Post-Combination Sequencing and ADC Integration

Following first-line combination therapy, sequencing becomes more complex as chemotherapy exposure limits subsequent options. The COMPEL data showing 8.4 versus 4.4 month progression-free survival and 15.9 versus 9.8 month overall survival provides some guidance, though applications remain limited for patients receiving upfront combination therapy.

Dr. Rodriguez notes that MARIPOSA-2 regimens become challenging following first-line chemotherapy exposure, though limited CHRYSALIS data suggest potential second-line amivantamab utility. For high-burden disease with poor-risk characteristics, she considers repeat amivantamab given its demonstrated efficacy in heavily pretreated populations.

Repeat biopsy or liquid biopsy at progression provides crucial information for sequencing decisions. MET amplification represents a clear indication for amivantamab following FLAURA2 progression, whereas other resistance mechanisms may favor alternative approaches.

The panelists acknowledge uncertainty about resistance pattern evolution with different first-line regimens. MARIPOSA may reduce MET-mediated resistance while potentially creating alternative resistance mechanisms that remain poorly understood or therapeutically challenging.

Trial design limitations complicate long-term outcome interpretation, particularly MARIPOSA's lack of crossover arms preventing assessment of sequential therapy benefits. The treatment arm demonstrates curve separation with plateau effects suggesting durable responses, though mechanisms remain unclear.

Antibody-drug conjugates represent important emerging options, with datopotamab deruxtecan showing activity in EGFR-mutant disease. However, optimal sequencing relative to amivantamab and chemotherapy combinations requires additional investigation.

Future real-world data will provide insights into optimal sequencing as these regimens become more widely adopted outside clinical trial populations.