Multiple Studies Highlight Differing Immunotherapy Outcomes in Advanced NSCLC
Multiple recent studies evaluate different immunotherapy approaches for advanced NSCLC, including long-term benefits for nivolumab plus ipilimumab with chemotherapy in PD-L1-negative tumors, limited advantages from PD-(L)1 rechallenge strategies, and early positive signals from combining TIGIT and PD-1 inhibitors in PD-L1-high patients.
Recent studies in advanced non-small cell lung cancer (NSCLC) demonstrate varying outcomes for different immunotherapy strategies, with one showing a long-term survival advantage for nivolumab plus ipilimumab with chemotherapy in PD-L1-negative tumors, another finding limited benefits from PD-(L)1 rechallenge after immunotherapy resistance, and a third reporting promising early results from combining TIGIT and PD-1 inhibitors.
A multicenter retrospective cohort study published in Lung Cancer compared two first-line immunotherapy regimens in 457 patients across 13 institutions in Japan between 2019 and 2022. The study found that nivolumab plus ipilimumab with chemotherapy (NICT) provided a sustained long-term survival advantage over pembrolizumab with chemotherapy (PCT) in patients with PD-L1-negative advanced NSCLC, defined as PD-L1 tumor proportion score (TPS) below 1%. With a median follow-up exceeding 40 months, median overall survival was 47.4 months with NICT compared with 16.6 months with PCT. The adjusted hazard ratio was 0.50 (95% CI 0.31–0.83, p=0.007), indicating approximately 50% lower risk of death. The 36-month overall survival rate was 51.5% with NICT versus 28.2% with PCT. Among patients with PD-L1 TPS 1% or higher, survival outcomes were similar between the two regimens.
Separately, a systematic review and meta-analysis of PD-(L)1 rechallenge strategies after immunotherapy resistance in advanced NSCLC analyzed 10 randomized controlled trials involving 3,081 patients and 106 non-randomized interventional studies. The analysis evaluated rechallenge approaches including PD-(L)1 inhibitors plus chemotherapy, VEGF-targeting combinations, tyrosine kinase inhibitor combinations, dual immune checkpoint blockade, and bispecific regimens. The pooled overall survival hazard ratio was 0.91, indicating statistically significant but clinically marginal improvement over standard chemotherapy. The pooled progression-free survival hazard ratio was 0.89, and the odds ratio for objective response rate was only 1.12. The study distinguished between primary and acquired resistance, finding that patients with acquired resistance demonstrated more favorable outcomes with pooled overall survival hazard ratios of approximately 0.83–0.86, while those with primary resistance showed essentially no meaningful benefit.
The ARC-10 phase 2 study evaluated domvanalimab, a TIGIT inhibitor with a silent Fc domain, combined with zimberelimab, a PD-1 inhibitor, as first-line therapy for 98 patients with stage IIIB–IV NSCLC and PD-L1 TPS ≥50%. Patients were randomized 2:2:1 to receive domvanalimab plus zimberelimab, zimberelimab monotherapy, or platinum-doublet chemotherapy. Median progression-free survival was 11.5 months with the combination versus 6.2 months with zimberelimab alone and 9.6 months with chemotherapy. The hazard ratio for progression-free survival was 0.69 for the combination versus zimberelimab. Median overall survival was not reached in the combination arm, versus 24.4 months with zimberelimab alone and 11.9 months with chemotherapy. One-year survival rates were approximately 68% for the combination versus 57% for zimberelimab and 50% for chemotherapy. Objective response rates were 44.7% with the combination versus 35.0% with zimberelimab and 35.3% with chemotherapy.