Opdivo (nivolumab) Plus Yervoy (ipilimumab) Treatments: CheckMate 743 Study
[Opdivo plus Yervoy treatments have] 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 [Opdivo plus Yervoy treatments] 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, [Opdivo plus Yervoy treatments were] 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 [Opdivo plus Yervoy treatments] 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.
Opdivo (nivolumab) Plus Yervoy (ipilimumab) Treatments: 5-Year Study Results
With a median follow-up of 66.8 months, [Opdivo plus Yervoy] 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 [Opdivo plus Yervoy treatments] was observed.
Improved survival and response outcomes with [Opdivo plus Yervoy treatments] 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, [Opdivo plus Yervoy treatments] significantly improved OS versus chemotherapy, similar to benefit with bevacizumab plus chemotherapy or pembrolizumab plus chemotherapy. The magnitude of clinical benefit with [Opdivo plus Yervoy treatments] 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 [Opdivo plus Yervoy treatments] 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 [Opdivo plus Yervoy treatments] (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 [Opdivo plus Yervoy treatments] in patients with PM, regardless of tumor histology. Future prospective analyses are needed to evaluate the prognostic or predictive value
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