S18 Ep34: Integrating Precision Pathways in HER2+ Gastroesophageal Adenocarcinoma—Testing, Treatment, and Supportive Care

In this episode of Oncology Unplugged, host Chandler Park, MD, a medical oncologist at Norton Cancer Institute in Louisville, Kentucky, was joined by Pashtoon Kasi, MD, MS, the medical director of GI Medical Oncology, the Rad Family Chair in Gastrointestinal Oncology, and an associate clinical professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Orange County in Irvine, California.Their discussion centered on the rapid rise of neoadjuvant immunotherapy in colorectal cancer (CRC) management, framing the shift in which immunotherapy is given upfront and surgery becomes the adjuvant step as a genuine paradigm change. Drs Park and Kasi grounded the conversation in the biology of mismatch repair–deficient (dMMR)/microsatellite instability–high tumors, which harbor a high neoantigen load, rendering them sensitive to checkpoint blockade.A major focus was the treatment evolution that stemmed from data from the phase 3 ATOMIC trial (NCT02912559), which added atezolizumab (Tecentriq) to FOLFOX (leucovorin, fluorouracil, oxaliplatin) in stage III dMMR disease, to the NICHE clinical trial series from the Netherlands, in which brief neoadjuvant nivolumab (Opdivo) plus 1 dose of ipilimumab (Yervoy) produced near-universal responses. Dr Kasi then detailed his own NEST trials, which replicated this short-course design using the Fc-enhanced CTLA-4 inhibitor botensilimab plus balstilimab, notably extending activity into the larger mismatch repair–proficient/microsatellite stable (MSS) population with sustained disease-free survival.Drs Park and Kasi explored mechanistic insights that have been seen with CRC drugs, including an "inside-out" serosal-to-mucosal response pattern, regulatory T cell depletion, and the rationale that an intact tumor and lymph nodes provide more antigens than the postsurgical setting. They also discussed circulating tumor DNA as an emerging surrogate end point, the implications of data from the phase 3 STELLAR-303 trial (NCT05425940) of an immunomodulatory TKI plus atezolizumab (Tecentriq) in patients with MSS disease, liver metastases as an immunosuppressive niche, and the alarming rise of early-onset CRC.

In today’s episode, we spoke with Nataliya Uboha, MD, PhD. Dr Uboha is an associate professor and researcher in the Department of Medicine at the University of Wisconsin School of Medicine in Madison.In our exclusive interview, Dr Uboha discussed the August 2026 FDA approval of zanidatamab (Ziihera)-based regimens for first-line HER2-positive locally advanced or metastatic gastric cancer, and unpacked data from the phase 3 HERIZON-GEA-01 trial (NCT05152147) that supported the regulatory decision. She also shed light on where zanidatamab fits in the gastric cancer treatment paradigm in combination with PD-1 inhibitors like tislelizumab (Tevimbra) and alongside other options like trastuzumab (Herceptin).

In today’s episode, Narjust Florez, MD, and Jonathan Wesley Riess, MD, MS, hosted a discussion about the distinction between HER2 overexpression and HER2 mutations in non–small cell lung cancer (NSCLC). Dr Florez is the associate medical director of the Cancer Care Access Program and a physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine and a faculty member at Harvard Medical School, both in Boston, Massachusetts. Dr Riess is the director of Thoracic Oncology and an associate professor of medicine in the Division of Hematology and Oncology at the University of California (UC) Davis Health Medical Center and the UC Davis Comprehensive Cancer Center in Sacramento.In our exclusive interview, Drs Florez and Riess clarified that HER2 mutations, commonly exon 20 insertions, are genomic drivers sensitive to TKIs, whereas HER2 overexpression is a protein finding identified by immunohistochemistry (IHC). They discussed the use of fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of patients with HER2 IHC 3+ NSCLC, reviewed efficacy data from the DESTINY-Lung studies, and worked through a treatment sequencing case. Their conversation also addressed toxicity management, particularly aggressive nausea prophylaxis and vigilance for interstitial lung disease, and emphasized the importance of upfront HER2 testing to preserve tissue and save time.

