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.
Introduction
Nivolumab plus ipilimumab has demonstrated long-term, durable survival benefit as first-line treatment in patients with various solid tumor types. The randomized phase III CheckMate 743 study demonstrated significant overall survival (OS) benefit with nivolumab plus ipilimumab versus chemotherapy in patients with unresectable pleural mesothelioma (PM; hazard ratio [HR], 0.74 [96.6% CI, 0.60 to 0.91] P = .0020). Subsequently, nivolumab plus ipilimumab was approved as a first-line treatment option for patients with unresectable PM in several countries, including the United States and the European Union.
Four-year follow-up data from CheckMate 743 showed sustained OS benefit with nivolumab plus ipilimumab versus chemotherapy (HR, 0.73 [95% CI, 0.61 to 0.87]). Here, we report 5-year clinical outcomes from CheckMate 743, the longest follow-up to date, to our knowledge, for first-line immunotherapy in PM. Additionally, we report exploratory biomarker analyses and treatment switching–adjusted analyses in patients who received subsequent immunotherapy after first-line chemotherapy.
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Discussion
With a median follow-up of 66.8 months, nivolumab plus ipilimumab demonstrated long-term, durable survival and response benefit versus chemotherapy in all randomly assigned patients and across most subgroups. In patients with evaluable blood M-MDSC measurements, elevated baseline M-MDSC levels trended toward reduced benefit. After adjusting for treatment switching in the chemotherapy arm, a greater magnitude in OS benefit with nivolumab plus ipilimumab was observed.
Improved survival and response outcomes with nivolumab plus ipilimumab were consistent with or better than other first-line immunotherapy-based treatments for unresectable PM. In a meta-analysis comparing six randomized controlled trials of first-line treatments for PM, nivolumab plus ipilimumab significantly improved OS versus chemotherapy, similar to benefit with bevacizumab plus chemotherapy or pembrolizumab plus chemotherapy. The magnitude of clinical benefit with nivolumab plus ipilimumab versus chemotherapy was greater in patients with nonepithelioid PM versus epithelioid PM in CheckMate 743, consistent with results for pembrolizumab plus chemotherapy versus chemotherapy in KEYNOTE-483, and may have resulted from differences in immune-related gene expression across tumor histology subgroups, higher levels of tumor-infiltrating lymphocytes in nonepithelioid PM, and/or worse OS with chemotherapy in patients with nonepithelioid PM.
M-MDSCs have been associated with immunotherapy resistance and worse prognoses in patients with PM. In CheckMate 743, OS and PFS with nivolumab plus ipilimumab were worse in patients with high M-MDSC levels in all randomly assigned patients and patients with epithelioid PM; however, additional prospective studies are needed to confirm correlations between M-MDSC levels and clinical outcomes with first-line immunotherapy.
Patients with relapsing PM after first-line chemotherapy may benefit from second-line treatment. The IPCW-adjusted median OS analysis in the chemotherapy group decreased from 14.1 months to 12.1 months, amplifying the clinical benefit of nivolumab plus ipilimumab (HR adjusted from 0.75 to 0.64).
In conclusion, this 5-year update from CheckMate 743 demonstrated continued long-term, durable clinical benefit of first-line nivolumab plus ipilimumab in patients with PM, regardless of tumor histology. Future prospective analyses are needed to evaluate the prognostic or predictive value of M-MDSCs in patients with PM treated with first-line immunotherapy and their role in the treatment selection process beyond current guidelines. [footnotes omitted]
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