Raffaele Califano, MD, on EGFR-Mutant Advanced NSCLC: MARIPOSA-2

Today I'm going to discuss with you the data that we are reporting at ASCO 2025 from the MARIPOSA-2 study. The MARIPOSA-2 study was a large phase three randomized clinical trial which evaluated patients with advanced EGFR-mutant non-small cell lung cancer whose disease had progressed after osimertinib as a later line, and patients were treated with standard chemotherapy—carboplatin and pemetrexed—or chemotherapy with carbo/pemetrexed plus amivantamab, which is a dual EGFR and MET inhibitor, or carbo/pemetrexed plus amivantamab and lazertinib, which is a third-generation EGFR TKI. The study has already been reported a number of months ago as a positive study which showed that patients who received the amivantamab-containing regimen had a longer progression-free survival when compared to standard chemotherapy alone. At ASCO, we are now reporting the outcomes according to the baseline mechanism of resistance to osimertinib for MARIPOSA-2 patients. So all patients who were enrolled in the study had a blood sample taken at baseline. The blood sample was analyzed for ctDNA and approximately 87% of the patients in this dataset had a sample which was available for ctDNA. We performed next-generation sequencing using Guardant360 and the Personalis NeXT assay, and we were able to report the baseline mechanism of resistance and therefore perform an analysis looking at the PFS and the overall response rate impact from the baseline mutations. What we saw with the median follow-up of 8.7 months was that for patients with ctDNA at baseline, chemotherapy plus amivantamab achieved a longer progression-free survival when compared to standard chemotherapy alone. And the same was seen for patients with a baseline C797S mutation. If you look at the mechanisms of resistance that we reported, the most commonly reported ones were MET amplification—around 15% of the patients—or secondary EGFR resistance mutations, around 13–18% of the patients. What we saw was that for patients with EGFR- and MET-dependent mechanisms of resistance, there was a longer progression-free survival if they received chemo/amivantamab when compared to chemotherapy. But the same was also seen for EGFR- and MET-independent mechanisms of resistance or unknown mechanisms of resistance. Most importantly, if you look at the MET amplification-only subgroup, the progression-free survival favored again chemo/amivantamab with a hazard ratio of 0.51. Looking at the secondary EGFR resistance mutation, the hazard ratio for PFS was 0.55. In summary, what we saw from this dataset is that patients who received chemo/amivantamab had a longer progression-free survival over standard chemotherapy alone regardless of the mechanism of resistance post-osimertinib at baseline. And what this means is that the MARIPOSA-2 regimen—i.e., chemotherapy plus amivantamab—remains the standard of care in this setting.