Dual immunotherapy with checkpoint inhibitors nivolumab and ipilimumab works better to slow disease progression in patients with microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) when compared with single-agent nivolumab, as shown in the phase III CheckMate 8HW trial.

Preliminary data presented at ASCO GI and concurrently published on The Lancet indicated that nivolumab plus ipilimumab yielded “significant and clinically meaningful” progression-free survival gains relative to nivolumab (hazard ratio [HR], 0.62, 95 percent confidence interval [CI], 0.48?0.81; p=0.0003). [Lancet 2025;405:383-395]

Over a median follow-up of 47 months, the median PFS was not reached (95 percent CI, 53.8 to not estimable) with the immunotherapy combination vs 39.3 months with nivolumab (22.1 to not estimable), reported first author Prof Thierry Andre from Sorbonne University in Paris, France.

The respective 2- and 3-year PFS rates were 71 percent and 68 percent with nivolumab plus ipilimumab and 56 percent and 51 percent with nivolumab.

Andre noted an early and sustained separation of PFS curves after the first scan, with consistent PFS benefit across subgroups defined by age, sex, region, ECOG PS, tumour sidedness, metastasis sites, PD-L1 expression, BRAF/KRAS/NRAS mutation status, and Lynch syndrome history.

Response, safety, and HRQoL

Objective response rate (ORR) was also significantly higher with nivolumab plus ipilimumab at 71 percent than with nivolumab at 58 percent (difference, 13 percent; p=0.0011), with complete responses in 30 percent and 28 percent of the patients, respectively. Progressive disease as best response was documented in 10 percent of patients on the immunotherapy combination and in 19 percent of those on nivolumab.

Duration of response was not reached in both treatment arms, according to Andre.

Treatment-related adverse events (TRAEs) of any grade occurred in 81 percent of patients in the nivolumab plus ipilimumab arm and in 71 percent of those in the nivolumab arm. Grade 3 or 4 TRAEs were reported in 22 percent and 14 percent of patients, while TRAEs leading to treatment discontinuation were documented in 14 percent and 6 percent, respectively.

There were three treatment-related deaths: one event of myocarditis and pneumonitis each in the nivolumab plus ipilimumab arm and one pneumonitis event in the nivolumab arm.

“Most immune-mediated AEs were grade I or II, with grade III or IV events occurring in less than 5 percent of patients in either treatment arm. A higher incidence of immune-mediated endocrine AEs has been noted with immunotherapy combination vs monotherapy, most of which were grade I or II,” Andre said. “These events were manageable using established guidelines, with or without the need for ongoing hormone replacement therapy.”

As for health-related quality of life (HRQoL), the mean change from baseline in the EORTC Global Health Status scale scores was consistently positive in both treatment arms, with nivolumab plus ipilimumab reaching the prespecified limit for meaningful change starting at week 21 and remaining at or near the minimally-important change from baseline at most time points, as Andre pointed out.

New standard of care

CheckMate 8HW included 707 patients with MSI-H/dMMR mCRC treated at hospitals and cancer centres across 23 countries. These patients randomly assigned to nivolumab plus ipilimumab (n=354, median age 62 years, 54 percent female), nivolumab (n=353, median age 63 years, 46 percent female), or investigator’s choice of chemotherapy (mFOLFOX6 or FOLFIRI with or without bevacizumab or cetuximab; n=132). In the nivolumab plus ipilimumab and nivolumab monotherapy arms specifically, half of the patients had ECOG PS score of 0, and 57 percent are being treated in the first-line setting.

“In our previous report, nivolumab plus ipilimumab showed superior PFS versus chemotherapy in the first-line setting (HR, 0.21, 95 percent CI, 0.14?0.32),” Andre said. [N Engl J Med 2024;391:2014-2026]

Taken together, the present and prior results point to the potential of nivolumab plus ipilimumab to be the new standard of care for patients with MSI-H/dMMR mCRC, he added.