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Dr. Ticiana Leal, professor and director of the Thoracic Program at the Winship Cancer Institute of Emory University, presents a single-expert discussion on treatment selection and sequencing for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC), focusing on data presented at ELCC 2026.

The discussion covers frontline decision-making between osimertinib monotherapy, osimertinib plus chemotherapy (FLAURA2), and amivantamab plus lazertinib (MARIPOSA), with updated overall survival data favoring combination strategies for the majority of patients harboring high-risk features. Key topics include TP53 co-mutation and ctDNA-driven risk stratification, new TOP trial data, real-world toxicity management including the COCOON dermatologic prophylaxis strategy, the shift to subcutaneous amivantamab, time toxicity considerations, second-line sequencing including COMPEL, MARIPOSA-2, and datopotamab deruxtecan, chemotherapy rechallenge data from FLAURA2, and CNS and leptomeningeal disease management. Dr. Leal closes with anticipated developments in early-stage and perioperative EGFR-mutated NSCLC treatment.

Dr. Seema Nagpal, clinical professor of neurology in the Division of Neuro-oncology at Stanford University, and Dr. Laura Alder, assistant professor of thoracic medical oncology at Duke University, discuss CNS disease management in EGFR-mutated non-small cell lung cancer (NSCLC).

The program covers first-line CNS efficacy data from the FLAURA2 and MARIPOSA trials, CNS surveillance standards and barriers to consistent practice, a clinical case of CNS-only progression on osimertinib, second-line sequencing across COMPEL, TROPION-Lung01 and TROPION-Lung05, and MARIPOSA-2, and emerging agents including datopotamab deruxtecan, ivonesimab, and izalontamab brengitecan. Critical gaps in CNS endpoint reporting, including treated versus untreated lesions, leptomeningeal disease inclusion, response criteria heterogeneity, are examined. Leptomeningeal disease management is discussed in depth, including osimertinib dose escalation and pulse dosing, amivantamab-lazertinib sequencing, intrathecal therapies, proton craniospinal irradiation, and cerebrospinal fluid liquid biopsy including circulating tumor cells. Strategies for community clinicians without access to specialized interventions are emphasized throughout.

Dr. Estelamari Rodriguez and Dr. Coral Olazagasti from the University of Miami discuss the groundbreaking TOP study, which provided the first prospective phase 3 evidence for treatment intensification in patients with EGFR-mutant non-small cell lung cancer harboring concurrent TP53 mutations.

The TOP study demonstrated remarkable benefits for osimertinib plus chemotherapy versus osimertinib alone in TP53-mutant patients, with median progression-free survival improving from 15.6 to 34 month, more than doubling survival outcomes. This represents an 18-month absolute gain, exceeding the average benefit observed in FLAURA2 for the entire population.

The discussion contextualizes these findings within the broader treatment landscape, comparing FLAURA2 and MARIPOSA regimens while addressing practical considerations for patient selection. Key topics include risk stratification beyond TP53 (including L858R mutations and central nervous system involvement), shared decision-making approaches, and sequencing strategies following first-line combination therapy.

Through clinical scenario-based discussions, the panelists emphasize that combination therapy should represent the new standard of care for most patients, with TP53 status providing additional confirmation for treatment intensification rather than serving as the sole decision-making factor.

Two lymphoma experts discuss how duvelisib, supported by the PRIMO study and the ongoing TERZO phase 3 trial, is reshaping the treatment of relapsed/refractory peripheral T-cell lymphoma.

Dr. Mrinal Gounder led a comprehensive discussion with Drs. Atrayee Basu Mallick and Nam Bui on evolving treatment strategies for desmoid tumors. The program highlighted the paradigm shift from surgical intervention to multimodal approaches emphasizing active surveillance and systemic therapies.

Key topics included patient selection criteria for watchful waiting versus treatment initiation, considering factors such as tumor location, size, symptoms, and growth trajectory. High-risk locations include head/neck, mesenteric areas, and proximity to neurovascular structures. The discussion emphasized moving away from surgery due to high recurrence rates and significant morbidity, particularly in challenging anatomical locations.

The RINGSIDE trial presented at ASCO 2026 demonstrated impressive efficacy for varagesestat, a once-daily gamma-secretase inhibitor, with an 84% reduction in progression risk and rapid pain relief within 4 weeks. This adds to the therapeutic armamentarium alongside nirogacestat, the first FDA-approved treatment.

Unmet needs include determining optimal treatment duration, understanding mechanisms of spontaneous regression in 20% of patients, managing fertility concerns in predominantly young female populations, and developing predictive biomarkers for treatment selection.

Dr. Jonathan Strosberg from Moffitt Cancer Center discussed the challenging landscape of extrapulmonary neuroendocrine carcinoma (NEC), a rare and aggressive malignancy distinct from well-differentiated neuroendocrine tumors. Through a case of a 64-year-old man with metastatic colonic NEC, Dr. Strosberg highlighted key diagnostic challenges and treatment limitations in this historically underappreciated disease.

