How to Select First-Line Immunotherapy for Metastatic NSCLC: PD-L1, Disease Burden, and Co-Mutations

Selecting first-line immunotherapy for patients with metastatic non–small cell lung cancer (NSCLC) requires consideration of PD-L1 expression, disease burden, genomic alterations, and individual patient characteristics. In this interview with Targeted Oncology^TM, Matthew Gubens, MD, MS, professor of medicine and thoracic oncologist at UCSF Health, discusses how clinicians can approach treatment selection among single-agent immunotherapy, dual immune checkpoint inhibition, and chemoimmunotherapy.

The discussion emphasizes the importance of comprehensive genomic profiling before initiating immunotherapy, particularly in patients with nonsquamous disease, to identify actionable mutations or fusions that may influence treatment decisions. Once actionable alterations have been ruled out, PD-L1 expression and the urgency of disease control help guide the choice of first-line regimen.

For patients with PD-L1 expression of 50% or higher and a relatively low disease and symptom burden, single-agent immunotherapy may be an appropriate option. Gubens explains that these patients may have sufficient time to assess their response before introducing chemotherapy if needed. Conversely, patients with a high disease burden or substantial symptoms may benefit from chemoimmunotherapy, which offers higher response rates than single-agent immunotherapy.

Gubens also explores clinical scenarios in which dual immunotherapy, with or without chemotherapy, may be considered. These include squamous histology, PD-L1–negative tumors, and tumors harboring co-mutations such as STK11 and KEAP1, which may be associated with resistance to immunotherapy. The expert notes that the lack of extensive head-to-head data across these patient populations makes treatment selection particularly nuanced.

Finally, the conversation highlights the importance of assessing performance status, overall fitness, and preexisting autoimmune conditions when weighing the potential benefits of dual checkpoint inhibition against the risk of immune-related adverse events. These factors can help community oncologists individualize first-line treatment for advanced NSCLC while balancing the potential for tumor response, disease control, and treatment tolerability.

For community oncologists, these insights underscore the importance of individualizing first-line treatment decisions to balance response potential, disease control, and treatment tolerability.