Immunotherapy combination maintains OS advantage in malignant pleural mesothelioma
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The combination of nivolumab and ipilimumab maintained its survival advantage over chemotherapy with at least 3 years of follow-up among patients with unresectable malignant pleural mesothelioma, according to CheckMate 743 study results.
Researchers observed the benefit of the first-line immunotherapy regimen despite patients having been off therapy for about 1 year. The findings, presented during the virtual ESMO Congress 2021, also showed no new safety signals with nivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy, Bristol Myers Squibb).
“Mesothelioma has historically been an extremely difficult‐to‐treat cancer, as it forms in the lining of the lungs rather than as a single tumor. It is also an aggressive cancer with poor prognosis and 5‐year survival rates of approximately 10%,” Solange Peters, MD, PhD, of the medical oncology service and chair of thoracic oncology at Lausanne University Hospital in Switzerland, told Healio. “Before the approval of nivolumab plus ipilimumab, no new systemic treatment options that could extend survival for patients with this devastating cancer had been available for more than 15 years.”
The randomized phase 3 CheckMate 743 trial included 605 patients with untreated malignant pleural mesothelioma, stratified according to sex and histology (epithelioid vs. non-epithelioid).
Researchers randomly assigned 303 patients to 3 mg/kg nivolumab, a PD-1 inhibitor, every 2 weeks and 1 mg/kg ipilimumab, which targets CTLA-4, every 6 weeks for up to 2 years. The other 302 patients received platinum-based doublet chemotherapy with 75 mg/m2 cisplatin or carboplatin area under the curve 5 plus 500 mg/m2 pemetrexed for six cycles.
As Healio previously reported, patients in the immunotherapy and chemotherapy groups had similar baseline characteristics, including median age (69 years for both), percentage of men (77% for both) and histology (epithelioid, 76% vs. 75%).
OS served as the primary endpoint, with safety and biomarker assessments as prespecified exploratory endpoints.
Researchers used RNA sequencing to estimate the association of OS with an inflammatory gene expression signature that included CD8A, PD-L1, STAT-1 and LAG-3, and they categorized expression scores as high vs. low in relation to median score. They also evaluated tumor mutational burden and assessed lung immune prognostic index based on lactate dehydrogenase levels and derived neutrophil-to-lymphocyte ratio at baseline using peripheral blood samples.
Results showed the immunotherapy regimen continued to confer an OS benefit compared with chemotherapy after minimum follow-up of 35.5 months (median OS, 18.1 months vs. 14.1 months; HR = 0.73; 95% CI, 0.61-0.87). Researchers reported 3-year OS rates of 23.2% among patients who received nivolumab plus ipilimumab vs. 15.4% among patients who received chemotherapy, and 3-year PFS rates by blinded independent central review of 13.6% vs. 0.8% (median PFS, 6.8 months vs. 7.2 months; HR = 0.92; 95% CI, 0.76-1.11).
“These results are promising, providing further proof of the durability of the outcomes achieved with this combination,” Peters told Healio.
Median OS among 455 patients with epithelioid disease was 18.2 months with the combination vs. 16.7 months with chemotherapy (HR = 0.85; 95% CI, 0.69-1.04) and among 150 patients with non-epithelioid disease was 18.1 months vs. 8.8 months (HR = 0.48; 95% CI, 0.34-0.69).
Exploratory biomarker analyses in the nivolumab-ipilimumab group showed longer median OS among patients with high vs. low inflammatory gene signature score (21.8 months vs. 16.8 months; HR = 0.57; 95% CI, 0.4-0.82). The score did not appear associated with longer OS in the chemotherapy group.
The combination showed a trend toward improved OS vs. chemotherapy across subgroups of patients with a good (HR = 0.78; 95% CI, 0.6-1.01) intermediate (HR = 0.76; 95% CI, 0.57-1.01) or poor (HR = 0.83; 95% CI, 0.44-1.57) baseline lung immune prognostic index.
Tumor mutational burden did not appear associated with survival benefit.
Objective response rates appeared comparable between the immunotherapy and chemotherapy groups (39.6% vs. 44%); however, duration of response was nearly twice as long among responders in the immunotherapy group (11.6 months vs. 6.7 months). Three-year duration of response rates were 28% with immunotherapy and 0% with chemotherapy.
Rates of grade 3 to grade 4 treatment-related adverse events remained consistent with those reported previously (30.7% with immunotherapy vs. 32% with chemotherapy), with no new safety signals identified.
A post-hoc analysis of 52 patients who discontinued all components of the combination due to treatment-related adverse events showed no negative impact on long-term benefits. “With these follow‐up data, CheckMate 743 remains the first and only phase 3 trial in which an immunotherapy has demonstrated a durable survival benefit vs. standard‐of‐care platinum plus pemetrexed chemotherapy in first‐line unresectable malignant pleural mesothelioma,” Peters told Healio.
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Peters S, et al. Abstract LBA65. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
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