Discussion

This retrospective analysis provides crucial clinical insights into the real-world performance of first-line dual checkpoint inhibition within an Indian clinical setting. Historically, diagnosing and managing MPM in India has been a challenge characterized by extreme rarity and low institutional tracking. Early literature reviews by Rao (2009) emphasized that Indian centers rarely encountered MPM, capturing a minimal number of cases over multi-decade tracking periods, heavily plagued by an absence of clear asbestos exposure history and highly delayed, advanced-stage presentations [1]. Our modern cohort reflects a transitioning clinical landscape where superior diagnostic imaging helps identify these advanced cases, highlighting the critical need for effective frontline interventions.

Our observed one-year overall survival rate of 60% aligns remarkably well with the 68% rate observed in the definitive CheckMate 743 trial [3]. While our survival rate is slightly lower - likely due to late-stage regional referrals and a wider performance status allowance (ECOG 0-2) - our ORR (60% PR) was notably higher than the 40% reported in the trial. This variance is driven by our strict inclusion of the epithelioid histotype, which tends to respond more uniformly to initial treatment interventions.

When evaluating long-term trends through successive trial readouts, the three-year update of CheckMate 743 (Peters et al., 2022) confirmed a sustained, clinically meaningful survival benefit with dual checkpoint inhibition over standard chemotherapy, establishing a median overall survival of 18.1 months and showcasing that survival benefits were maintained over time regardless of histology [9]. More recently, the five-year update (Scherpereel et al., 2025) provided the definitive long-term validation of this regimen, revealing a clear survival tail/plateau where a clinically significant proportion of patients achieved long-term survival that was historically impossible with cytotoxic doublets [10].

In our study, 60% of patients maintained a stable response through 12 months, mirroring this international trend of sustained immunological control. However, our 40% early progression rate highlights a clear subset of non-responders who suffer rapid clinical decline, emphasizing the global medical mandate to uncover predictive biomarkers. Recent studies by Mitra S et al. (2025) suggest that evaluating liquid biopsies, specifically monitoring soluble mesothelin-related peptides (SMRP), may serve as an effective prognostic tool to identify these non-responding individuals prior to the initiation of frontline dual immunotherapy and futures researches are required to prove its efficacy [11].

From a safety and compliance perspective, our toxicological profile bridges seamlessly with international real-world datasets. The multicenter German MesoNet study evaluated 135 unselected patients and noted a one-year survival profile of 56.2% and an ORR of 34%. These real-world data points indicate that unselected, everyday clinical cohorts show slightly lower survival statistics compared to strict randomized trials, a trend that directly contextualizes and validates our institutional outcomes. Furthermore, the MesoNet cohort noted that severe Grade 3/4 toxicity occurred in 21.4% of patients receiving the regimen [12].

This baseline is reinforced by the Australian RIOMeso registry, which evaluated 98 unselected real-world mesothelioma patients and reported a one-year survival rate of 58% alongside a Grade 3/4 toxicity profile of 23% [13]. Both registries highlight that while combination immunotherapy can be highly toxic in an unselected real-world population compared to controlled trials, careful patient selection and proactive management can mitigate risks. Our institutional Grade 3/4 toxicity rate of 26% matches these international registry limits. Much like the observations in the MesoNet and RIOMeso data, these real-world records confirm that immune-mediated toxicities, such as severe diarrhea and hepatitis, remain highly manageable through standardized corticosteroid algorithms without escalating baseline mortality risks [12,13].

Our study shows a 60% one-year overall survival rate for epithelioid malignant pleural mesothelioma, which is consistent with the 66.4% survival rate reported in the long-term, real-world Meso-Immune (GFPC 04-2021) study. While our study reported a lower 26% grade 3/4 toxicity rate compared to the 35.6% observed in the French Meso-Immune registry, both studies demonstrate that dual immunotherapy is a manageable, viable treatment option outside of controlled trials [14,15].

The primary limitations of this study include its retrospective design, absence of a comparator group, potential selection bias, limited follow-up single-center framework, and modest sample size. Nonetheless, it provides pivotal validation that the survival benefits and toxicological boundaries established in pristine Western clinical trials translate safely into real-world Indian oncological practice. Toxicity rates were found similar across larger trials, however.