A global meta-analysis combined detailed patient data from six major clinical trials to compare two types of immunotherapies for advanced non–small cell lung cancer (NSCLC): dual immunotherapy (a combination of CTLA-4 and PD-1/PD-L1 inhibitors) and single immunotherapy (PD-1/PD-L1 inhibitors alone). Its results were published by Di Federico et al in The Lancet Oncology.
Investigators conducted a search of PubMed, MEDLINE, and Embase for randomized phase III trials conducted through November 2024 that investigated PD-L1 or PD-1 inhibitors with or without CTLA-4 inhibitors in patients with advanced NSCLC, with a focus on those reporting Kaplan-Meier survival data at 5 years or biomarker analyses based on PD-L1, KRAS, and STK11 mutational status. They included six phase III trials in advanced NSCLC: CheckMate 227, CheckMate 9LA, POSEIDON, KEYNOTE-189, KEYNOTE-407, and IMpower150. They evaluated the efficacy of PD-1/PD-L1 monotherapy vs combining PD-1/PD-L1 inhibitors with CTLA-4 inhibitors, and if the regimens produced outcomes in different subpopulations of patients with NSCLC.
For the overall NSCLC population, they found survival was similar with both approaches. However, two key groups clearly benefited from the more intensive dual immunotherapy:
- Patients whose tumors were PD-L1–negative (PD-L1 < 1%) lived longer with dual immunotherapy, and at 5 years, 16.6% of these patients were still alive with dual therapy compared with 9.3% with single immunotherapy—nearly double the long-term survival rate.
- Patients whose tumors had STK11 mutations, a group that usually responds poorly to standard PD-1/PD-L1 immunotherapy, also had much better outcomes with dual immunotherapy.
For patients whose tumors had PD-L1 levels of 1% or higher or who did not have STK11 mutations, dual immunotherapy did not provide a clear survival advantage over single-agent PD-1/PD-L1 treatment. The study did not find meaningful differences based on KRAS mutations or tumor histology, suggesting that factors beyond KRAS status drive who benefits from dual therapy.
These findings support a more personalized approach to immunotherapy in patients with advanced NSCLC. Rather than giving dual checkpoint blockade to all patients, the results suggest it should be focused on those most likely to benefit—specifically, patients with PD-L1–negative tumors and those with STK11 mutations, who typically have limited benefit from standard single-agent immunotherapy. More research, including prospective, randomized clinical trials, is needed to confirm these results, refine patient selection using additional biomarkers, and better understand how to manage side effects and sequence dual vs single immunotherapy over the course of treatment, concluded the research team.
DISCLOSURE: This study received funding from NextGenerationUE. For full disclosures of the study authors, visit thelancet.com.
