An immunotherapy combination for advanced, highly mutated colorectal cancer has significantly delayed disease progression vs single-agent therapy, according to data presented at the 2025 ASCO Gastrointestinal Cancers Symposium.1
The phase III CheckMate 8HW trial compared the PD-1 inhibitor nivolumab plus the CTLA-4 inhibitor ipilimumab vs single-agent nivolumab in patients with microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer. At 47 months of follow-up, median progression-free survival has not yet been reached with the dual therapy vs 39.3 months with nivolumab alone, which translated into a 38% risk reduction in disease progression or death for the combination. Authors of the study emphasized that patients in the combination arm derived longer treatment durations without compromising overall quality of life.
“These results, combined with the previously reported superiority of nivolumab plus ipilimumab vs chemotherapy in the first-line setting,2 establish nivolumab/ipilimumab as a new standard of care for patients with MSI-H/dMMR metastatic colorectal cancer,” said Thierry André, MD, of Sorbonne University and Saint Antoine Hospital in Paris, who presented the findings.
Thierry André, MD
As Dr. André explained, MSI-H/dMMR tumors account for approximately 4% to 7% of all metastatic colorectal cancer and pose a unique challenge because of their inherent molecular features and historically limited responses to chemotherapy plus targeted agents. Earlier studies demonstrated that single-agent immunotherapy, such as pembrolizumab, can yield long-lasting responses in MSI-H/dMMR colorectal cancer, but approximately 29% of patients in that setting had primary disease progression.
“Combination immunotherapy has attracted interest because dual checkpoint blockade can mount a more robust immune response,” said Dr. André. He noted that phase II data from CheckMate 142 suggested a benefit for nivolumab plus ipilimumab, inspiring the larger phase III CheckMate 8HW trial.
Study Methods
CheckMate 8HW was designed as a randomized, international, multicenter trial for patients with advanced or metastatic MSI-H/dMMR colorectal cancer who were naive to immunotherapy. Patients could have received up to two lines of prior therapy before trial enrollment. All participants had tumors confirmed as MSI-H/dMMR by central testing.
The trial had two primary comparisons. The first report showed nivolumab plus ipilimumab was tested against physician’s choice of chemotherapy in the first-line setting. Previously published data from that arm showed an advantage for dual immunotherapy. This report showed the second comparison—nivolumab plus ipilimumab vs nivolumab alone across all lines of treatment—and this was the focus of Dr. André’s presentation, which was published in The Lancet.3
In total, 707 patients were allocated to these two treatment arms for a maximum of 2 years of treatment. The combination arm involved nivolumab and ipilimumab, administered intravenously, every 3 weeks for the first 12 weeks, followed by nivolumab at a dose of 480 mg, as monotherapy, every 4 weeks. In the single-agent arm, patients received nivolumab at a dose of 480 mg, as monotherapy, every 4 weeks. The co-primary endpoints were progression-free survival (by blinded independent central review) and response rates for patients with centrally confirmed MSI-H/dMMR status. Secondary endpoints included overall survival, safety, and quality-of-life changes as measured by a global health quality instrument.
Key Results
With a median follow-up of 47 months in patients with centrally confirmed MSI-H/dMMR colorectal cancer (n = 582), median progression-free survival had not been reached in the dual-immunotherapy arm, whereas the single-agent nivolumab arm had a median progression-free survival of 39.3 months. In the overall population (n = 707), the median
progression-free survival was 54.1 months with the combination vs 18.4 months with single-agent nivolumab. Nivolumab plus ipilimumab conferred a statistically significant hazard ratio of 0.62, representing a 38% lower risk of disease progression or death.
The objective response rate also favored combination treatment: 71% vs 58% with nivolumab alone. Median duration of response could not be calculated in either arm because the majority of patients were still responding at the time of analysis, said Dr. André.
Toxicity and Quality of Life
The dual-immunotherapy regimen did increase the incidence of treatment-related adverse events compared with single-agent nivolumab. All-grade treatment-related adverse events were reported in 81% of patients given the combination vs 71% in those given the monotherapy.
