Differentiating Between the Risk-Benefit Profiles for the Combination Therapies

The panel explored how to weigh the two2 major frontline combination regimens—osimertinib plus + chemotherapy (FLAURA2) and amivantamab plus + lazertinib (MariposaMARIPOSA)—both of which have demonstrated overall survival benefits over osimertinib monotherapy. From an efficacy standpoint, panelists agreed that the data appear broadly comparable across trials, acknowledging the limitations of cross-trial comparisons. Key endpointend points likesuch as progression-free and overall survival hazard ratiosHRs were similar, and while there were differences in CNScentral nervous system imaging schedules, these didn’t appear to tilt the efficacy balance significantly toward one regimen over the other.

However, toxicity and practical considerations were viewed as more differentiating factors. MariposaMARIPOSA was associated with higher rates of adverse events—including rash, diarrhea, infusion reactions, and thromboembolism—while FLAURA2’s chemotherapy-related toxicities were more familiar and manageable for clinicians. Panelists noted that while some toxicities (likesuch as a one-time infusion reaction) may be transient, others (such as persistent rash or daily diarrhea) can substantially impact quality of life. Supportive care for amivantamab-based regimens is more intensive, often requiring dermatologic support, anticoagulation, and close monitoring, which can increase the burden on both patients and care teams.

Ultimately, treatment decisions must account for both clinical and practical realities, including patient comorbidities, support systems, and willingness or ability to manage a more intensive regimen. While the survival gains are promising with both options, clinicians emphasized the importance of patient counseling and education, particularly when introducing newer regimens likesuch as amivantamab/lazertinib. With more familiarity and improved supportive protocols, some of the current challenges may become more manageable, but the learning curve and resource demands remain important considerations in selecting the optimal regimen.