WCLC 2025 | Dual checkpoint blockade in NSCLC: insights from meta-analysis

This study presented here at the World Conference on Lung Cancer focused on investigating the survival outcomes in patients with advanced previously untreated non-small cell lung cancer comparing dual immune checkpoint inhibition with CTLA-4 plus PD-1 or PD-L1 inhibition versus single immune checkpoint inhibition with PD-1 or PD-L1 inhibitors plus or minus chemotherapy in both cases. This is a reconstructed individual patient data meta-analysis. In this study we selected six randomized clinical trials that investigated these drugs and reconstructed outcomes through some statistical methods and procedures. These studies include the CheckMate 227, the IMpower150, the KEYNOTE-189 and KEYNOTE-407 and the CheckMate 9LA. So these trials have in common that they either provided long-term overall survival outcomes with a follow-up of at least five years or they showed some group analysis based on the presence of KRAS and or STK11 mutations. This study was born because we don’t really know which patient can benefit from the dual immune checkpoint inhibition, which we know that is more toxic compared to single PD-1 or PD-L1 blockade. These immune-related toxicities are higher, especially in terms of gastrointestinal toxicity or also pneumonitis. So we don’t really know if there are some populations identified by biomarkers where the potential harms of this treatment are overcome by potential benefits in terms of survival. In the study in the overall population, we didn’t observe significant differences in the overall survival between dual immune checkpoint blockade and single immune checkpoint blockade. But when exploring subgroups based on PD-L1 expression level, we did observe significant improvement in the median overall survival in patients with PD-L1 negative non-squamous cancer, meaning a tumor proportion score of less than 1%. The median in this case was 15.5 months versus 14.5 months with single immune checkpoint blockade. But this delta of only one month was underestimating the real effect because the separation of the curve became larger over time and after five years from the start there was a higher proportion of patients that were still alive, it was almost 17% with dual immune checkpoint blockade versus 9% with single immune checkpoint blockade, so almost doubled. Exploring other subgroups, there was no difference between the two treatments based on histology, squamous or non-squamous, or based on the presence or absence of KRAS mutation. But when we look at these outcomes in patients harboring STK11 mutations, we did see a significant difference in overall survival, favoring again the dual immune checkpoint blockade with CTLA-4 and PD-1 or PD-L1 inhibition, with a median OS of almost 14 months versus almost eight months with the single immune checkpoint blockade. And at three years, the survival rates with the immune checkpoint blockade in the STK11-mutated population were more than double, were roughly 28% versus 13% with single immune checkpoint blockade, while there were no differences between the two treatments in the STK11 wild-type population. So, this is, I think, it’s important because it confirms the findings of a recent study published by Dr Ferdinandos Skoulidis and the MD Anderson group in collaboration with the investigators of the POSEIDON trial that suggests that specifically in the population, the addition of the CTLA-4 blockade makes sense. Also in terms of, there are also mechanistic and biologic explanations for that. So our results confirm these recent findings in the same direction. So in conclusion, our study suggests that the two subpopulations that benefit from the addition of CTLA-4 blockade are those of patients with negative PD-L1 expression and or harboring STK11 mutations.

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