Considering Resistance Mechanisms When Choosing Therapy in the Frontline Setting

EP: 1.The Evolution of EGFR-Mutated Advanced NSCLC Treatment: Present Considerations and Future Treatment Options

EP: 2.Has Combination Therapy Become the New Frontline Treatment Standard for EGFR-Mutant Metastatic NSCLC?

EP: 3.Decision Points to Consider When Choosing Treatment With Monotherapy or Combination Therapy for EGFR-Mutant mNSCLC

EP: 4.Evaluating Patient Preferences for the Treatment of EGFR-Mutant mNSCLC

EP: 5.Comparing the Combination Therapies for the Treatment of EGFR-Mutant mNSCLC

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EP: 6.Considering Resistance Mechanisms When Choosing Therapy in the Frontline Setting

EP: 7.The Importance of Maintaining Quality of Life and Intervening Early When Adverse Events Occur in the Frontline Treatment Setting

EP: 8.Weighing the 1-Year Projected Overall Survival Benefit With MARIPOSA in the Frontline Treatment of EGFR-Mutant mNSCLC

EP: 9.Discussing the Time and Financial Toxicities Associated With Combination Therapies and Potential Mitigation Strategies

EP: 10.Discussing Potential Combination Therapy Medication-Associated Toxicities With Patients

EP: 11.Evaluating the Clinical Utility of Subcutaneous Amivantamab in the Treatment of EGFR-Mutant mNSCLC

EP: 12.The Importance of Multidisciplinary Collaboration With Subspecialty Physicians in the Toxicity Management With Treatment

EP: 13.Exploring Second-Line Treatment Options Including Targeted Radiation and Surgery for the Management of EGFR-Mutant mNSCLC

EP: 14.Tissue vs Plasma Biopsy After First Disease Progression in EGFR-Mutant NSCLC

EP: 15.Deciding Between a Biomarker-Directed Approach and a Biomarker-Agnostic Approach for Second-Line Treatment of EGFR-Mutant NSCLC

EP: 16.Continuing the Targeted TKI in the Second Line for the Treatment of EGFR-Mutant NSCLC

EP: 17.When to Consider Retreatment With Chemotherapy After FLAURA2 for EGFR-Mutant NSCLC

EP: 18.Patient Case Presentation: A 45-Year-Old With Newly Diagnosed EGFR-Mutant mNSCLC and Liver Metastases

EP: 19.Patient Case Presentation: A 69-Year-Old With Newly Diagnosed EGFR-Mutant mNSCLC and Symptomatic Brain Metastases

This segment explores how resistance mechanisms influence frontline treatment selection for EGFR-mutant metastatic non–small cell lung cancer. The discussion centers on whether anticipated resistance patterns should factor into initial treatment decisions or whether having multiple therapeutic options available for sequencing is more important. The panel emphasizes that resistance considerations do play a role in treatment selection, with specific attention to comutational status at diagnosis, brain involvement, liver involvement, and overall disease burden as key factors favoring combination therapy approaches.

The clinical rationale for combination therapy selection involves understanding specific resistance mechanisms and available therapeutic options. The panel notes that amivantamab’s bispecific mechanism inhibits both EGFR and MET pathways, potentially reducing MET resistance development. When MET resistance does occur, multiple treatment options remain available, including MET inhibitors like tepotinib and capmatinib, as well as amivantamab itself. However, the primary focus remains on achieving prolonged progression-free survival and optimal overall survival data rather than solely preventing specific resistance mechanisms. The goal is providing patients with the longest and most durable response possible while maintaining flexibility for future treatment decisions.

The treatment selection process is characterized as strategic, chess-like thinking that requires considering multiple moves ahead. However, this forward-thinking approach must be balanced against the sobering reality that approximately 25% to 30% of patients never receive second-line therapy, emphasizing the critical importance of frontline treatment optimization. This statistic underscores the tension between reserving certain therapies for later lines vs using the most effective combination up front. The discussion highlights the complexity of treatment sequencing decisions, where clinicians must weigh the potential benefits of aggressive initial therapy against maintaining future treatment options, all while acknowledging that a significant portion of patients may not have the opportunity to benefit from subsequent therapeutic interventions.