do have biomarkers in colorectal cancer that, in the neoadjuvant setting and in the metastatic setting, especially MSI, that we need to test for. And then, just to add from a clinical perspective, in rectal cancer, the large majority of patients that have mismatch-repair deficient or MSI tumors actually have Lynch syndrome. So really, if you identify a patient that's mismatch-repair deficient or MSI-high anywhere, but especially in the rectum, they absolutely should get germline testing. Dr. Mohamed Salem: I echo that and second that. And Dr. Cercek, thank you, and I know you did a lot of work in colorectal cancer in the younger adult population, too, so I think you've had a huge impact on that area too. I would like to thank both of you again for being here today, but more for the great work you and your teams are doing to advance the field. It's really a very exciting time in GI cancers now, and thank you so much for your work and for sharing your insights with us today on the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you so much for having me. It's been great. Dr. Andrea Cercek: Thank you for having me. Dr. Mohamed Salem: Of course, and thanks to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:     Dr. Mohamed Salem @SalemGIOncDoc   Dr. Myriam Chalabi @MyriamChalabi   Dr. Andrea Cercek @AndreaCercek   Learn about other key advances in GI Oncology: SWOG 1815, PARADIGM, and Other Advances at GI23   Follow ASCO on social media:      @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck Dr. Myriam Chalabi: Consulting or Advisory Role: MSD, Bristol-Myers Squibb/Celegne, Numab Research Funding (Institution): Bristol-Myers Squibb, Roche/Genentech, MSD Travel, Accommodations, Expenses: Roche/Genentech, Bristol-Myers Squibb Dr. Andrea Cercek: Consulting or Advisory Role: Bayer, GSK, Incyte, Merck, Janssen, Seattle Genetics, G1 Therapeutics Research Funding (Institution): Seattle Genetics, GSK, Rgenix          

Neste Vídeo-MOC, os Drs. Fabio Kater e Antonio C. Buzaid debatem sobre o uso de pembrolizumabe no tratamento de tumores com MSI-H e a incorporação da estratégia na prática clínica. Confira também o Vídeo-MOC completo. mocbrasil.com/blog/videos-moc/vol14num02/

CME credits: 0.50 Valid until: 30-11-2023 Claim your CME credit at https://reachmd.com/programs/cme/establishing-the-role-of-immunotherapy-in-microsatellite-instability-high-msi-h-or-mismatch-repair-deficient-dmmr-endometrial-cancer/14459/ Are you testing for MSI-H/dMMR in your patients with advanced endometrial cancer? Listen in as Drs. Robert Coleman, Susana Campos, and Ana Oaknin break down the progress being made in biomarker testing and immunotherapy treatment for these patients.

CME credits: 0.50 Valid until: 04-11-2023 Claim your CME credit at https://reachmd.com/programs/cme/advances-in-the-care-of-patients-with-msi-hdmmr-or-her2-colorectal-cancers/14480/ In this chapterized panel discussion, Drs. Aparna Parikh, Dustin Deming, and Scott Kopetz take us through NCCN recommended guidelines and best practices for identifying biomarkers. Armed with this knowledge, you'll be able to select systemic therapies more accurately for your patients with MSI-high disease, as well as patients with HER2-amplified CRC.

Are the results from Luis Diaz as good as touted. What trial should they do going forward? A 100% CR rate in Stage II and III rectal cancer??

TRACON Pharmaceuticals Inc CEO Charles Theuer tells Proactive that its partners had announced that envafolimab had received marketing authorization from the Chinese National Medical Products Administration - the first approval of a subcutaneously administered checkpoint inhibitor. Theuer says Envafolimab has been given the go-ahead for adults with microsatellite instability-high (MSI-H), or deficient MisMatch Repair (dMMR) advanced solid tumors. This includes patients with advanced colorectal cancer, where the disease has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, as well as those with other advanced solid tumors.