In today’s episode, we spoke with Davide Melisi, MD, PhD. Dr Melisi is an associate professor of medical oncology at the University of Verona in Italy.In our exclusive interview, Dr Melisi discussed the investigational oral KRAS G12D inhibitor INCB161734, its mechanism of action, what early data have shown with the agent, and the aims of the ongoing phase 3 DAWN-303 trial (NCT07522073) evaluating it in patients with KRAS G12D–mutated metastatic pancreatic ductal adenocarcinoma. He also explored how the agent could be integrated into treatment sequencing alongside the August 2026 FDA approval of daraxonrasib (Rasonque) for the treatment of patients with metastatic disease.

In today’s episode, we spoke with Raji Shameem, MD, and Shubham Pant, MD, MBBS. Dr Shameem is a clinical assistant professor of medicine at the Orlando College of Osteopathic Medicine, an assistant professor of Medicine at the University of Central Florida, and a physician at Orlando Health. Dr Pant is a professor in the Department of Gastrointestinal Medical Oncology and the Department of Investigational Cancer Therapeutics, as well as the director of Clinical Research at The Sheikh Zayed Center For Pancreatic Cancer Research at The University of Texas MD Anderson Cancer Center in Houston.In our exclusive interview, Drs Shameem and Pant discussed the rapidly evolving pancreatic cancer treatment paradigm, going in-depth on topics like the role of liposomal irinotecan (Onivyde), the FDA approval of daraxonrasib (Rasonque) for patients with metastatic disease, and novel treatments that are in development. The 2 experts also covered which directions they see the pancreatic cancer field moving towards in the future.

Highlights from the PER® CME activity "SimulatED: Integrating Precision Pathways in HER2+ Gastroesophageal Adenocarcinoma — Testing, Treatment, and Supportive Care" — this podcast is not certified for credit. To participate in the full accredited activity and earn CME credit, use the link below.In this podcast, experts Geoffrey Y. Ku, MD, and Sunnie Kim, MD, discuss essential biomarker testing for advanced gastroesophageal adenocarcinoma, first-line treatment selection for HER2-positive metastatic disease in light of data from HERIZON-GEA-01 (NCT05152147), management of treatment-related diarrhea and other adverse events, and HER2 retesting at disease progression.Earn CME credit by completing the full accredited activity (available through August 31, 2027): https://www.gotoper.com/courses/simulated-integrating-precision-pathways-in-her2-gastroesophageal-adenocarcinoma-testing-treatment-and-supportive-careThis podcast, including the narration, was developed by PER® (Physicians’ Education Resource®, LLC) editorial staff from the full online CME activity developed with these faculty. The narration was voiced by a PER staff member or by an AI tool. The podcast contains no product advertising. The full activity is supported by an educational grant from Jazz Pharmaceuticals, Inc.This content is for educational purposes only and is not a substitute for the independent clinical judgment of a health care professional. Faculty may discuss investigational or off-label uses; consult prescribing information for any products discussed.

In this episode of Oncology Unplugged, host Chandler Park, MD, a medical oncologist at Norton Cancer Institute in Louisville, Kentucky, was joined by Joshua Brody, MD, the director of the Lymphoma Immunotherapy Program at the Mount Sinai Tisch Cancer Center and a faculty member of the Icahn Genomics Institute in New York, New York.Their discussion centered on the rapidly evolving treatment landscape for B-cell non-Hodgkin lymphomas, highlighting a wave of recent advances across frontline and relapsed diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) management. Drs Park and Brody framed this current era as one of unusually fast progress after decades of failed attempts to improve upon R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone).A major focus was the phase 3 frontMIND trial (NCT04824092), which added tafasitamab-cxix (Monjuvi) and lenalidomide (Revlimid) to R-CHOP in patients with frontline DLBCL. Dr Brody discussed the significant progression-free survival benefit with the experimental combination that extended across patient subgroups rather than being confined to patients with activated B-cell–like or non–germinal center disease, with only a modest increase in the rate of high-grade febrile neutropenia. He contextualized this against earlier trials in the DLBCL space.The discussion then turned to relapsed disease, where Dr Brody described the benefits of CAR T-cell therapy over stem cell transplant and reviewed bispecific antibody/chemotherapy combinations, including glofitamab-gxbm (Columvi) and epcoritamab-bysp (Epkinly) plus gemcitabine and oxaliplatin. He also emphasized the importance of clinical trials.Drs Park and Brody also explored the evolving MCL treatment paradigm, highlighting glofitamab's complete remission rate and the FDA approval of the BCL-2 inhibitor sonrotoclax (Beqalzi), alongside strategies to mitigate cytokine release syndrome and tumor lysis syndrome. The conversation concluded with a look at emerging therapies, including CD19-directed bispecific antibodies and in vivo CAR T-cell therapy delivered via viral and mRNA lipid nanoparticle vectors.

