Colon to Rectum
Lancet. 2025;405(10476):383-395
Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): A randomised, open-label, phase 3 trial
Background: CheckMate 8HW prespecified dual primary endpoints, assessed in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient status: progression-free survival with nivolumab plus ipilimumab compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab compared with nivolumab alone, regardless of previous systemic treatment for metastatic disease. In a previous report, nivolumab plus ipilimumab showed superior progression-free survival versus chemotherapy in first-line microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the CheckMate 8HW trial. Here, the authors report results from the prespecified interim analysis for the other primary endpoint of progression-free survival for nivolumab plus ipilimumab versus nivolumab across all treatment lines. Methods: CheckMate 8HW is a randomised, open-label, international, phase 3 trial at 128 hospitals and cancer centres across 23 countries. Immunotherapy-naive adults with unresectable or metastatic colorectal cancer across different lines of therapy and microsatellite instability-high or mismatch repair-deficient status per local testing were randomly assigned (2:2:1) to nivolumab plus ipilimumab (nivolumab 240 mg, ipilimumab 1 mg/kg, every 3 weeks for 4 doses; then nivolumab 480 mg every 4 weeks; all intravenously), nivolumab (240 mg every 2 weeks for 6 doses, then 480 mg every 4 weeks; all intravenously), or chemotherapy with or without targeted therapies. The dual independent primary endpoints were progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus chemotherapy (first line) and progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus nivolumab (all lines) in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Findings: Between August 16, 2019, and April 10, 2023, 707 patients were randomly assigned to nivolumab plus ipilimumab (n = 354) or nivolumab alone (n = 353). 296 of 354 patients (84%) in the nivolumab plus ipilimumab group and 286 of 353 patients (81%) in the nivolumab group were centrally confirmed to have microsatellite instability-high or mismatch repair-deficient status. At the data cutoff on August 28, 2024, median follow-up (from randomisation to data cutoff) was 47.0 months (interquartile range [IQR], 38.4–53.2). Nivolumab plus ipilimumab treatment showed significant and clinically meaningful improvement in progression-free survival versus nivolumab (hazard ratio = 0.62, 95% confidence interval [CI]: 0.48–0.81; p = 0.0003). Median progression-free survival was not reached with nivolumab plus ipilimumab (95% CI: 53.8 to not estimable) and was 39.3 months with nivolumab (22.1 to not estimable). Treatment-related adverse events of any grade occurred in 285 of 352 patients (81%) receiving nivolumab plus ipilimumab and in 249 of 351 patients (71%) receiving nivolumab; grade 3 or 4 treatment-related adverse events occurred in 78 (22%) and 50 (14%) patients, respectively. There were 3 treatment-related deaths: 1 event of myocarditis and pneumonitis each in the nivolumab plus ipilimumab group and 1 pneumonitis event in the nivolumab group.
Interpretation: Nivolumab plus ipilimumab showed superior progression-free survival versus nivolumab across all treatment lines, with a manageable safety profile, in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These results, together with the first-line results of superior progression-free survival with nivolumab plus ipilimumab versus chemotherapy, suggest nivolumab plus ipilimumab as a potential new standard of care for patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.
DOI: 10.1016/s0140-6736(24)02848-4
Prof. Dr. Michael Quante
Head of Gastrointestinal Oncology, Department of Internal Medicine II, University Medical Center Freiburg (Germany)
Dual-agent immunotherapy now standard for MSI-high colorectal cancer
The CheckMate 8HW study, published in The Lancet on February 1, 2025, evaluates the efficacy of the immunotherapy combination nivolumab (NIVO) plus ipilimumab (IPI) compared to nivolumab monotherapy in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC).
In this multicenter, open-label phase 3 trial, conducted across 128 centers in 23 countries, NIVO + IPI demonstrated a significant improvement in progression-free survival (PFS) (hazard ratio [HR] = 0.62; p = 0.0003) along with a higher objective response rate (71% vs. 58%) and reduced disease progression (10% vs. 19%) compared to monotherapy. The PFS rates at 12, 24, and 36 months were higher with NIVO + IPI (76%, 71%, and 68%) than with NIVO alone (63%, 56%, and 51%).
However, adverse events of any grade were more frequent with NIVO + IPI (81% vs. 71%), and severe adverse events (grade 3–4) occurred in 22% versus 14% of patients. Treatment discontinuation due to adverse events was also more common in the combination group (14% vs. 6%), although they remained generally manageable.
The broad application of this study across first-, second-, and third-line treatments strengthens its clinical relevance. However, a direct comparison with pembrolizumab, which is approved as a first-line treatment for MSI-H/dMMR mCRC, is lacking. KEYNOTE-177 trial data confirm pembrolizumab’s superiority over chemotherapy (overall survival [OS]: 77.5 vs. 36.7 months; HR = 0.73) and improved PFS (16.5 vs. 8.2 months; HR = 0.60). In contrast, the CheckMate 142 study, which evaluated pretreated patients, showed superior 1-year PFS (71% vs. 50.4%) and OS (85% vs. 73.4%) rates with NIVO + IPI compared to NIVO alone. In CheckMate 8HW, median PFS was not reached for NIVO + IPI, while it was 39.3 months for NIVO alone. The NIPICOL study confirmed these long-term benefits, reporting 3-year PFS and OS rates of 70% and 73%, respectively.
Although direct comparisons between these studies are limited due to differences in trial design, the data indicate that both pembrolizumab monotherapy and NIVO + IPI offer significant clinical benefits for MSI-H/dMMR mCRC. While combination therapy may provide long-term advantages, pembrolizumab monotherapy remains a viable alternative with a more favorable safety profile. The choice between these therapies should be patient-specific, considering tumor burden, adverse-effect management, and progression risk.
The CheckMate 8HW study provides strong evidence supporting the efficacy of NIVO + IPI across all treatment lines and has approval for first-line therapy. The most important clinical takeaway remains the routine determination of MSI/MMR status in colorectal cancer patients to enable personalized treatment decisions.
Comparison of progression-free survival (PFS) and overall survival (OS) across studies on microsatellite instability-high colorectal cancer
| Study | Treatment | Setting | Median PFS | Median OS | Long-term results |
| KEYNOTE-177 | Pembrolizumab | First-line | 16.5 months | 77.5 months | 5-year OS rate: 54.8% |
| KEYNOTE-177 | Chemotherapy | First-line | 8.2 months | 36.7 months | 5-year OS rate: 44.2% |
| CheckMate 142 | Nivolumab | ≥ 1 pretreatment | Not reported | Not reported | 1-year PFS: 50.4%, 1-year OS: 73.4% |
| CheckMate 142 | Nivolumab + Ipilimumab | ≥ 1 pretreatment | Not reported | Not reported | 1-year PFS: 71%, 1-year OS: 85% |
| CheckMate 8HW | Nivolumab + Ipilimumab | All lines | Not achieved | Not reported | 3-year PFS rate: 68% |
| CheckMate 8HW | Nivolumab | All lines | 39.3 months | Not reported | 3-year PFS rate: 51% |
| Real-world study | Different immune therapies | Mixed | 37.9 months | 65.4 months | 47% of the patients with PFS > 24 months |