Em 2020 terá havido 5 367 novos diagnósticos de cancro colorectal, sendo um dos tipos de cancro mais frequente em ambos os sexos. Cerca de 5% dos doentes com cancro Colorectal tem instabilidade de Microsatélites em estadio IV. Sendo uma patologia que está a ter cada vez mais diagnósticos numa população mais jovem, é essencial discutir novas abordagens terapêuticas.Dra. MarianaOncologista Médica no hospital são francisco Xavier e no hospital CUF Infante SantoProf. Doutor Mário Fontes e SousaEspecialista em Oncologia Médica no Hospital CUF TejoOlho Clínico é um Podcast da MSD de atualização científica, direcionado exclusivamente a Profissionais de Saúde. O conteúdo do mesmo não tem por objetivo induzir qualquer alteração de comportamento na prescrição ou toma de medicamentos. PT-NON-01059 06/2021

CME credits: 0.25 Valid until: 30-03-2022 Claim your CME credit at https://reachmd.com/programs/cme/latest-clinical-considerations-non-small-cell-lung-cancer-global-approach/12363/ Are dMMR and MSI-H both markers that will soon replace or work in conjunction with PD-L1 when determining immunotherapy for patients with metastatic NSCLC? Accurate testing and treatment selection is critical in identifying patients who will benefit from these therapies. Dr. Federico Cappuzzo, Dr. Solange Peters, and Professor Yi-Long Wu discuss emerging data from the recent WCLC, ESMO, and ASCO virtual conferences and offer their international and regional perspectives on the evolving use of immunotherapies in advanced NSCLC.

CME credits: 0.25 Valid until: 30-03-2022 Claim your CME credit at https://reachmd.com/programs/cme/latest-clinical-considerations-non-small-cell-lung-cancer-global-approach/12363/ Are dMMR and MSI-H both markers that will soon replace or work in conjunction with PD-L1 when determining immunotherapy for patients with metastatic NSCLC? Accurate testing and treatment selection is critical in identifying patients who will benefit from these therapies. Dr. Federico Cappuzzo, Dr. Solange Peters, and Professor Yi-Long Wu discuss emerging data from the recent WCLC, ESMO, and ASCO virtual conferences and offer their international and regional perspectives on the evolving use of immunotherapies in advanced NSCLC.

Host: Federico Cappuzzo Guest: Professor Solange Peters Guest: Professor Yi-Long Wu Are dMMR and MSI-H both markers that will soon replace or work in conjunction with PD-L1 when determining immunotherapy for patients with metastatic NSCLC? Accurate testing and treatment selection is critical in identifying patients who will benefit from these therapies. Dr. Federico Cappuzzo, Dr. Solange Peters, and Professor Yi-Long Wu discuss emerging data from the recent WCLC, ESMO, and ASCO virtual conferences and offer their international and regional perspectives on the evolving use of immunotherapies in advanced NSCLC.

Host: Edward Chu, MD Guest: Michael J. Overman, MD Recent immunotherapy approvals have changed the treatment paradigm for first and subsequent lines of treatment for patients with microsatellite-high or mismatch repair deficient metastatic colorectal cancer. Join us as we deep dive into recent and newly emergent data to better understand how to bring these advances into the clinic.

CME credits: 0.25 Valid until: 23-12-2021 Claim your CME credit at https://reachmd.com/programs/cme/keeping-pace-gi-cancer-advances-immunotherapy-msi-hdmmr-metastatic-colorectal-cancer/12082/ Recent immunotherapy approvals have changed the treatment paradigm for first and subsequent lines of treatment for patients with microsatellite-high or mismatch repair deficient metastatic colorectal cancer. Join us as we deep dive into recent and newly emergent data to better understand how to bring these advances into the clinic.

Host: Edward Chu, MD Guest: Michael J. Overman, MD Recent immunotherapy approvals have changed the treatment paradigm for first and subsequent lines of treatment for patients with microsatellite-high or mismatch repair deficient metastatic colorectal cancer. Join us as we deep dive into recent and newly emergent data to better understand how to bring these advances into the clinic.

This episode is hosted by Dr. Leah Biller and features Dr. Zsofia Stadler, a medical oncologist at Memorial Sloan Kettering Cancer Center and CGA council member, and Dr. Michael Hall, a medical oncologist at Fox Chase Cancer Center and CGA past president. They discuss data from Abstract 1500 (https://meetinglibrary.asco.org/record/185963/abstract), which reports on targeted therapy based on germline analysis of tumor-normal sequencing in a pan-cancer population, as well as data from the plenary presentation about the clinical trial KEYNOTE-177 (https://meetinglibrary.asco.org/record/186928/abstract), a study of pembrolizumab versus standard therapy for treatment of MSI-H metastatic colorectal cancer. This episode was recorded on August 28, 2020 and reflects expert opinion at the time of the recording.

