1st line treatment for EGFRm mNSCLC

In this video, Dr Charlotte De Bondt, thoracic oncology at the ZAS hospitals in Antwerp tackles one of the more debated topics at ELCC 2025: What is the best first line treatment for patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC).

The current standard of care for these patients, at least if they are harbouring a ‘classic’ EGFR mutation, consists of osimertinib monotherapy. The latter is based on the results of the pivotal FLAURA trial in which this thrid generation EGFR TKI significantly outperformed gefitinin/erlotinib.¹ More recently, however, this standard of care was challenged in two large-scale, phase III studies: FLAURA-2 and MARIPOSA.

In FLAURA-2, the combination of osimertinib wandith chemotherapy led to a significant 38% lower risk for disease progression or death compared to osimertinib alone. At the 2 year landmark, this translated into a 16% absolute benefit in PFS rate in favour of the osimertinib-chemotherapy combination (57% vs. 41%).² Importantly, also the time to intracranial progression proved to be significantly better with the osimeritnib-chemotherapy combination. For the moment, results for overall survival (OS) in this trial were not yet reported. Not surprisingly, adding chemotherapy to osimertinib did result in a more pronounced toxicity burden, with an incidence of grade ≥3 adverse events (AEs) of 64% and 27%, respectively (serious AEs: 38% vs. 19%).

In the MARIPOSA trial, 1017 patients with locally advanced or metastatic EGFR-mutant non-small-cell lung cancer (NSCLC) were randomly assigned (2:2:1) to receive osimertinib monotherapy, a combination of lazertinib and the EGCFR-MET directed bispecific antibody amivantamab, or lazertinib alone. Previously, this study showed that the lazertinib-amivantamab combination was associated with a significant 30% reduction in the risk of disease progression or death compared to osimertinib.³ In addition, solid intracranial activity was shwon with this combination. During ELCC 2025 it became clear that this delayed disease progression also translates into a significantly longer OS for patients in the lazertinib-amivantamab arm (HR[95%CI]: 0.75[0.61-0.92]; p< 0.005). After a median follow-up of 37.8 months, the median OS with lazertinib-amivantamab was not yet reached, while this was reported at 36.7 months for osimertinib. The OS curves continue to widen over time and the investigators project that the median OS in the experimental arm will eventually be more than a year longer than what is seen with osimertinib.However, this benefit again came at the cost of important toxicity, with skin rash, venous thromboembolism and infusion-related reactions as the most prominent and bothersome adverse events (AEs). While strategies, such as specific dermatological care, prophylactic anticoagulation and premedication with corticosteroids, can mitigate these AEs to a certain extent, this increased toxicity will continue to be an important consideration in 1st line treatment decisions. In addition, the lazertinib-amivantamab treatment currently requires 2-weekly visits to the hospital to receive the intravenous therapy, whereas osimertinib is orally available, meaning that patients only have to come to the hospital every three months. With respect to the latter, a subcutaneous formulation of amivantamab is under development which will reduce the treatment burden (and the incidence of infusion-related reactions).

How these different trials will impact clinical practice in the years to come remains to be seen. First of all, OS data of FLAURA-2 will add further information to the discussion. In addition to this, physicians will have to make an important trade-off between a superior efficacy and an (important) increase in toxicity and treatment burden. Unfortunately, we will probably never see a head-to-head comparison between osimertinib-chemotherapy and lazertinib-amivantamab, leaving the oncological community with the scientifically unsound task of making cross-trial comparisons.