Immune Checkpoint Inhibitors Show Promise in Patients with Oncogene Driver-Negative NSCLC Who Have Never Smoked

In the evolving treatment landscape of non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) have expanded therapeutic options. Yet, one subgroup has remained underrepresented in both research and clinical trials: patients who have never smoked and lack actionable oncogenic drivers.

That’s why a multi-institutional study presented at ASCO 2025 sheds light on the clinical and molecular features influencing ICI responses in this distinct population.

A Distinct Yet Understudied Subset

Among 5,639 patients with metastatic NSCLC reviewed across five academic centers in the U.S. and Europe, 708 individuals (12.6 percent) were identified as never-smokers without driver mutations such as EGFR, ALK, ROS1, RET, or MET. This population had a median age of 64 years, a predominance of female patients (59.5 percent), and mostly adenocarcinoma histology (83.8 percent).

Historically, never-smokers have been associated with lower tumor mutational burden (TMB) and reduced tumor immunogenicity, which are factors traditionally considered predictive of poor ICI response. However, the new data suggest a more heterogeneous biological profile.

Identifying Predictors of Response

At a median follow-up of 36.9 months, response to ICIs in this cohort were modest with 21.8 percent objective response rate (ORR), 4.5-month median progression-free survival (mPFS), and 16.9-month median overall survival (mOS). However, subgroup analyses revealed important predictors of benefit:

• PD-L1 ≥ 1 percent: Patients with PD-L1 protein expression in tumor cells of at least one percent had a significantly improved ORR (31.1 percent versus 16.1 percent, p <0.01) and longer mPFS (HR 0.74, p <0.01) than those with PD-L1 below one percent.
• TMB ≥90th percentile: Patients who had very high tumor mutational burden (TMB), in at least the 90^th percentile, also experienced significantly improved outcomes compared to those with lower levels. This included a higher ORR of 52.2 percent compared to 22.8 percent (p <0.01), longer mPFS (HR 0.5, p <0.01), and longer mOS (HR 0.4, p <0.01), respectively.
• Co-Presence of Both Biomarkers: Patients whole tumors expressed both of these features, PD-L1 ≥1 percent and TMB ≥ 90^th percentile,had the most favorable outcomes, suggesting that dual biomarker presence may help refine patient selection.

These findings emphasize the need for biomarker assessment even in patients lacking traditional oncogenic drivers.

Exploring Combination Strategies

The study also examined treatment modality as a factor in outcomes across three treatment types: dual PD-(L)1 plus CTLA-4 blockade, PD-(L)1 blockade with chemotherapy, and PD-(L)1 monotherapy. The results showed improvement in outcomes for both combination regimens over monotherapy:

• ORR: 30 versus 36.5 versus 10.3 percent, p <0.01
• mPFS: 9.4 versus 6.9 versus 2.9 months, p <0.01
• mOS: 47.5 versus 19.7 versus 14.7 months, p <0.01

These outcome differences persisted even in first-line therapy settings, prompting reconsideration of whether monotherapy should remain the default approach for this subgroup. The findings support further exploration of combination regimens as potentially more effective alternatives.

Insights into Underlying Pathways

Gene set enrichment analysis from the Stand Up To Cancer (SU2C) cohort examined patients who never smoked and had no oncogenic drivers to provide mechanistic context for the clinical outcomes. Patients in this population who responded to ICI regimens showed enhancement in immune-related pathways, including increased MHC class I/II presentation as well as higher T-cell activation, proliferation, and chemotaxis. These immune signatures may serve as additional predictors of response or targets for new therapies.

Clinical Implications and Future Directions

This research challenges the long-standing notion that never-smokers with oncogene driver-negative NSCLC are unlikely to benefit from immunotherapy as these findings support a personalized, biomarker-informed use of ICIs in this previously under-characterized population.

Reference:
Gariazzo E, Elkrief A, Concannon K, Metro G, Dodi A, Favorito V, et al. Clinical outcomes and predictors of response to PD-(L)1 blockade in patients with oncogene-driver negative NSCLC who have never smoked. J Clin Oncol. 2025;43(16_suppl):8563. doi:10.1200/JCO.2025.43.16_suppl.8563