MARIPOSA study: mechanisms of acquired resistance

Prof Mariana Brandão, medical oncologist at the Institut Jules Bordet, Brussels, discusses resistance mechanisms to amivantamab and osimertinib with Prof Benjamin Besse, medical oncologist at Institut Gustave Roussy, Paris, based on an early analysis of the MARIPOSA trial.

This trial randomised treatment-naïve, EGFR-mutant, advanced/metastatic NSCLC patients to either amivantamab plus lazertinib (amilaz) or osimertinib. Paired blood samples were collected at baseline and at disease progression or within 90 days of treatment discontinuation to analyse ctDNA using next-generation sequencing (Guardant 360 CDx).

In patients who discontinued treatment, 56% for osimertinib and 53% for amilaz had matched ctDNA data. Acquired MET amplifications and secondary EGFR resistance mutations were significantly lower for amilaz compared to osimertinib (MET: 4.4% vs 13.6%, p=0.017; EGFR: 0.9% vs 7.9%, p=0.014). This suggests that amilaz likely targets both MET and EGFR pathways. No significant differences were found for other resistance mechanisms, and amilaz had a low rate (0.9%) of TP53/RB1 loss, which is linked to SCLC transformation.

Many patients are still on treatment in the study, and as they progress, resistance mechanisms may change. Early progressors (those progressing within six months) showed more MET amplification in the osimertinib arm, indicating these patients could benefit from second-line amivantamab with chemotherapy.

Some resistance mechanisms remain unknown, as Guardant 360 CDx cannot detect protein levels like HER3, which could be important for ADCs. Complex mutations—multiple resistance mechanisms in one patient—occurred in about 40% of osimertinib patients and 27% of amilaz patients. It is unclear how these complex mutations affect responses to chemotherapy, but they may correlate with higher tumour burden and increased resistance.