Entrectinib and larotrectinib have been approved to treat tumors with fusions in the neurotrophic tropomyosin receptor kinase (NTRK) gene – irrespective of the tumor’s site of origin. These drugs are the second and third agents, overall, to have a tissue-agnostic indication approved by the FDA. The first was pembrolizumab, an immunotherapy agent, indicated for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017. Have we finally reached the point where tumor biology has become a more important consideration than site of origin?

Consensus or Controversy? Clinical Investigators Provide Perspectives on the Current and Future Management of Prostate Cancer — Part 1: Our one-on-one interview with Dr Antonarakis featuring emerging research and cases from his practice. Initial evaluation of prognostic indicators in hormone-sensitive prostate cancer (HSPC) versus castration-resistant prostate cancer (CRPC) (0:00) Effect of prostate-specific antigen (PSA) doubling time on time to metastasis and overall survival in nonmetastatic CRPC; improvement in metastasis-free survival with androgen receptor antagonist therapy (4:16) Perspective on the use of intermittent androgen deprivation therapy (ADT) for patients with nonmetastatic HSPC and rising PSA levels (12:35) Structural and mechanistic similarities and differences between available (apalutamide, enzalutamide) and investigational (darolutamide) androgen receptor antagonists (19:39) Initial results of the Phase III ARAMIS trial: Metastasis-free survival improvement and tolerability of darolutamide versus placebo for nonmetastatic CRPC (22:41) ARASENS: An ongoing Phase III trial evaluating darolutamide versus placebo in combination with standard ADT and docetaxel for patients with metastatic HSPC (25:38) Perspective on the new drug application and potential FDA approval of darolutamide for nonmetastatic CRPC (27:02) Spectrum and frequency of systemic and CNS-related side effects associated with apalutamide, enzalutamide and darolutamide (28:29) Updated analysis of progression-free survival with first subsequent therapy (PFS2) in the SPARTAN study of apalutamide for high-risk nonmetastatic CRPC (31:50) ARCHES: Design, efficacy and tolerability results from a Phase III trial of ADT with enzalutamide or placebo for metastatic HSPC (36:22) Selection and sequencing of therapy for patients with metastatic prostate cancer (42:01) Correlation between the presence of androgen receptor splice variant 7 (AR-V7) and outcomes with secondary hormonal therapy and chemotherapy in metastatic CRPC (45:58) Prevalence and detection of AR-V7 in patients with metastatic CRPC (50:48) Overview of BRCA1/2 and other DNA repair gene mutations that may confer sensitivity to PARP inhibition (54:32) Efficacy and FDA breakthrough therapy designations for olaparib and rucaparib for metastatic CRPC (58:49) GALAHAD: Preliminary results of a Phase II trial of niraparib for patients with metastatic CRPC and biallelic DNA repair gene defects (1:1:10) Response to PARP inhibitor therapy in patients with metastatic CRPC with BRCA1/2 versus ATM mutations (1:4:06) Activity of platinum-based chemotherapy in patients with metastatic CRPC and germline BRCA mutations (1:7:29) Clinical experience with PARP inhibitor-associated side effects in men with metastatic CRPC (1:12:35) Perspective on the negative results of the Phase III ERA 223 trial evaluating radium-223 dichloride in combination with abiraterone acetate for patients with chemotherapy-naïve metastatic CRPC and bone metastases (1:14:56) Appropriate use of radium-223 for the treatment of symptomatic metastatic CRPC (1:19:54) Biologic rationale for and ongoing investigation of lutetium-177-prostate-specific membrane antigen (PSMA)-617 for progressive PSMA-positive metastatic CRPC (1:23:03) KEYNOTE-199: Updated analysis of a Phase II trial of pembrolizumab monotherapy for patients with metastatic CRPC previously treated with docetaxel (1:27:39) Initial results of the Phase II CheckMate 650 trial of nivolumab with ipilimumab for metastatic CRPC (1:30:11) Prevalence of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) molecular phenotype and response to immune checkpoint blockade in patients with prostate cancer (1:35:02) Emerging data with olaparib in combination with anti-PD-1/PD-L1 checkpoint blockade for metastatic CRPC (1:37:38) Select publications  

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

These tests can evaluate your tumor for different biomarkers, including MSI-H or dMMR. Some biomarkers are used to help select patients that may benefit from certain treatments. Talk to your doctor to see if a laboratory test for the MSI-H or dMMR biomarker is right for you. A tissue sample (biopsy) of your tumor is taken, and your doctor orders the test.Your doctor typically gets the results in 10 to 14 days.You talk with your doctor to discuss treatment options based on your results.   

