WCLC 2025 | MARIPOSA: resistance mechanisms of amivantamab & lazertinib in NSCLC

At the World Lung Meeting, we presented our updated data on mechanisms of resistance on patients participating in the MARIPOSA trial. You’ll remember these are patients with common EGFR advanced non-small cell lung cancer mutation positive disease who were randomized to receive combination amivantamab-lezertinib or osimertinib with a small lezertinib monotherapy arm. We’d reported previously that there was a strong and meaningful large PFS benefit reaching the primary endpoint. And at the ELCC meeting earlier this year, Dr. Yang presented the overall survival follow-up data confirming a significant and clinically meaningful survival advantage for the combination with projected at least one year median difference in survival. At the ESMO meeting last year, my colleague Dr. Bess presented the initial data that we had on mechanisms of resistance, perhaps explaining why with the survival advantage that we now see might have occurred. And at that meeting, Dr. Bess presented data based on Foundation 360 analysis of patients progressing or end of treatment, identifying that the patients that progressed on combination amivantamab-lezertinib had far fewer met operations and on-target HFR mutations than patients randomized to osimertinib. At the World Lung Meeting, we have updated this data and looked a bit deeper. And indeed, what we find is that amivantamab lezertinib seems to be altering the biology of the disease. Remember, amivantamab is a combined MET-EGFR inhibitor. And so when we give a highly potent drug designed to switch off MET and EGFR pathways up front, we shouldn’t be so surprised that we don’t see so much on-target MET and EGFR resistance mechanisms. And indeed, that’s exactly what we see in this updated analysis, that compared to osimertinib, we see significantly fewer MET and EGFR on target resistance genetic alterations. What we see in the osimertinib arm is exactly what we’d expect to see as a diversity of genetic alterations, including MET amplification, as has been identified before. So what we now see perhaps propose is that this strong on-target effect is altering the natural history of patients treated with amivantamab in conjunction with lezertinib to meaningfully improve progression-free survival and thereby overall survival through this direct inhibition of MET and EGFR, which is strong and maintained. Thank you.

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