Dr Shum on the Evolving Treatment Paradigm for EGFR+ NSCLC

"In 2025, we are certainly seeing [a shift], especially in the first-line setting for treatment of EGFR-mutated lung cancer, where combination treatments or regimens have definitely entered our paradigm—marking a significant change from how it used to be with just single-agent EGFR inhibitors."

Elaine Shum, MD, a thoracic medical oncologist at NYU Langone’s Perlmutter Cancer Center, discussed the shifting treatment paradigm in EGFR-mutated non–small cell lung cancer (NSCLC), emphasizing the growing role of combination regimens in the frontline setting and the implications of recent phase 3 trial data.

Historically, first-line treatment for patients with EGFR-mutated NSCLC has centered on single-agent EGFR TKIs, with osimertinib (Tagrisso) representing the standard of care in this patient population based on its intracranial activity and survival benefits. However, Shum noted that the field has reached a turning point with increasing clinical evidence supporting the integration of combination strategies aimed at delaying resistance and improving long-term outcomes.

Two key studies driving this evolution were the phase 3 FLAURA2 (NCT04035486) and the MARIPOSA (NCT04487080) trials. In FLAURA2, the addition of platinum-based chemotherapy to osimertinib was evaluated in the frontline setting, with data showing a clinically meaningful improvement in progression-free survival compared with osimertinib alone. This approach sought to broaden therapeutic impact by addressing both EGFR-dependent and -independent disease mechanisms.

MARIPOSA investigated the combination of amivantamab-vmjw (Rybrevant) and lazertinib (Lazcluze), in treatment-naive patients. This regimen was compared against osimertinib monotherapy and lazertinib monotherapy, and findings from the study supported the August 2024 FDA approval of amivantamab plus lazertinib.

The trials have highlighted the trend toward redefining first-line standards for EGFR-mutant NSCLC, with combination approaches increasingly favored in select patient populations. Shum noted that these strategies may be particularly beneficial for patients at higher risk of early progression, though optimal patient selection remains an area of ongoing investigation.

Although osimertinib monotherapy continues to offer a favorable safety profile and remains a key therapeutic option, the addition of chemotherapy or targeted biologics reflects a nuanced shift in treatment strategy. Shum emphasized that as more data mature, the field must continue to refine first-line approaches based on clinical risk factors, molecular profiles, and emerging resistance patterns.