Poorly differentiated NECs demonstrate high Ki-67 proliferation indices (>55%), aggressive histology with necrosis and pleomorphism, and distinct mutational patterns including p53 and RB1 alterations similar to small cell lung cancer. Traditional platinum-based chemotherapy yields poor outcomes, with median progression-free survival of 2 to 6 months in second-line settings.

DLL3 emerges as a promising therapeutic target, expressed in approximately 75% of extrapulmonary NECs. Bispecific T-cell engagers like tarlatamab targeting DLL3 show encouraging activity in patients with high DLL3 expression (>50%), achieving approximately 40% response rates versus 3% in low expressors.

Vasomotor symptoms (VMS) are among the most clinically consequential adverse events of endocrine therapy in patients with hormone receptor–positive breast cancer, affecting the majority of treated patients and contributing to suboptimal treatment adherence. In this video series, Carmine Valenza, MD, MPH, PhD(c), reviews the neurobiology underlying VMS, explaining how estrogen deprivation leads to hyperactivation of hypothalamic KNDy neurons and how dual NK1/NK3 receptor antagonism with elinzanetant (Lynkuet) targets this pathway through a nonhormonal mechanism considered safe for use in patients with breast cancer.

The phase 2 ARASEC trial (NCT02799602) evaluated darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the United States, utilizing an innovative synthetic historical control design derived from the prospective, randomized phase 3 CHAARTED trial (NCT00309985). Neal D. Shore, MD, FACS, and Rana R. McKay, MD, FASCO, co-led the trial, which met its primary end point of radiographic progression-free survival, with an HR of 0.29 compared with the ADT monotherapy control arm, and demonstrated a statistically significant overall survival benefit (HR, 0.50). In this Investigator Perspectives program, Shore and McKay explore design, key findings, and significance of ARASEC.

The Moonlight Shift, with host Gina Mauro, features leading and early-career oncologists from the Tri-State corridor in peer-level conversations about where the field is going — and what it still has to work out.

Dr. Edwin Choy from the sarcoma oncology program and Dr. Sarah Bouberhan from gynecologic medical oncology at Massachusetts General Hospital discussed perivascular epithelioid cell tumors (PEComas), rare mesenchymal neoplasms affecting approximately 75% of patients with benign or uncertain malignant potential. PEComas occur predominantly in women aged 20 to 55 years, commonly affecting the uterus, kidney, retroperitoneum, gastrointestinal tract, liver, and lungs. Diagnosis requires expert pathological evaluation with specific immunohistochemical markers including melanocytic markers (HMB-45, Melan-A) and smooth muscle markers (SMA, desmin, caldesmon).

Molecular characterization reveals approximately 50% harbor TSC1 or TSC2 loss affecting mTOR pathway signaling, whereas others demonstrate TFE3 gene rearrangements. The AMPECT phase 2 trial established nab-sirolimus as FDA-approved first-line therapy for advanced disease, demonstrating 39% response rates with 10.6-month progression-free survival and 40.8-month overall survival. Patients with TSC2 mutations showed nearly 90% response rates versus 13% for non-TSC2 mutations.

Dr. Megan Melody from Tampa General Hospital Cancer Institute and Dr. Mark Roschewski from Memorial Sloan Kettering Cancer Center discussed how circulating tumor DNA (ctDNA) testing is transforming lymphoma care through enhanced risk stratification, treatment monitoring, and personalized patient management.

Key insights emphasized ctDNA as an emerging risk factor superior to baseline assessments, with most patients achieving undetectable levels after 2 cycles. Combined negative positron emission tomography and ctDNA results reduce relapse risk from 15% to 20% to single digits. However, ctDNA currently serves as a prognostic marker rather than treatment-guiding tool, with ongoing ALPHA3 trial investigating ctDNA-guided therapy using allogeneic CAR-T cells.

Clinical Implementation:

• Seventy-five percent concordance between ctDNA and PET imaging results

• Serial testing preferred over single time-point assessments for surveillance

• Technology varies across lymphoma subtypes, with phased variant assays showing superior sensitivity

• Quantitative values enable kinetic monitoring for individual patients with baseline controls

Dr. Helena Yu of Memorial Sloan Kettering Cancer Center and Dr. Sonam Puri of Moffitt Cancer Center discuss the phase 3 TOP study, presented at the European Lung Cancer Congress (ELCC) 2026, which evaluated osimertinib plus carboplatin/pemetrexed versus osimertinib monotherapy in non–small cell lung cancer (NSCLC) patients with EGFR mutations and concurrent TP53 alterations. The study showed a median progression-free survival (PFS) of 34.0 versus 15.6 months (hazard ratio [HR], 0.44), with consistent benefit across subgroups including central nervous system (CNS) and liver metastases. The experts contextualize TOP within FLAURA2 and MARIPOSA, address patient selection beyond TP53, walk through safety and toxicity management for combination regimens, and outline sequencing strategies at progression. They close with practical guidance for community oncologists and unanswered questions, including the role of circulating tumor DNA (ctDNA) dynamics as an emerging predictive biomarker.

