MARIPOSA-2: Second interim analysis for overall survival

Previously, the randomized phase III MARIPOSA trial demonstrated that the addition of amivantamab to chemotherapy significantly boosted the progression-free survival (PFS) of patients with EGFR-mutant non-small-cell lung cancer (NSCLC) who progressed on first line osimertinib.¹ At the time of this primary analysis, the follow-up was only about 8 months, which proved to be too short to see a significant impact of amivantamab on overall survival (OS). During ESMO 2024, updated results of this trial were presented with a median follow-up of 18.1 months (75% of OS events).² In this video, Prof Dr Mariana Brandao (Institut Jules Bordet, Brussels, Belgium) and Prof Dr Sanjay Popat (Royal Marsden Hospital, London, UK) summarize the results of this updated analysis and discuss their potential impact on clinical practice.

MARIPOSA-2 is a phase III study in which 657 patients with advanced NSCLC and a common EGFR mutation who progressed on first line osimertinib were randomly assigned to receive chemotherapy, chemotherapy plus amivantamab or chemotherapy + amivantamab and lazertinib (of note, this third arm is not addressed in this presentation). The primary endpoint of the study was PFS, with OS as a key secondary objective. During ESMO 2024, a second interim analysis for OS was presented. In order not to spend too much statistical power for the final analysis, the investigators opted for a conservative threshold for statistical significance in this interim analysis with a p-value of 0.01.^1,2

After 18.1 months of median follow-up, chemotherapy + amivantamab was associated with a 27% lower death risk compared to chemotherapy alone (HR[95%CI]: 0.73[0.54-0.99]). However, the corresponding p value of 0.039 did not cross the (conservative) boundary of statistical significance (0.01). Importantly, the curves for OS separated early and continued to do so over time. At 12 months, the absolute difference in OS between both arms was 7% (70% vs. 63%), increasing to 10% after 18 months (50% vs. 40%).² In addition to the trend for a better OS, the combination of chemotherapy and amivantamab also proved to be associated with a longer time to symptomatic progression (median: 16 vs. 11.8 months; HR[95%CI]: 0.73[0.55-0.96]; p= 0.026), a longer time to treatment discontinuation (median:  10.4 vs. 4.5 months; HR[95%CI]: 0.42[0.33-0.53]; p< 0.001) and a longer time to the need for a subsequent treatment line (median: 12.2 vs. 6.6 months; HR[95%CI]: 0.51[0.39-0.65]; p< 0.001).² Finally, Prof Popat underscored that the chemotherapy-amivantamab combination comes with an impressive intracranial activity, a characteristic that is of particular clinical relevance in the context of progressive EGFR-mutant NSCLC.

As such, these results reaffirm the combination of chemotherapy and amivantamab as an effective treatment option for patients with EGFR-mutant NSCLC who progress after first line osimertinib. The results of the final OS analysis are eagerly awaited.