Jonathan Riess, MD, MS

Two clinical scenarios illustrated shared decision-making in practice: a 58-year-old woman with TP53 mutation, L858R, and asymptomatic brain metastases drew unanimous consensus for treatment intensification with either FLAURA2 or MARIPOSA, given her high-risk features and flexible schedule.

The debate examined whether amivantamab-lazertinib or osimertinib-chemotherapy more favorably reshapes resistance biology, with the MARIPOSA team citing data showing lower rates of MET amplification (7.3% vs. 13.1%) and secondary EGFR mutations (1.4% vs. 7.6%) compared to osimertinib monotherapy, alongside a potential immune-activating effect of amivantamab and a possible curve-flattening signal suggesting disease course modification.

Panelists agreed that subcutaneous amivantamab represents meaningful progress over the IV formulation, nearly eliminating infusion reactions, reducing dosing frequency to every four weeks, and lowering high-grade dermatologic toxicity, although grade 1-2 rash and the burden of the COCOON prophylaxis regimen remain relevant considerations for patients.

The debate centered on CNS efficacy comparisons between MARIPOSA and FLAURA2, with the key distinction being that MARIPOSA mandated serial brain MRIs for all patients, enabling full intracranial PFS analysis across all 429 participants, whereas FLAURA2 only required serial imaging in patients with baseline CNS metastases, limiting the robustness of its CNS data.

The TOP trial, a phase three study focused exclusively on TP53-mutant EGFR-mutant non-small cell lung cancer, validated the FLAURA2 findings in this high-risk subset, showing a striking PFS benefit of 34.0 versus 15.6 months (HR 0.44) for osimertinib plus chemotherapy over monotherapy, with a favorable duration of response of 32.7 versus 15.9 months, though overall survival data remain immature.

The FLAURA2 phase three trial demonstrated that adding platinum-based chemotherapy to osimertinib significantly improved outcomes over osimertinib monotherapy in first-line EGFR-mutant non-small cell lung cancer, with a median PFS of 29.4 versus 19.9 months and a statistically significant overall survival benefit of 47.5 versus 37.6 months.

The COPERNICUS study, an ongoing phase two trial, evaluated amivantamab-based regimens in EGFR-mutant non-small cell lung cancer across two cohorts, first-line and post-osimertinib progression, with a key focus on implementing mandatory prophylactic skin and DVT regimens, resulting in dramatically lower rash rates (4% grade 3+) compared to the original MARIPOSA trial.

Panelists discuss the pivotal MARIPOSA trial, which examined combining amivantamab with lazertinib versus osimertinib monotherapy, showing improvements in progression-free survival (23.7 vs. 16.6 months), overall survival, CNS efficacy, and particularly strong benefits in high-risk subgroups such as TP53-mutant patients. Safety data from the trial highlighted the importance of prophylactic measures, especially for rash and other adverse events, noting that with current prophylaxis protocols, serious toxicity rates have been significantly reduced compared to the original study.

Zoldonrasib has elicited good responses and progression-free survival in an area with a large unmet need, said Jonathan Wesley Riess, MD, MS.

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