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Pembrolizumab plus Chemotherapy for Pleural Mesothelioma
First-line immunotherapy with ipilimumab and nivolumab is the first new standard of care for mesothelioma since the introduction of pemetrexed in 2004. However, not all patients benefit, and there is interest in development of chemoimmunotherapy regimens. In an international, open-label, randomized, phase 3 trial, researchers evaluated platinum plus pemetrexed chemotherapy with or without pembrolizumab in 440 patients with untreated, unresectable, advanced pleural mesothelioma. Patients were stratified by histologic subtype before randomization; chemotherapy was given for up to 6 cycles, pembrolizumab for up to 2 years.
At a median follow-up of 16.2 months, overall survival (OS) was longer with pembrolizumab than with chemotherapy alone (median, 17.3 vs. 16.1 months; hazard ratio, 0.79). Exploratory analysis showed that the OS benefit with pembrolizumab was maintained regardless of PD-L1 expression, and the magnitude of benefit was greater in patients with the nonepithelioid subtype. The addition of pembrolizumab also improved the objective response rate (62% vs. 38%; P<0.0001; odds ratio, 2.7). Grade 3 or 4 treatment-emergent adverse events occurred in 27% of patients receiving pembrolizumab and 15% receiving chemotherapy alone.
Given the improvement in response rates and survival, pembrolizumab plus chemotherapy could represent a new treatment option for patients with pleural mesothelioma. However, it should be noted that although statistically significant, the OS benefit was modest and largely driven by the small subset of patients with nonepithelioid histology.
In the context of the randomized Checkmate 743 trial (NEJM JW Oncol Hematol Feb 12 2021 and Lancet 2021; 397:375) that found an OS advantage of 4 months with nivolumab plus ipilimumab versus chemotherapy, with the benefit driven predominantly by patients with nonepithelioid histology, it is likely that immunotherapy in the frontline setting is appropriate for some patients. However, we do not know which approach (dual immunotherapy or chemoimmunotherapy) is superior in the absence of a head-to-head comparison. It is likely that the benefit of immunotherapy for patients with the more common epithelioid subtype is minimal, and chemotherapy alone may be reasonable.
Chu Q et al.
Title: Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: A phase 3, open-label, randomised controlled trial.
Source: Lancet 2023 Nov 3; [e-pub]. (Abstract/FREE Full Text)