Grade 3 or 4 events occurred in 22% of participants receiving both agents compared with 14% of those given nivolumab alone. Serious adverse events were reported in 18% with dual therapy and in 8% with nivolumab alone.
Common toxicities across both arms included pruritus, diarrhea, hypothyroidism, asthenia, and fatigue, with more hypothyroidism and adrenal insufficiency in the combination arm. The immunologic nature of the dual regimen led to more immune-mediated events with nivolumab plus ipilimumab, as expected from prior experiences with checkpoint inhibitors. However, Dr. André emphasized that most adverse events remained manageable with standard immunosuppressive or supportive interventions.
Despite the higher rate of severe adverse events in the combination arm, overall quality of life did not appear to suffer. Patient-reported outcomes indicated stable or improved quality of life over time, said Dr. André, suggesting the benefits in disease control might offset potential toxicity burdens.
Although future analyses will provide deeper insight into overall survival and the optimal treatment duration (2 years), the current findings confirm that a dual immunotherapy approach can be a “powerful” first- or subsequent-line option for this subset of metastatic colorectal cancer, according to Dr. André.
Expert Point of View
Invited discussant Wells Messersmith, MD, FASCO, FACP, Professor and Head, Division of Medical Oncology, University of Colorado Cancer Center, highlighted the significant results of the CheckMate 8HW study, particularly with respect to the progression-free survival curves.
Wells Messersmith, MD, FASCO, FACP
“It’s very gratifying to see the curves almost flattened out at the end, which is exactly what we hope for with immunotherapy,” said Dr. Messersmith. He noted that the dual regimen of nivolumab plus ipilimumab added approximately 13% to the response rate and achieved a hazard ratio of 0.62 compared with nivolumab alone.
Dr. Messersmith also emphasized that, unlike in microsatellite-stable (MSS) colorectal cancer, the presence of liver metastases did not appear to affect treatment outcomes in patients with microsatellite instability–high (MSI-high) disease. “For some reason, MSI-high disease seems less influenced by liver metastases,” he explained. “Understanding that biology might help us treat MSS colorectal cancer with liver metastases more effectively down the road.”
Addressing safety, Dr. Messersmith observed that although dual immune checkpoint blockade came with an increased incidence of immune-related adverse events, “the toxicity price is there, but it’s actually pretty low, especially for severe toxicities.” He noted that most adverse events could be managed with standard interventions and that quality-of-life scores improved over time.
Clinical Implications and Remaining Questions
Reflecting on clinical practice, Dr. Messersmith shared these thoughts: “If a patient with MSI-high disease values response and higher progression-free survival, I would use low-dose ipilimumab plus nivolumab. I’ll be changing what I do and use combination therapy.” However, questions remain about the optimal duration, he added, with some evidence suggesting patients may not need the full 2 years of nivolumab.
“At this point, you should commit at the start to either give a doublet or a singlet,” Dr. Messersmith concluded. “We don’t have data on escalating from one to two drugs.”
DISCLOSURE: This study was funded by Bristol Myers Squibb. Dr. André reported financial relationships with AbbVie, Aptitude Health, Bristol Myers Squibb, GlaxoSmithKline, Inspirna, Merck Serono, MSD Oncology, Nimbus Therapeutics, Nordic Bioscience, Pfizer, Sanofi, Seagen, Servier Pharmaceuticals, and Takeda. Dr. Messersmith reported institutional relationships with, and/or support from, Amgen, Criterium. Experimental Drug Development Centre, Agenus, ALX Oncology, AstraZeneca/Medimmune, BeiGene, CanBas, Exelixis, FATE Therapeutics, Mirati Therapeutics, Nurix, Pfizer, PureTech, RasCal, and Revolution Medicines.
REFERENCES
1. André T, et al: 2025 ASCO Gastrointestinal Cancers Symposium. Abstract LBA143. Presented January 23, 2025.
2. André T, et al: N Engl J Med 391:2014-2026, 2024.
3. André T, et al: Lancet 405:383-395, 2025.