David Henry, MD, welcomes Daniel G. Haller, MD, to rehash research from ESMO 2018 as well as the way the meeting itself was run.  And Ilana Yurkiewicz, MD, stops by for this week’s Clinical Correlation. Dr. Yurkiewicz is a Hematology Fellow at Stanford and is also a columnist at MDedge Hematology/Oncology. More from Dr. Yurkiewicz here. Contact us: podcasts@mdedge.com MDedge on Twitter: @mdedgehemonc Dr. Ilana Yurkiewicz on Twitter: @ilanayurkiewicz SHOW NOTES By Emily Bryer, DO Resident in the department of internal medicine, University of Pennsylvania Health System CheckMate 142: Durable clinical benefit with nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite high (MSI-H) and non-MSI-H colon cancer Phase 2 study included 45 patients with metastatic colorectal cancer Overall response rate (primary end point) was 60% and disease control rate was 84% Almost every patient had some response and the therapy was well-tolerated https://bit.ly/2TljlQE    Tribe 2: FOLFOXIRI plus bevacizumab followed by reintroduction of FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab Phase 3 study of 654 patients with unresectable metastatic colorectal cancer Progression free survival (primary end point) of FOLFOXIRI regimen was 18.9 months, compared with 16.2 months of the FOLFOX then FOLFIRI regimen Side effects of FOLFOXIRI: febrile neutropenia, neutropenia, GI toxicities https://bit.ly/2EMKBOa    Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomized, double-blind, placebo-controlled, phase 3 trial Phase 3 study included 506 patients with metastatic gastric cancer Trifluridine/tipiracil (oral drug) provided a 2-month overall survival advantage (primary end point), compared with placebo Major side effect: neutropenia https://bit.ly/2tW7PMI    Safety and clinical activity of 1L atezolizumab plus bevacizumab in a phase 1b study in hepatocellular carcinoma (HCC) Phase 1B study included 100 patients with HCC who had not received prior therapy Disease control rate was high as was duration of response Primary outcomes included safety and efficacy The overall response rate was 34% and the most common side effect was hypertension https://bit.ly/2EEPKaO   

