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Health Canada has approved nivolumab (Opdivo) plus ipilimumab (Yervoy) for the first-line treatment of patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) colorectal cancer (CRC) and patients with unresectable or advanced hepatocellular carcinoma (HCC).1
Data from the phase 3 CheckMate-8HW (NCT04008030) and CheckMate-9DW (NCT04039607) trials supported the approval of nivolumab plus ipilimumab for the respective patient populations. Of note, the CheckMate-8HW study demonstrated progression-free survival (PFS) benefit in patients with MSI-H/dMMR CRC, and the CheckMate-9DW study showed overall survival (OS) improvements in patients with HCC.
“Although we’ve seen progress, MSI-H or dMMR metastatic CRC is clinically complex, particularly in the first-line setting, where there remains an ongoing need for additional treatments,” Sharlene Gill, MD, MPH, MBA, FRCPC, professor in the Department of Medicine in the Division of Medical Oncology at The University of British Columbia in Vancouver, Canada, stated in a news release. “The approval of [nivolumab] plus [ipilimumab], supported by CheckMate-8HW, the largest phase 3 immunotherapy trial to date in this population, offers a well-studied and very clinically meaningful option for patients and clinicians treating this distinct molecular subtype of CRC.”
Efficacy and Safety Data From the CheckMate-8HW Study
In the CheckMate-8HW study, at a data cutoff date of August 28, 2024, the median follow-up was 47.0 months (IQR, 38.4-53.2).2 Patients treated with nivolumab plus ipilimumab demonstrated a significant and clinically meaningful improvement in PFS compared with nivolumab alone (HR, 0.62; 95% CI, 0.48-0.81; P = .0003). Notably, the median PFS was not reached (95% CI, 53.8-not estimable [NE]) with the combination compared with 39.3 months (95% CI, 22.1-NE) with nivolumab alone.
Regarding safety, treatment-related adverse effects (TRAEs) of any grade were observed in 81% of patients (n = 285 of 352) treated with nivolumab plus ipilimumab, and 71% (n = 249 of 351) of those treated with nivolumab alone. Additionally, grade 3 or 4 TRAEs occurred in 22% and 14% of patients in the respective arms. Three treatment-related deaths were reported, with one death each caused by myocarditis and pneumonitis in the combination arm, and one death from pneumonitis in the monotherapy arm.
CheckMate-8HW Study Design
The international, open-label, randomized study included patients who are immunotherapy naive with unresectable or metastatic CRC with MSI-H/dMMR status. Patients were randomly assigned 2:2:1 to receive either nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies.
The dual independent primary end points are PFS by blinded independent central review (BICR) with nivolumab plus ipilimumab compared with chemotherapy and PFS by BICR with nivolumab plus ipilimumab versus nivolumab.
Efficacy and Safety Data From the CheckMate-9DW Study
Following a median follow-up of 35.2 months (IQR, 31.1-39.9), a significant improvement in OS was observed with nivolumab plus ipilimumab compared with lenvatinib (Lenvima) or sorafenib (Nexavar), with a median OS of 23.7 months (95% CI, 18.8-29.4) vs 20.6 months (95% CI, 17.5-22.5), respectively (HR, 0.79; 95% CI, 0.65-0.96; 2-sided log-rank P = .018).3 The OS rates were 49% (95% CI, 44%-55%) and 39% (95% CI, 34%-45%) at 24 months with nivolumab plus ipilimumab vs lenvatinib or sorafenib; these respective rates were 38% (95% CI, 32%-43%) and 24% (95% CI, 19%-30%) at 36 months.
“For patients with unresectable or advanced HCC, improving outcomes continues to be a critical priority,” Hatim Karachiwala, MD, a medical oncologist at Alberta Health Services in Canada, added in the news release.1 “Data from CheckMate-9DW provides useful insights into how the [nivolumab] plus [ipilimumab] dual immunotherapy strategy might be considered as part of the initial treatment approach.”
Moreover, grade 3/4 TRAEs were observed in 41% of patients (n = 137 of 332) in the nivolumab plus ipilimumab arm and 42% (n = 138 of 325) of those treated with lenvatinib or sorafenib.3 Twelve deaths were due to treatment with nivolumab plus ipilimumab, and 3 deaths were due to treatment with lenvatinib or sorafenib.
CheckMate-9DW Study Design
The open-label, randomized study included patients who were at least 18 years of age with unresectable HCC who did not previously receive systemic therapy. Patients on the study were required to have at least 1 measurable lesion per RECIST 1.1 criteria, a Child-Pugh score of 5 or 6, and an ECOG performance status of 0 or 1. Patients were randomly assigned 1:1 to receive either nivolumab plus ipilimumab, or investigator’s choice of lenvatinib or sorafenib.
The primary end point is OS, and safety comprised an exploratory end point.
“These approvals mark important progress for both the [CRC] and liver cancer communities. For those facing aggressive disease, time matters,” Filomena Servidio-Italiano, president and chief executive officer of Colorectal Cancer Resource & Action Network, stated in the news release.1 “Expanding access to first-line immunotherapy—particularly with combination strategies that enhance the immune system engagement—responds to an important unmet need.”
References
- Health Canada approves dual immunotherapy Opdivo plus Yervoy for colorectal and liver cancers. News release. Bristol Myers Squibb. August 19, 2025. Accessed August 20, 2025. https://www.bms.com/ca/en/media/press-release-listing/2025-08-19-press-release.html
- André T, Elez E, Lenz HJ, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025;405(10476):383-395. doi:10.1016/S0140-6736(24)02848-4
- Yau T, Galle PR, Decaens T, et al. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Lancet. 2025;405(10492):1851-1864. doi:10.1016/S0140-6736(25)00403-9