Two Onc Docs, hosted by Samantha A. Armstrong, MD, and Karine Tawagi, MD, is a podcast dedicated to providing current and future oncologists and hematologists with the knowledge they need to ace their boards and deliver quality patient care. Dr Armstrong is a hematologist/oncologist and assistant professor of clinical medicine at Indiana University Health in Indianapolis. Dr Tawagi is a hematologist/oncologist and assistant professor of clinical medicine at the University of Illinois in Chicago.In this episode, OncLive On Air® partnered with Two Onc Docs to deliver a comprehensive, board-focused review of metastatic non–small cell lung cancer (NSCLC) diagnosis and management for 2026, reflecting the rapidly expanding treatment landscape that is growing to include chemotherapy, immunotherapy, and targeted agents.The discussion began with molecular workup, emphasizing the importance of conducting upfront multigene next-generation sequencing plus PD-L1 testing by immunohistochemistry (IHC) for all nonsquamous disease, with HER2 and c-MET IHC now part of routine evaluation. Drs Armstrong and Tawagi stressed that circulating tumor DNA complements but does not replace tissue biospy, and that a targetable driver generally prompts the initiation of first-line targeted therapy, except in the case of KRAS G12C and NRG1 fusions.Regarding EGFR-mutated disease, they reviewed 3 category 1 first-line options: osimertinib (Tagrisso) monotherapy, osimertinib plus chemotherapy, and amivantamab (Rybrevant) plus lazertinib (Lazcluze), cautioning against overlapping immunotherapy. They detailed post-osimertinib resistance testing and EGFR exon 20 insertions, then addressed ALK, ROS1, BRAF V600E, RET, MET exon 14, NTRK, and NRG1 alterations, noting preferred agents and characteristic toxicities, such as lorlatinib (Lorbrena)–associated hyperlipidemia.Drs Armstrong and Tawagi also covered HER2-directed therapies, including fam-trastuzumab deruxtecan-nxki (Enhertu), as well as antibody-drug conjugates for EGFR-mutated and c-MET–high disease. For driver-negative disease, they stratified first-line therapy by PD-L1 status and histology, discussing immunotherapy monotherapy, chemoimmunotherapy, and dual checkpoint blockade, before reviewing second-line options for patients with or without prior immunotherapy.

