At the National Comprehensive Cancer Network (NCCN) 2025 Annual Conference in Orlando, Florida, experts highlighted that immune checkpoint inhibitors (ICIs) have established themselves as standard of care options for patients with early-stage non-metastatic non-small cell lung cancer (NSCLC). The presentation, led by Dr. Jonathan W. Riess of UC Davis Comprehensive Cancer Center, emphasized how these treatments have significantly expanded therapeutic options and improved patient outcomes.
The discussion centered on the growing role of PD-L1 inhibitors including nivolumab (Opdivo; Bristol Myers Squibb), atezolizumab (Tecentriq; Genentech), pembrolizumab (Keytruda; Merck), and durvalumab (Imfinzi; AstraZeneca) in neoadjuvant, adjuvant, and perioperative settings for early-stage NSCLC.
Neoadjuvant Immunotherapy Shows Significant Benefits
Neoadjuvant treatment—administered before surgery—offers several advantages according to Dr. Riess. These include using pathological response as an early efficacy marker, inducing stronger T cell responses, and potentially facilitating easier surgical procedures.
The phase III CheckMate816 trial demonstrated that neoadjuvant nivolumab plus chemotherapy significantly improved event-free survival (EFS) compared to chemotherapy alone in patients with resectable stage IB-IIIA NSCLC (43.8 months vs. 18.4 months; HR: 0.66). The trial also showed a favorable trend in overall survival (OS), with a hazard ratio of 0.71.
Importantly, the data revealed a correlation between PD-L1 expression levels and treatment response. Patients with PD-L1 expression of 1% or higher showed enhanced median EFS and OS when treated with the nivolumab-chemotherapy combination.
"PD-L1 expression matters and is important," Dr. Riess emphasized during his presentation.
Adjuvant Therapy Extends Disease-Free Survival
Shifting to adjuvant therapies—treatments given after surgery—Dr. Riess highlighted two pivotal trials: IMpower010 and KEYNOTE-091.
In IMpower010, 1,280 patients with completely resected stage IB-IIIA NSCLC were randomized to receive either atezolizumab for one year or best supportive care (BSC). Patients with PD-L1 levels of 1% or higher in the stage II-IIIA population showed improved median disease-free survival (DFS) with adjuvant atezolizumab compared to BSC (68.5 months vs. 37.3 months; HR: 0.70).
The most striking benefit was observed in patients with high PD-L1 expression (≥50%), who demonstrated a hazard ratio of 0.48 for DFS. The 5-year OS rates in this high PD-L1 population further confirmed the significant benefits of adjuvant ICI treatment.
KEYNOTE-091 provided additional evidence supporting adjuvant immunotherapy. In this trial, patients treated with adjuvant pembrolizumab had a median DFS of 53.6 months compared to 42.0 months for those receiving placebo. Unlike IMpower010, PD-L1 status did not appear to be as determinative for treatment response, though patients with PD-L1 ≥50% still showed favorable outcomes.
Perioperative Regimens Demonstrate Robust Efficacy
Dr. Riess also presented data from three clinical trials—AEGEAN, KEYNOTE-671, and CheckMate 77T—that evaluated perioperative ICI regimens combining both neoadjuvant and adjuvant approaches.
All three trials showed statistically significant improvements in EFS with perioperative immunotherapy:
- AEGEAN: Durvalumab plus chemotherapy followed by adjuvant durvalumab (HR: 0.68)
- KEYNOTE-671: Pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab (HR: 0.58)
- CheckMate 77T: Nivolumab plus chemotherapy followed by adjuvant nivolumab (HR: 0.58)
Consistent with other findings, patients with higher PD-L1 expression (≥50%) derived the greatest benefit across all three trials, with robust EFS improvements observed across all NSCLC stages.
Despite these positive results, Dr. Riess noted potential challenges with perioperative approaches, including increased toxicity, financial burden, and more complex treatment management. He also mentioned FDA concerns regarding potential overuse of immunotherapy in this patient population.
Novel Approaches Target Immunotherapy Resistance
Complementing these findings, researchers are exploring innovative strategies to overcome resistance to checkpoint inhibitors in NSCLC. At the 2025 American Association for Cancer Research (AACR) annual meeting, Dr. Prantesh Jain of Roswell Park Comprehensive Cancer Center presented promising results from a phase 1 trial of JNJ-86974680, an investigational A2a receptor antagonist.
The drug targets the adenosine pathway, a major driver of immunosuppression in the tumor microenvironment. In the multicenter study (NCT06116786), JNJ-86974680 was evaluated alone and in combination with cetrelimab, an investigational PD-1 inhibitor, in patients with advanced NSCLC who had progressed on prior anti-PD-1 therapy.
No dose-limiting toxicities were observed, and the drug demonstrated near-complete blockade of A2a receptors on circulating immune cells. Among 41 patients with advanced NSCLC who had progressed on prior anti-PD-1 therapy, stable disease was the best overall response, with one patient remaining on treatment for more than eight months.
"While immunotherapy has transformed the treatment landscape for non-small cell lung cancer, most patients do not achieve durable responses to checkpoint inhibitors," noted Dr. Jain. "These results suggest that targeting the adenosine pathway may offer a promising new strategy for improving outcomes with immunotherapy in this disease."
Future Directions
Looking ahead, Dr. Riess emphasized the need for further research into novel biomarkers of response and comparative trials for more thorough analyses. He also highlighted the importance of developing new agents for patients who may not achieve pathological complete response with ICI treatment.
The ongoing evolution of immunotherapy approaches in NSCLC represents a significant advancement in the treatment landscape, offering new hope for patients with early-stage disease. As researchers continue to refine these approaches and explore novel mechanisms to overcome resistance, the therapeutic options for NSCLC patients are likely to expand further, potentially improving long-term outcomes for this challenging disease.