080 | Pursuing cures and advancing innovation   Welcome to another episode of Biotechnology Focus radio! I am your host – Michelle Currie – here to give you the rundown on what’s been happening on Canada’s biotech scene. It has been a busy last couple of weeks as the new genomics cloud platform was launched, a researcher from Roche Canada shares her input on future of innovation in cancer care, and the fight against cancer innovation trust invests almost half a mil in Ontario research technologies.   +++++  The world is opening up to the idea of genome sequencing. What was once a far-fetched idea is now beginning to materialize – and we are only at the tip of the iceberg. Information technology like Facebook, Google, Wikipedia and Uber are all prime examples of impactful software platforms that connect people with data that have set the stage for the next act.  When you look at where DNA sequencing began back in the 1970’s with the “Sanger sequencing method” as a process of determining the order of bases in the length of DNA, we’ve come a long way. But still, researchers are at the forefront of this revolution of gathering our personalized genetic information and using it to power the next generation of safer and more effective “precision” medicines.  This is where Marc Fiume and his team from DNAstack, a Toronto-based cloud genomics company, have their role to play. Started in 2014, the company began work with some exciting researchers from around Canada whose hot topics included autism and cancer research. But constantly they were told that the researchers just didn’t have enough samples to make sense of all the data they were collecting and that they really needed a platform that would connect them with other researchers globally who found themselves in the same position. Inspired by the concept of Facebook, they decided to build their own platform where genetic research could transpire among researchers worldwide.  He refers to the lack of data access as “potentially keeping life-saving information in a basement server room” and is one of his biggest frustrations when it comes to genomic research. Unveiling the sequence of a genome is challenging, time-consuming and expensive. Perhaps that is the reason why such a platform can no longer be just a notion, but become a mandatory tool so we can further our knowledge unified, instead of trying to connect the dots apart.  Genome sequencing is a lot like “decoding” of a foreign script or ciphering out a code of each individual’s personal genome. It is a long string of letters that forms a sort of molecular blueprint that is unique for each of us. These “strings” of letters are about six billion long, and currently, researchers are only grasping about a very small per cent of what those letters represent. This is why the need for sharing information should be a necessity.  In an attempt to break this societal self-inflicted mold, Marc worked with Dr. Stephen Scherer from The Centre of Applied Genomics on the “Personal Genome Project Canada” to facilitate the publication of health and genome records online for free. The intention being that whether you are sick or healthy, it is incredibly useful personally and for the research community to have your genome sequenced. Perhaps you have a predisposition to a potentially harmful genetic disease that you were not aware of before and could catch it before it starts, or if you are a carrier, or if you simply want to learn more about your ancestry. All of this is possible with genome sequencing. While some may not be ready to have theirs published online, it could still be made available to you in the privacy of your own home.  Marc and Ryan Cook, the other co-founder of DNAstack, have both tried to decrease the unease attached to publicly airing one’s genome sequence by publishing their own. “It’s about empowering and making key decisions about their healthcare in a way that’s not scary and also to break down barriers about data sharing,” comments Marc.  There are now 56 genome researchers that are bearing it all for the world to see, and encouragingly are following up on some of the data that they have found.  DNAstack recently launched their Canadian Genomics Cloud platform that is designed to better connect data, researchers and systems across the country to accelerate genomic discoveries and the implementation of precision medicine. It was invented by Canadian leaders with decades of experience in genomics, sequencing, cloud computing, software, security, and policy to democratize access to best-in-class infrastructure while respecting the unique national and provincial requirements for data privacy and security. Their aim is to service the needs of Canadian genome scientists from research institutions, clinical laboratories, pharmaceutical companies, hospitals, and industry.  The hope is to demonstrate that Canada now does have the capacity to do a precision medicine initiative at scale. Canada is really ready for this.” – says Marc.   +++++  For most of us, the start of a new year is a natural time to reflect on our progress as individuals. We take stock of the lives we’ve lived, the advances we’ve made, the impact we’ve had on those around us and the steps we need to take in the year ahead to achieve our goals.   For the Pharmaceutical and Biotechnology industry, the start of the new year is much the same. Standing at the doorstep of 2018, many of us who have spent our lives trying to advance healthcare around the globe believe that we are at a point in our careers, where science is progressing at a rapid rate.  In fact, some of us would venture that science is progressing at a rate that is outpacing our ability – as healthcare providers, as governments, as payers and as hospital institutions – to integrate these cutting-edge advances into clinical practice. While this reality poses significant challenges, it’s exciting to be on the threshold of so many unprecedented discoveries and novel treatment approaches for some of the world’s most devastating diseases.  The field of biotechnology is rich with discoveries that will have a dramatic impact on Canadians in 2018 and beyond. However, there are three key developments in the area of oncology in which we can expect to see some of the most transformative and immediate changes. These include:  the expanded role of diagnostics to optimize treatment choice;  the adoption of histology-agnostic treatment approaches; and  the next phase of true precision medicine     Expanded Role of Diagnostics  In recent years, the use of diagnostic tests within the Canadian cancer care setting has become an increasingly important practice, particularly for guiding treatment decisions and optimizing the patient’s chances for positive outcomes. In fact, it’s estimated that nearly 70 per cent of all treatment decisions today involve a pathology and/or laboratory investigation.  While the role of predictive biomarker testing has already been well established for some time in certain tumour types (such as HER2 in breast cancer or EGFR and ALK in lung cancer) we are witnessing the emergence of two trends that could further enhance patients’ care and their experience with our healthcare system. These include the ability to simultaneously look beyond a single biomarker through genomic profiling, and the viability of liquid/blood-based biomarker testing.  In 2018 we can expect to see a continued shift among healthcare providers to rely more on comprehensive genomic profiling to map each patient’s unique genomic profile to identify alterations across hundreds of genes known to be relevant in the development and progression of cancer. This broad approach optimizes the use of the available tumour tissue and provides physicians with the most comprehensive information to help guide their treatment selection. There is particular value in this approach for patients who have exhausted all standard treatment options or for those with rare forms of cancer with limited known effective treatment options.  Canadian institutions, like the British Columbia Cancer Agency, University Health Network in Toronto and The Jewish General Hospital in Montreal among many others, have already begun to demonstrate international leadership in this area with their in-house testing platforms and world-class genomic research programs.  We are also seeing the emergence of third-party molecular information providers, such as Foundation Medicine Inc., an organization that has partnered with Roche to offer genomic tests to provide physicians with information about a tumour’s unique genomic profile based on an interrogation of over 300 genes. These external services provide options for institutions that may not have the internal capabilities to offer such testing services and for patients who are looking for more comprehensive diagnostic information. All of these efforts are striving to rapidly expand treatment options by matching patients with approved targeted therapies, immunotherapies, and clinical trials based on their tumour’s molecular profile.  