In this episode of Oncology Unplugged, host Chandler Park, MD, a medical oncologist at Norton Cancer Institute in Louisville, Kentucky, was joined by Joshua Brody, MD, the director of the Lymphoma Immunotherapy Program at the Mount Sinai Tisch Cancer Center and a faculty member of the Icahn Genomics Institute in New York, New York.Their discussion centered on the evolving frontline and relapsed treatment landscape in Hodgkin lymphoma, highlighting the field’s decades-long shift away from intensive chemotherapy and radiation toward better-tolerated, biologically targeted regimens. Drs Park and Brody framed Hodgkin lymphoma as a rare success story in oncology, noting that a once-uniformly fatal disease is now curable in more than 90% of patients, and emphasized that the modern treatment goal has moved from maximizing efficacy at any cost to preserving efficacy and minimize long-term toxicity, particularly given the disease’s young patient population and correspondingly long survivorship horizon.A major focus of the conversation was the retirement of bleomycin from frontline regimens. Dr Brody explained that bleomycin carried substantial risk of pneumonitis and pulmonary fibrosis without strong single-agent antitumor activity and traced its decline to the phase 3 RATHL trial (NCT00678327), which established that patients with a clean interim PET scan after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) could safely omit bleomycin from subsequent cycles. He noted that this PET-adapted approach helped set the stage for the 2 trials that have since reshaped frontline advanced-stage therapy: the phase 3 ECHELON-1 trial (NCT01712490), which showed that brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, and dacarbazine (AVD) outperformed standard ABVD, and the phase 3 SWOG S1826 (NCT03907488) trial, in which nivolumab (Opdivo) plus AVD produced a significantly lower relapse rate than brentuximab vedotin plus AVD, with durable benefit confirmed at the 2025 ASH Annual Meeting. Dr Brody described nivolumab plus AVD as the current standard of care for most patients with advanced-stage disease in the United States, citing both its efficacy and its more favorable toxicity profile relative to brentuximab vedotin, which carries a meaningful risk of peripheral neuropathy.The discussion then turned to the underlying biology that makes Hodgkin lymphoma so responsive to PD-1 blockade. Dr Brody explained that the malignant Reed-Sternberg cell relies heavily on PD-L1 overexpression, frequently driven by 9p24 amplifications or translocations, to evade T-cell surveillance, leaving the tumor unusually vulnerable once that mechanism is blocked pharmacologically. He noted that this single dominant immune-evasion pathway helps explain why response rates to anti–PD-1 therapy in Hodgkin lymphoma exceed those seen in melanoma and non–small cell lung cancer.Drs Park and Brody also explored treatment selection in early-stage disease, where Dr Brody noted that multiple regimens now achieve cure rates exceeding 90%, leaving no single clear standard. Options include traditional ABVD with low-dose radiation, radiation-free approaches with intensified chemotherapy, and emerging nivolumab-inclusive regimens, with selection often individualized based on disease location and patient-specific factors, such as the feasibility of giving radiation to sensitive anatomic sites.On relapsed disease, Dr Brody emphasized that outcomes remain favorable even after treatment failure, with second-line therapy typically incorporating whichever novel agent, anti–PD-1 or brentuximab vedotin, was not used in the frontline setting, often combined with chemotherapy. He noted that some patients achieve durable remission without proceeding to autologous stem cell transplant, though transplant remains an option for appropriate candidates, and flagged older patients as an ongoing unmet need given poorer transplant tolerability in this population.The conversation concluded with a look at emerging therapies beyond current CD30- and PD-1-targeted approaches, including CD70-directed antibody-drug conjugates and CD30-directed CAR T-cell therapy, both still early in development. Dr Brody highlighted new data presented at the 2026 ASCO Annual Meeting on an investigational PRMT5 inhibitor among heavily pretreated patients. He described the finding as unexpected and among the most promising developments on the horizon for relapsed and refractory disease.

Highlights from the PER® CME activity "The ADC Revolution in Metastatic Breast Cancer: Redefining Treatment Selection and Sequencing" — this podcast is not certified for credit. To participate in the full accredited activity and earn CME credit, use the link below.In this podcast, experts Seth A. Wander, MD, PhD, Reshma L. Mahtani, DO, and Shanu Modi, MD, review pivotal data regarding the use of antibody-drug conjugates in the treatment of metastatic triple-negative breast cancer, and discuss how they apply these data in the management of their patients.Earn CME credit by completing the full accredited activity (available through July 31, 2027): https://www.gotoper.com/courses/the-adc-revolution-in-metastatic-breast-cancer-redefining-treatment-selection-and-sequencing-kpppThis podcast, including the narration, was developed by PER® (Physicians’ Education Resource®, LLC) editorial staff from the full online CME activity developed with these faculty. The narration was voiced by a PER staff member or by an AI tool. The podcast contains no product advertising. The full activity is supported by educational grants from AstraZeneca and Daiichi Sankyo, Inc.This content is for educational purposes only and is not a substitute for the independent clinical judgment of a health care professional. Faculty may discuss investigational or off-label uses; consult prescribing information for any products discussed.