Zalcman, Gérard

In this 5-year follow-up from the CheckMate 743 study in patients with unresectable pleural mesothelioma (PM), we evaluated updated efficacy and safety outcomes and biomarkers and performed treatment-switching analyses with first-line nivolumab plus ipilimumab versus chemotherapy. With a median follow-up of 66.8 months, nivolumab plus ipilimumab demonstrated continued overall survival (OS) benefit versus chemotherapy in all randomly assigned patients (5-year OS rates, 14% v 6%; hazard ratio [HR], 0.74 [95% CI, 0.62 to 0.88]); similar benefit was observed regardless of tumor histology. Of biomarker-evaluable patients treated with nivolumab plus ipilimumab (n = 242), high baseline monocytic myeloid-derived suppressor cell (M-MDSC) levels correlated with worse OS versus low M-MDSC levels (HR, 1.25 [95% CI, 1.09 to 1.43]). After adjusting for 24% of patients in the chemotherapy arm who received subsequent immunotherapy, nivolumab plus ipilimumab demonstrated continued OS benefit versus chemotherapy (HR, 0.64 [95% CI, 0.53 to 0.78]). No new safety signals were observed. These results demonstrate long-term, durable clinical benefit with nivolumab plus ipilimumab versus chemotherapy, which continued to be preserved even after treatment-switching adjustment in the chemotherapy arm. Exploratory analyses suggested greater benefit with nivolumab plus ipilimumab in the low M-MDSC subgroup. These results further support first-line nivolumab plus ipilimumab as standard of care for unresectable PM.

TPS8581 Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer with a 5-year overall survival (OS) rate of < 10%. At diagnosis, most patients (pts) have unresectable disease. Combination chemotherapy of cisplatin (or carboplatin as an alternative) + pemetrexed is the approved first-line standard of care. Phase 1 and 2 data suggest that targeting immune checkpoint pathways (eg, programmed death [PD]-1/PD-ligand 1 [PD-L1] and/or cytotoxic T-lymphocyte antigen-4 [CTLA-4]) may provide benefit with acceptable safety in MPM. In pts with previously treated, malignant mesothelioma, single-agent tremelimumab (a CTLA-4 inhibitor antibody) was active but did not improve OS vs placebo. In a phase 2 study of nivo (a fully human PD-1 immune checkpoint inhibitor antibody) in 34 pts with MPM that progressed after first-line platinum-based chemotherapy, 12-week disease control rate (DCR) was 50%, 5 pts had partial response, and 12 pts had stable disease. Given the data with single-agent CTLA-4 and PD-1 inhibitors and that CTLA-4 inhibition can induce PD-L1 expression, there is reason to anticipate synergy when combining CTLA-4 and PD-1 inhibitors in MPM. A phase 2 study assessing nivo alone and nivo + ipi (a CTLA-4 inhibitor antibody) in MPM is ongoing. CheckMate 743 (NCT02899299) is a phase 3 study that will evaluate the efficacy and safety of first-line nivo + ipi vs chemotherapy for MPM. Methods: Approximately 600 adult pts with unresectable MPM and ECOG performance status 0–1 will be randomized. Pts are ineligible if they have primary peritoneal, pericardial, or tunica vaginalis testis mesotheliomas; have active, untreated CNS metastases; or had received prior systemic therapy for pleural mesothelioma or a prior PD-1/PD-L1 or CTLA-4 checkpoint inhibitor antibody. Pts are randomized 1:1 to receive nivo + ipi or pemetrexed + cisplatin/carboplatin. Primary endpoints are OS and progression-free survival (PFS), assessed by blinded independent central review. Secondary endpoints are objective response rate (ORR), DCR, and correlation of PD-L1 expression level and efficacy (ORR, PFS, and OS). Clinical trial information: NCT02899299.