The second emerging trend in the space of predictive biomarkers is blood-based testing, which offers physicians a less-invasive testing mechanism for cases, in which there is insufficient tissue available for analysis. This may also prove to be a better option when a traditional tissue biopsy is not feasible due to tumour location, when a patient is in poor health, or when a physician and/or patient simply prefer a non-surgical option. In addition to supporting initial treatment choice, blood-based testing may also offer physicians the potential for continued monitoring in the future, resulting in earlier detection of disease progression and an assessment of resistance mutations to inform subsequent lines of therapy.     A Change in Mindset  Further to the evolution of diagnostic technologies, the increasing prevalence of targeted medicines is fundamentally challenging the way cancer research is conducted.  We are no longer seeing only large randomized Phase III studies measuring overall survival for drug development, but more novel trial designs, including basket and umbrella studies, as well as smaller Phase II designs to measure the safety and efficacy of a drug.  These new study approaches are aimed to accelerate scientific advancement and are addressing the challenges that exist when the prevalence of a particular molecular alteration is so limited that traditional trials seeking a large bolus of patients simply aren’t feasible.  In a basket trial, the impact of a single treatment across a spectrum of tumour types harbouring a particular alteration can be investigated. In contrast, umbrella trials inverse the approach, where multiple treatments are studied in patients with a common tumour type but who are stratified by molecular subtype.  Close to home, the Canadian Profiling and Targeted Agent Utilization (CAPTUR) trial sponsored by the Canadian Clinical Trials Group in partnership with several pharmaceutical companies and academic institutions across the country is a combined basket/umbrella study enrolling patients of all cancer types who are stratified into different arms of the study to receive treatments based on the genomic profile of their tumours.  Studies like CAPTUR will fundamentally shift how physicians view cancer, forcing them to look less at the type of cancer (e.g., breast, lung, colorectal) and focus on the molecular structure of the tumour.  This histology-agnostic approach is one that is also gaining traction with regulatory authorities around the globe. In fact, the U.S. Food and Drug Administration (FDA) recently approved a PD-1 inhibitor to treat patients with any cancer type, provided their tumours were unresectable or metastatic and classified as microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR).  This approval represented a significant departure from the traditional evidence requirements expected from a regulatory body and opens the door for further discussions and opportunities in other countries.  The final development, which seems like a natural extension of our evolving mindset around the use of diagnostics and targeted medicines in oncology is our view regarding how medicines can be engineered to offer truly individualized treatments to patients.  Though personalized medicines and immunotherapies are no longer considered ‘new’ in the rapidly evolving clinical landscape, the emergence of two types of truly bespoke cancer therapies marry these concepts to create what many consider a bold step in our quest to cure cancer.  Recently, two chimeric antigen receptor (CAR) T-cell therapies were approved in the United States, ushering in the next wave of personalized cancer care. These therapies involve the genetic engineering and reinfusion of a patient’s own T-cells to fight their unique cancers.  While approved in specific hematologic cancers today, researchers are also exploring these therapies in many solid tumours and the hope remains that they will offer a whole new way to think of treatment in cancer.  Still in its infancy, the second area of significant research is personalized cancer vaccines developed and manufactured for an individual patient based on the molecular profile of their tumours. Where off-the-shelf cancer vaccines have failed in the past, there is hope that these custom, uniquely tailored vaccines, in combination with checkpoint inhibitor therapies will succeed in transforming cancer care.  Close  In closing, while it’s easy to become discouraged by the often necessary hurdles required to integrate transformative products into current clinical practice, there has never been a more exciting time for those of who have built a career in the biotechnology industry; and there has never been a more exciting time for those of who have waited for a cure to cancer – a disease that has ravaged many of our families and has taken many of our friends and loved ones.  The reality is that science will continue to outpace clinical practice. But the promise of these discoveries can be realized if we – as stakeholders within the healthcare system – are willing and open-minded to collaborate on solutions, especially as we look at the impact personalized medicines can have in therapeutic areas beyond oncology, offering meaningful solutions to an infinitely greater number of patients, enabling them to live longer, healthier lives.  +++++  The fight against cancer innovation trust announces four new recipients of funding through its prospects oncology investment competition. Those recipients are Dalriada Therapeutics Inc., 16-Bit Inc., a cancer biomarker study at the Ontario Institute for Cancer Research (OICR), and a virus-based therapeutic under development at the Ottawa Hospital and the University of Ottawa.  FACIT’s investments are imperative in bridging the capital gap often experienced by early-stage Ontario companies, helping corporations establish jobs and build roots in the province. The wide-ranging scope of the innovations, which span therapeutics, machine learning and biomarker development, reflect the rich talent pool within the Ontario oncology research community.  Dalriada is a Canadian start-up founded with a mission to develop small molecule-based therapeutic technologies to battle diseases for which current treatment strategies are suboptimal or non-existent. With broad expertise in drug discovery, their efforts are currently centred on the preclinical development of a novel class (DT1) of small molecule inhibitors in cancers of the blood and brain as well as the development of a natural product for topical treatment of psoriasis and other inflammatory skin disorders.  16-Bit, a start-up founded by two medical doctors from the University of Toronto’s Diagnostic Radiology Program, is developing a machine learning algorithm to automate triaging of screening mammograms for breast cancer detection. Their focus is to utilize modern developments in machine intelligence to improve the accuracy, reliability, and speed of medical image interpretation while decreasing cost and barriers to healthcare.  Diagnostics Development Program at OICR leader Dr. John Bartlett has developed a diagnostic gene test to predict which breast cancer patients can benefit from anthracycline chemotherapy and which patients can avoid the associated toxicity because the drug may not be effective against their cancer.  The Ottawa Hospital and the University of Ottawa have developed a tumour-destroying virus based on the Vaccinia virus which adds a micro-RNA payload to enhance cell killing against pancreatic cancer. This targeted therapy is expected to be more precise and less toxic than conventional therapies for this difficult-to-treat tumour.  The Prospects Oncology Fund delivers on FACIT and OICR’s shared vision of advancing breakthrough innovations to the benefit of patients and Ontario’s knowledge economy.  Translating early-stage innovations and positioning them to raise additional funding supports Ontario’s competitive position as a destination for biotechnology.  Congratulations to all the strong applicants and in particular these outstanding awardees in their quest to make a difference for patients living with cancer.  +++++  Well, that wraps up another episode of Biotechnology Focus radio. I hope you enjoyed it. If you have a story idea or would like to be on the show, please email me at press@promotivemedia.ca. To see the articles in full check out the website biotechnologyfocus.ca and laboratoryfocus.ca so you don’t miss a beat! Have a momentous week. From my desk to yours – this is Michelle Currie.      

