First-line nivolumab-ipilimumab combination improves OS in mesothelioma subset
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First-line nivolumab plus ipilimumab significantly extended OS compared with platinum-based chemotherapy for patients with unresectable malignant pleural mesothelioma, according to results of an interim analysis of the CheckMate 743 trial.
Paul Baas, MD, researcher at Netherlands Cancer Institute and University of Leiden in Amsterdam, presented the results during the International Association for the Study of Lung Cancer World Conference on Lung Cancer Virtual Presidential Symposium.
“We have been trying to improve the OS of patients with mesothelioma for many decades,” Bass said during the presentation. “CheckMate 743 met its primary endpoint of statistically improved OS with nivolumab plus ipilimumab vs. standard-of-care chemotherapy in first-line treatment of patients with mesothelioma. These clinically meaningful data represent the first positive phase 3 trial of immunotherapy in first-line malignant pleural mesothelioma and should be considered as a new standard of care.”
Five-year survival rates for malignant pleural mesothelioma, a highly aggressive cancer, remain below 10%, according to researchers. The combination of nivolumab (Opdivo, Bristol-Myers Squibb), which restores antitumor T-cell function, and ipilimumab (Yervoy, Bristol-Myers Squibb), which targets CTLA-4, has shown promising activity in single-arm studies for this patient population.
Bass and colleagues analyzed the combination among 605 adults with previously untreated, unresectable, histologically confirmed malignant pleural mesothelioma and an ECOG performance status 0 or 1. Researchers randomly assigned patients to 3 mg/kg nivolumab once every 2 weeks plus 1 mg/kg ipilimumab once every 6 weeks for up to 2 years (n = 303) or platinum-based doublet chemotherapy with 75 mg/kg2 cisplatin or carboplatin area under the curve 5 plus 500 mg/m2 pemetrexed (n = 302) for six cycles.
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. Secondary endpoints included objective response rate, disease control rate and PFS.
Median follow-up was 29.7 months.
Results showed a higher rate of 2-year OS with the immunotherapy combination vs. chemotherapy (41% vs. 27%). Median OS was 18.1 months (95% CI, 16.8-21.4) with immunotherapy vs. 14.1 months (95% CI, 12.4-16.2) with chemotherapy (HR = 0.74; 95% CI, 0.6-0.91).
The immunotherapy combination conferred superior median OS for patients with an epithelioid histotype (18.7 months vs. 16.5 months; HR = 0.86; 95% CI, 0.69-1.08), those with a nonepithelioid histotype (18.1 months vs. 8.8 months; HR = 0.46; 95% CI, 0.31-0.68) and those with tumor PD-L1 expression of 1% or greater (18 months vs. 13.3 months; HR = 0.69; 95% CI, 0.55-0.87).
Researchers reported an ORR of 40% with immunotherapy vs. 43% with chemotherapy, a disease control rate of 76.6% vs. 85.1%, and median PFS of 6.8 months vs. 7.2 months (HR = 1; 95% CI, 0.82-1.21).
“Looking at PFS, we know from experience that the way tumors grow that PFS may be difficult to interpret in some cases,” Baas said. “Within the first 6 months, the chemotherapy arm performs a little better, but then the curves cross and the advantage is for the immunotherapy arm."
Baas also acknowledged that the response rates were very similar in both groups.
“In the chemotherapy arm, only partial responses were observed,” he said. “For the immunotherapy arm, 2% of patients had a complete response — these complete responses were a great advantage for the immunotherapy arm with 32% of patients at 2 years still having no signs of progression.”
Grade 3 or grade 4 treatment-related adverse events occurred among 30.3% of patients in the immunotherapy combination group, of whom 15% discontinued treatment, compared with 32% of patients in the chemotherapy arm, of whom 7.4% discontinued treatment.
“We observed a survival benefit with nivolumab plus ipilimumab vs. chemotherapy, regardless of histology,” Baas said. “Nivolumab plus ipilimumab performed similarly in both histologies, [whereas] chemotherapy performed better in epithelioid histology. In addition, PD-L1 data were descriptive in nature, precluding firm conclusions.”
Perspective
Back to TopDean A. Fennell , PhD, FRCP
CheckMate 743 has shown a transformative improvement among patients with nonepithelioid mesothelioma and heralds a new standard of care. Nonepithelioid histology exhibited marked chemoresistance, potentially associated with epithelial-to-mesenchymal transition, but was not positively predictive. Looking forward, chemoimmunotherapy for patients with all histologies or selective targeting of nonepithelioid mesothelioma could further extend benefit for patients with nivolumab-ipilimumab combination treatment.
Perspective
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Howard (Jack) West, MD
The CheckMate 743 trial is an important and practice-changing trial, at least for a subset of patients. The benefit observed with nivolumab-ipilimumab was particularly striking and highly statistically significant for approximately 25% of patients with nonepithelioid malignant pleural mesothelioma, a subset for whom our historic standard therapies have been consistently disappointing. I would consider nivolumab-ipilimumab to be an extremely compelling new option for this population.
The benefit of nivolumab-ipilimumab also was limited to patients in whom the marker of tumor PD-L1 expression was greater than 1%. It would be valuable to learn the results among patients with epithelioid malignant pleural mesothelioma who also had tumor PD-L1 expression greater than 1%. Especially because the combination of cisplatin-pemetrexed with the antiangiogenic agent bevacizumab (Avastin, Genentech) has already demonstrated superiority to the same cisplatin-pemetrexed standard in malignant pleural mesothelioma in the MAPS trial, it remains unclear whether nivolumab-ipilimumab should become a new standard for patients with epithelioid malignant pleural mesothelioma.
Reference:
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Baas P, et al. Abstract LBA 3. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer Virtual Presidential Symposium; Aug. 8, 2020.
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