Drs Lee and Saxena on Future Directions for PD-L1 Evaluation in EGFR-Mutated NSCLC

“The single-agent EGFR-targeting drug osimertinib remains a viable option in a selected patient population. Whether this binding influences [the] sequence of therapy is an interesting question, and one that should be explored in retrospective studies.”

Jonathan Wennan Lee, MD, MSc, chief hematology/oncology fellow in the Weill Department of Medicine at NewYork Presbyterian-Weill Cornell Medicine; and Ashish Saxena, MD, PhD, an associate professor of clinical medicine at Weill Cornell Medical College and an assistant attending physician at NewYork-Presbyterian Hospital, discuss ways that PD-L1 expression may influence future treatment decision-making for the management of EGFR-mutated non–small cell lung cancer (NSCLC).

Lee, Saxena, and colleagues conducted a retrospective analysis that investigated the potential of PD-L1 expression as a predictive biomarker of response to first-line osimertinib (Tagrisso) monotherapy in patients with this disease. Lee observed thatalthough compelling data from trials such as the phase 3 FLAURA2 (NCT04035486) and MARIPOSA (NCT04487080) trials—which evaluated first-line osimertinib with or without chemotherapy and amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze), respectively—have pushed the EGFR-mutated NSCLC field toward combination strategies, single-agent osimertinib remains a viable option for select patient populations.

A critical area of inquiry involves how PD-L1 expression might influence the sequence of therapy, a challenge that has become increasingly complicated following recent regulatory decisions, such as the June 2025 FDA accelerated approval of datopotamab deruxtecan-dlnk (Datroway) for the treatment of patients with locally advanced or metastatic EGFR-mutated NSCLC who have been treated with prior platinum-based chemotherapy and EGFR-directed therapy. Lee highlighted the potential for PD-L1 expression levels to eventually serve as a biomarker to guide or influence clinical decisions in subsequent-line settings, though data are still evolving.

However, Saxena emphasized that because current research has focused on first-line approaches, it does not yet provide definitive guidance for subsequent treatment selections. Saxena explained that the ideal clinical outcome would involve using PD-L1 expression to help determine when to intensify therapy with combination regimens vs maintaining single-agent TKI therapies. To bridge this gap in clinical application, Lee advocated for the development of additional retrospective studies to explore these sequencing approaches further.