Background: Genetically, colorectal cancers (CRCs) can be subdivided into tumors with chromosomal instability (CIN) or microsatellite instability (MSI). In both types of CRCs genes that are involved in the degradation of beta-CATENIN are frequently mutated. Whereas in CIN CRCs APC (Adenomatous Polyposis Coli) is affected in most cases, high grade MSI (MSI-H) CRCs frequently display mutations in various genes, like the APC-, AXIN2- or CTNNBI (beta-CATENIN) gene itself. Recently in Wilms tumors, WTX (Wilms tumor gene on the X-chromosome) was discovered as another gene involved in the destruction of beta-CATENIN. As the WTX-gene harbors a short T(6)-microsatellite in its N-terminal coding region, we hypothesized that frameshift-mutations might occur in MSI-H CRCs in the WTX gene, thus additionally contributing to the stabilization of beta-CATENIN in human CRCs. Methods: DNA was extracted from 632 formalin-fixed, paraffin-embedded metastatic CRCs (UICCIV) and analyzed for MSI-H by investigating the stability of the highly sensitive microsatellite markers BAT25 and BAT26 applying fluorescence capillary electrophoresis (FCE). Then, in the MSI-H cases, well described mutational hot spot regions from the APC-, AXIN2- and CTNNBI genes were analyzed for genomic alterations by didesoxy-sequencing while the WTX T(6)-microsatellite was analyzed by fragment analysis. Additionally, the PCR products of T(5)-repeats were subcloned and mutations were validated using didesoxy-sequencing. Furthermore, the KRAS and the BRAF proto-oncogenes were analyzed for the most common activating mutations applying pyro-sequencing. mRNA expression of WTX from MSI-H and MSS cases and a panel of colorectal cancer cell lines was investigated using reverse transcription (RT-) PCR and FCE. Results: In our cohort of 632 metastatic CRCs (UICCIV) we identified 41 MSI-H cases (6.5%). Two of the 41 MSI-H cases (4.8%) displayed a frameshift mutation in the T(6)-repeat resulting in a T(5) sequence. Only one case, a male patient, expressed the mutated WTX gene while being wild type for all other investigated genes. Conclusion: Mutations in the WTX-gene might compromise the function of the beta-CATENIN destruction complex in only a small fraction of MSI-H CRCs thus contributing to the process of carcinogenesis.

