Adding pembrolizumab to standard chemotherapy significantly prolongs the survival of patients with previously untreated malignant pleural mesothelioma
Phase III results presented at ASCO 2023 show that the addition of pembrolizumab to standard chemotherapy results in a significant improvement in the overall (OS) and progression-free survival (PFS) of patients with previously untreated malignant pleural mesothelioma (MPM). Furthermore, the combination treatment was well-tolerated with less than one out of five patients experiencing a grade ≥3 adverse event (AE). As such, these results identify pembrolizumab plus chemotherapy as an attractive novel treatment option for these patients.
Background
MPM continues to be an incurable disease for the vast majority of patients. For these unresectable MPM patients, the long-standing first line standard of care has consisted of platinum-pemetrexed (CP) doublet chemotherapy, resulting in a median OS of 13-14 months. More recently, the phase III CheckMate743 trial showed that dual immunotherapy with ipilimumab and nivolumab (ipi/nivo) significantly improved the OS of these patients compared to CP, with a median OS of 18.1 months. In this, the most pronounced treatment effect with ipi/nivo was observed in patients with a non-epithelioid histology. Unfortunately, however, a treatment with ipi/nivo comes with considerable toxicity, with about a third of patients experiencing grade ≥3 AEs. As such, there remains to be a need for more tolerable alternatives that are able to improve the OS compared to CP. Previously, single agent pembrolizumab proved to be effective in previously treated MPM patients and the combination of this agent with CP proved to be tolerable in the metastatic non-small cell lung cancer setting. This formed the rationale to evaluate the pembrolizumab plus CP as a first line treatment for patients with unresectable MPM.
Study design
IND 227 is an academic, open-label, randomized phase III study conducted by the Canadian Cancer Trials Group (CCTG) together with the National Cancer Institute of Naples (NCIN) and the Intergroupe Francophone de Cancérologie Thoracique (IFCT). In this trial, a total of 440 patients with unresectable MPM were randomized (1:1) to receive CP with or without pembrolizumab. In order to be eligible for the study, patients had to be at least 18 years, have an ECOG performance status of 0-1 and have adequate hematological, renal and hepatic function. Patients with active autoimmune disease, brain metastases, interstitial lung disease or other active co-morbidities were excluded from the study. Of note, cisplatin was preferred in the chemotherapy doublet, but carboplatin was allowed in case of a cisplatin contraindication. The primary endpoint of this trial was OS, with PFS, response rate (RR) and QoL as secondary objectives.
Results
About three quarters of the patients enrolled in the study were male, with about 60% of patients having prior asbestos exposure. The majority of patients (~77%) had an epithelioid histology and about 60% was positive for PD-L1. The combination of pembrolizumab with chemotherapy proved to be associated with a 21% reduced risk of death compared to chemotherapy alone, with a median OS of 17.28 and 16.13 months, respectively (HR[95%CI]: 0.79[0.64-0.98]; p= 0.0324). At the 2-year landmark, this translated into an OS rate of 39% and 33% for pembrolizumab-chemotherapy and chemotherapy alone, respectively. At three years, these rates were reported at 25% and 17%. Also the PFS proved to be significantly longer with the pembrolizumab-chemotherapy combination with a 1-year PFS rate of 26% and 17%, respectively (9% vs. 4% at 2 years) (HR[95%CI]: 0.80[0.65-0.99]; p= 0.0372). The RR with pembrolizumab-chemotherapy was reported at 61%, which is significantly higher than the 38% RR seen with chemotherapy alone (OR[95%CI]: 2.7[1.8-4]; p< 0.0001).
An exploratory analysis of OS in function of histology suggests that the OS benefit obtained from the addition is mainly driven by patients with a non-epithelioid histology. In fact, in this subgroup of patients the HR for OS was reported at 0.57 (95%CI: 0.36-0.89), with 3-year OS rates of 23% and 7% for platinum-CP and CP alone, respectively. In contrast, among patients with an epithelioid histology, this OS difference was non-significant, with a HR of 0.89 (95%CI: 0.7-1.13) and 3-year OS rates of 26% and 20%, respectively. In contrast, the PD-L1 status did not seem to have a big impact on the OS data with similar 3-year OS rates among patients with PD-L positive (23% vs. 16%) and negative disease (28% vs. 18%).
With respect to safety, the pembrolizumab-chemotherapy combination did come with a higher rate of grade ≥3 AEs than chemotherapy alone (29% vs. 15%). Importantly, grade 4 AEs were rare at less than 1% in the chemotherapy alone arm and 5% in the pembrolizumab-CP arm.
Conclusion
Adding pembrolizumab to chemotherapy results in a significant improvement in OS, PFS and RR in previously untreated MP patients. Importantly, this clinical benefit came at the cost of only a limited increase in the incidence of high-grade AEs. The difference in clinical benefit between patients with an epithelioid and non-epithelioid tumor histology deserves further study.
Reference
Chu Q, et al. IND227 phase III (P3) study of cisplatin/pemetrexed (CP) with or without pembrolizumab (pembro) in patients (pts) with malignant pleural mesothelioma (PM): A CCTG, NCIN, and IFCT trial. Presented at ASCO 2023; Abstract LBA8505.
