EGFR-Targeted Therapy Sequencing After Resistance in NSCLC

Dr. Singhi frames the discussion by noting that while EGFR-targeted therapy remains the cornerstone of precision medicine in lung cancer, resistance inevitably emerges. He asks Dr. Jani how he approaches sequencing after progression on first-line therapy.

Dr. Jani explains that sequencing depends on the frontline regimen. After osimertinib monotherapy, limited progression—such as isolated bone metastases—may be managed with radiation while continuing therapy. More extensive visceral or CNS progression prompts a change: options include adding chemotherapy to osimertinib, switching to amivantamab plus chemotherapy, or using an ADC such as datopotamab deruxtecan (DATO). He specifies that DATO can follow prior osimertinib directly, or serve as a third-line option after both osimertinib and platinum-based chemotherapy.

After amivantamab-based frontline therapy (e.g., amivantamab plus lazertinib, referencing the Mariposa trial), Dr. Jani notes that next-step decisions depend on comorbidities, CNS status, and co-mutations such as TP53. Options include ADCs or alternative amivantamab combinations. He highlights ivanesimab and TROP2-directed agents as emerging therapies, with ongoing investigation into whether TROP2-targeted treatment can move into earlier lines.

Throughout, Dr. Jani emphasizes that repeat molecular testing, tissue or liquid biopsy with NGS, is essential to identify resistance alterations and guide individualized sequencing. The takeaway is that post-EGFR resistance management is highly personalized, shaped by prior therapy, site of progression, comorbidities, and evolving tumor biology.

In the next episode, "Emerging Biomarkers in NSCLC: TROP2 Scoring and MTAP Loss," the experts discuss how AI-driven biomarker refinement and MTAP loss are expanding precision medicine in NSCLC.