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Nivolumab plus Ipilimumab in MSI-High Metastatic Colorectal Cancer
1. Progression-free survival at 12 months was 79% with nivolumab/ipilimumab vs 21% with chemotherapy, and 24-month PFS was 72% and 14%, respectively.
2. Grade 3-4 treatment-related adverse events occurred in 23% in the nivolumab/ipilimumab group vs 48% in the chemotherapy group.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Colorectal cancer with DNA repair defects like MSI-H or dMMR is often associated with poor outcomes with standard chemotherapy. Immune checkpoint inhibitors such as nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor) have shown promising efficacy in these patients, with combination therapy demonstrating deep and durable responses in prior studies. This study evaluated the combination of nivolumab and ipilimumab vs nivolumab alone vs chemotherapy. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), safety, and quality-of-life (QoL). This interim analysis explored patients with no prior treatments were randomized to nivolumab/ipilimumab vs chemotherapy. Median follow-up time was 31.5 months. PFS at 12 months was 79% with nivolumab/ipilimumab vs 21% with chemotherapy, and 24-month PFS was 72% and 14%, respectively. PFS was greater with nivolumab/ipilimumab than with chemotherapy across all subgroups (RAS or BRAF mutations; baseline liver, lung, or peritoneal metastases; and the Lynch syndrome). With regards to safety, grade 3-4 treatment-related adverse events occurred in 23% in the nivolumab/ipilimumab group vs 48% in the chemotherapy group with the most common events being neutropenia (0% vs 10%), asthenia (1% vs 6%), and diarrhea (1% vs 5%). Two deaths were reported to be treatment-related and they occurred in the nivolumab/ipilimumab group, one from myocarditis, and the other from pneumonitis. With regards to QoL, the differences between patient reported outcomes on questionnaires among the two groups exceeded the pre-specified threshold for meaningful change from week 13 onward, with nivolumab/ipilimumab being superior as compared with chemotherapy. The strengths of this study included the methodology, and the limitations included the small sample size. Overall, this interim analysis found PFS improvements in nivolumab/ipilimumab vs chemotherapy in first-line treatment of MSI-H or dMMR metastatic colorectal cancer.
Click to read the study in NEJM
In-Depth [randomized controlled trial]: This multinational, open-label, phase 3 trial enrolled adults with unresectable or metastatic colorectal cancer and MSI-H or dMMR status, and randomized them (2:2:1) to nivolumab/ipilimumab, nivolumab alone, or the investigator’s choice of chemotherapy/targeted therapy. This interim analysis explored patients with no prior treatments who were randomized to nivolumab/ipilimumab (n=202) vs chemotherapy (n=101). Median follow-up time was 31.5 months (range, 6.1-48.4). PFS at 12 months was 79% (95%CI, 72-84) with nivolumab/ipilimumab vs 21% (95%CI, 11-32) with chemotherapy, and 24-month PFS was 72% (95%CI, 64-79) and 14% (95%CI, 6-25), respectively. PFS was greater with nivolumab/ipilimumab than with chemotherapy across all subgroups (RAS or BRAF mutations; baseline liver, lung, or peritoneal metastases; and the Lynch syndrome). With regards to safety, grade 3-4 treatment-related adverse events occurred in 23% in the nivolumab/ipilimumab group vs 48% in the chemotherapy group with the most common events being neutropenia (0% vs 10%), asthenia (1% vs 6%), and diarrhea (1% vs 5%). Two deaths were reported to be treatment-related and they occurred in the nivolumab/ipilimumab group, one from myocarditis, and the other from pneumonitis. With regards to QoL, the differences between patient reported outcomes on questionnaires among the two groups exceeded the pre-specified threshold for meaningful change from week 13 onward, with nivolumab/ipilimumab being superior as compared with chemotherapy. Overall, this interim analysis found PFS improvements in nivolumab/ipilimumab vs chemotherapy in first-line treatment of MSI-H or dMMR metastatic colorectal cancer.
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