Sequencing Strategy in EGFR-Mutant NSCLC: How Frontline Choices Shape Later Options

May 11, 2026

Post-TTLC 2026: Dr. Patel asks how anticipated next-line options factor into upfront treatment choice, framing it as a chessboard where early moves determine what is available later. Dr. Doroshow says she tries to think one step at a time because she cannot see three moves ahead, given how many ways therapies can be mixed and matched.

Walking through a case, she explains that for a patient on single-agent osimertinib because of borderline performance status, she would re-biopsy if possible at progression and repeat liquid biopsy to look for resistance mechanisms, which she finds in less than half of cases but always pursues. She describes recently identifying an acquired BRAF V600E mutation in a patient progressing on single-agent osimertinib. For these borderline patients, she finds COMPEL (continuing osimertinib with carboplatin-pemetrexed) better tolerated than amivantamab-based combinations, which she tends to save for later. She also highlights radiotherapy for oligoprogression.

Dr. Patel agrees the upfront decision has downstream repercussions. If a patient receives FLAURA2 (chemotherapy plus osimertinib) frontline, the timing and reason for stopping chemotherapy shapes whether to use chemotherapy-containing options later. If a patient receives amivantamab-based therapy frontline, second-line chemotherapy and datopotamab deruxtecan (Dato-DXd, a TROP2-directed ADC) become natural options. He notes amivantamab itself targets MET, influencing which resistance mechanisms emerge. Dr. Doroshow adds single-agent amivantamab has worked well for some patients who progressed on osimertinib plus chemotherapy. Both close by emphasizing patients are not the same person across treatment lines.