Dr. Pedro Barata and Dr. Johann De Bono discuss recent advances in metastatic castration-resistant prostate cancer, with a focus on the evolving role of radiopharmaceuticals across the treatment landscape. They review key clinical updates from recent meetings, including emerging data on both established therapies and next-generation PSMA-targeted approaches, and examine how these findings are shaping treatment selection and sequencing strategies.

Dr. Mazyar Shadman from the University of Washington/Fred Hutchinson Cancer Center and Dr. Danielle Brander from Duke Cancer Institute discuss matching adjusted indirect comparisons (MIACs) for first-line chronic lymphocytic leukemia (CLL) treatment decisions. The discussion explores how these statistical methodologies help compare treatments from different clinical trials when direct head-to-head comparisons are unavailable, acknowledging their limitations while recognizing their value in rapidly evolving treatment landscapes.

Key analyses include zanubrutinib (SEQUIOA trial) comparisons with venetoclax-based fixed-duration regimens, CLL14 (venetoclax-obinutuzumab), and AMPLIFY (acalabrutinib-venetoclax). Results consistently favored continuous BTK inhibitor therapy for progression-free survival, particularly after 3 years, while demonstrating favorable safety profiles despite longer treatment exposure.

Clinical Considerations:

• MIACs provide systematic comparisons beyond separate trial evaluations but cannot replace randomized head-to-head trials
• Anchored analyses (shared control arms) offer stronger evidence than unanchored methodologies
• Patient goals regarding treatment duration, efficacy priorities, and risk tolerance remain paramount in decision-making
• Disease markers including IGHV mutation status and TP53 aberrations influence optimal treatment selection between continuous versus fixed-duration approaches

A panel of exerts focus on the management of advanced renal cell carcinoma, emphasizing why the first-line treatment decision is the most critical opportunity to influence patient outcomes. This initial treatment decision can shape the entire patient journey and remains central to achieving optimal outcomes. Experts explore the importance of early and effective disease control, including how tumor biology, disease burden, and patient fitness shape treatment selection and prognosis. We’ll also discuss key clinical considerations and real-world patterns, including the fact that some patients may not receive subsequent therapy. Finally, they will review emerging clinical data and consider how these insights can be applied to optimize outcomes for the patient in front of us.

Lori Wirth, MD, discusses the latest NCCN guideline updates in differentiated thyroid cancer. This program focuses on evolving strategies for managing patients with progressive, radioactive iodine–refractory disease, with particular emphasis on the growing role of next-generation sequencing (NGS) and precision oncology. Dr. Wirth highlights how identifying actionable molecular alterations such as kinase fusions have transformed first-line treatment decisions, enabling more targeted and effective therapies that are reshaping the standard of care.

Supported in part by Eisai, content independently produced by OncLive.

We will be discussing the current management approach for patients with differentiated thyroid cancer, with a focus on the role of surgery within the broader treatment landscape.

Supported in part by Eisai, content independently produced by OncLive.

Neil M. Iyengar, MD, and Kelsey Natsuhara, MD, explore the evolving role of antibody-drug conjugates in the treatment of breast cancer.

Martin F. Dietrich, MD, PhD, and Ticiana Leal, MD, highlight evolving treatment approaches for HER2-mutated non–small cell lung cancer.

Heather Wakelee, MD, and Helena Yu, MD, discuss sequencing strategies in EGFR-mutant NSCLC, including frontline choices, resistance, and emerging targeted therapies.

Jonathan Riess, MD, MS, and Nicolas Villanueva, MD, discuss evolving frontline and sequencing strategies in EGFR-mutant non–small cell lung cancer.

Christine Lovly, MD, PhD, and Matthew Lee, MD, discuss evolving treatment considerations in EGFR-mutated non–small cell lung cancer.

Loretta J. Nastoupil, MD, and Amitkumar Mehta, MD, discuss sequencing considerations in relapsed/refractory follicular lymphoma.

Natalie Vokes, MD, and Sid Devarakonda, MBBS, MD, discuss evolving frontline treatments and sequencing considerations in EGFR-mutated NSCLC.

Samuel Rosner, MD, and Laura Alder, MD, discuss optimal approaches to the current management of EGFR-mutated non–small cell lung cancer.

Luis Raez, MD, FACP, FCCP, and Alexander I Spira MD, PhD, FACP, FASCO, share evolving treatment considerations in EGFR-mutated NSCLC.

Narjust Florez, MD, and Stephanie J. McDonald, MSN, FNP-BC, AOCNP, discuss management and adherence strategies in EGFR-mutated non–small cell lung cancer.

Prithviraj Bose, MD, and Pankit Vachhani, MD, discuss the exploration of combination treatment approaches in myelofibrosis.

Joel Neal, MD, PhD, and Sarah Goldberg, MD, MPH, discuss frontline treatment considerations in EGFR-mutated advanced non–small cell lung cancer.

Stephen Lam Chan, MBBS, MD, FRCP, FHKCP, FHKAM, and Gonzalo Cantis, MD, highlight ongoing research in unresectable, nonmetastatic HCC.