Background: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder predisposing to predominantly colorectal cancer (CRC) and endometrial cancer frequently due to germline mutations in DNA mismatch repair (MMR) genes, mainly MLH1, MSH2 and also MSH6 in families seen to demonstrate an excess of endometrial cancer. As a consequence, tumors in HNPCC reveal alterations in the length of simple repetitive genomic sequences like poly-A, poly-T, CA or GT repeats (microsatellites) in at least 90% of the cases. Aim of the Study: The study cohort consisted of 25 HNPCC index patients ( 19 Amsterdam positive, 6 Bethesda positive) who revealed a microsatellite stable (MSS) - or low instable (MSI-L) - tumor phenotype with negative mutation analysis for the MMR genes MLH1 and MSH2. An extended marker panel (BAT40, D10S197, D13S153, D18S58, MYCL1) was analyzed for the tumors of these patients with regard to three aspects. First, to reconfirm the MSI-L phenotype found by the standard panel; second, to find minor MSIs which might point towards an MSH6 mutation, and third, to reconfirm the MSS status of hereditary tumors. The reconfirmation of the MSS status of tumors not caused by mutations in the MMR genes should allow one to define another entity of hereditary CRC. Their clinical features were compared with those of 150 patients with sporadic CRCs. Results: In this way, 17 MSS and 8 MSI-L tumors were reclassified as 5 MSS, 18 MSI-L and even 2 MSI-H ( high instability) tumors, the last being seen to demonstrate at least 4 instable markers out of 10. Among all family members, 87 malignancies were documented. The mean age of onset for CRCs was the lowest in the MSI-H-phenotyped patients with 40.5 +/- 4.9 years (vs. 47.0 +/- 14.6 and 49.8 +/- 11.9 years in MSI-L- and MSS-phenotyped patients, respectively). The percentage of CRC was the highest in families with MSS-phenotyped tumors (88%), followed by MSI-L-phenotyped ( 78%) and then by MSI-H-phenotyped (67%) tumors. MSS tumors were preferentially localized in the distal colon supposing a similar biologic behavior like sporadic CRC. MSH6 mutation analysis for the MSI-L and MSI-H patients revealed one truncating mutation for a patient initially with an MSS tumor, which was reclassified as MSI-L by analyzing the extended marker panel. Conclusion: Extended microsatellite analysis serves to evaluate the sensitivity of the reference panel for HNPCC detection and permits phenotype confirmation or upgrading. Additionally, it confirms the MSS status of hereditary CRCs not caused by the common mutations in the MMR genes and provides hints to another entity of hereditary CRC. Copyright (C) 2004 S. Karger AG, Basel.