Nivolumab/Ipilimumab Combination Represents Potential Standard-of-Care Shift in MSI-H/dMMR mCRC

Nivolumab (Opdivo) in combination with ipilimumab (Yervoy) has the potential to shift the treatment paradigm of microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) following robust results from the phase 3 CheckMate 8HW trial (NCT04008030), according to Thierry André, MD.

Findings from CheckMate 8HW presented during the 2025 Gastrointestinal Cancers Symposium (ASCO GI) indicated that patients who received nivolumab plus ipilimumab (n = 296) experienced a median progression-free survival (PFS) of not reached (95% CI, 53.8-not estimable [NE]) compared with 39.3 months (95% CI, 22.1-NE) among patients who received nivolumab monotherapy (n = 286; HR, 0.62; 95% CI, 0.48-0.81; P = .0003).1 The 36-month PFS rates were 68% vs 51%, respectively.

“The primary objective was met, [with] a HR [for PFS] in favor of the combination and the P value was statistically significant for the population of patients with MSI-H/dMMR [mCRC]….The balance between benefit and toxicity is clearly in favor of [nivolumab plus ipilimumab] and [it represents a new] standard of care [SOC],” André said in an interview with OncLive. André isa professor of medical oncology at Sorbonne Université and the head of the Medical Oncology Department at the Saint Antoine Hospital, Assistance Publique Hôpitaux de Paris, in France.

Based on findings from CheckMate 8HW, on February 24, 2025, theFDA accepted a supplemental biologics license application (sBLA) seeking the approval of nivolumab plus ipilimumab for the first-line treatment of adult and pediatric patients at least 12 years of age with MSI-H/dMMR mCRC.2 The sBLA was also granted breakthrough therapy designation and priority review status by the agency. The Prescription Drug User Fee Act target action date is set for June 23, 2025.

In the interview, André detailed the background of CheckMate 8HW, the key findings from the study he presented during ASCO GI, and the potential impact of the data on the treatment landscape of MSI-H/dMMR mCRC.

OncLive: What was the rationale for CheckMate 8HW?

André: The [finding that] pembrolizumab [Keytruda] improves PFS compared with chemotherapy has changed the paradigm of therapy for MSI-H/dMMR mCRC. Unfortunately, some patients experience progressive disease [with this therapy] and some unmet needs remain.

The [first] step [to fill this need] was to compare nivolumab[in] combination with ipilimumab withchemotherapy [in terms of PFS]; this was the first dual primary objective of CheckMate 8HW. [Data] published in The New England Journal of Medicine showed that [PFS results] were in favor of the of the immunotherapy [combination vs chemotherapy] with a HR of 0.21. The next step was to compare nivolumab/ipilimumabvs nivolumab [in terms of PFS]; this was the second dual primary objective of CheckMate 8HW.

What were the key safety and efficacy data from the study you presented at this year’s ASCO GI meeting?

[Beyond the] improvement in PFS, [there was] also an improvement in overall response rate, [at] 71% [95% CI, 65%-76%] with the combination vs 58% [95% CI, 52%-64%] for the monotherapy [P = .0011].

There was a moderate increase in toxicity [with the combination], [including] a moderate increase in grade 3/4 [events] and a moderate increase in [the frequency of] stopping therapy. This was not a surprise because it’s clear that CTLA4 inhibitors increase toxicity, especially immune-mediated and endocrine toxicities. The most frequent grade 1 to 4 [immune-mediated event] was hypothyroidism/thyroiditis [which necessitated] some patients to [undergo] hormone therapy for a long time. This was also [present] in the nivolumab alone arm, but it was a bit more [common] with the combination.

Are there any factors that could contribute to which patients receive the combination vs nivolumab monotherapy?

In this study, [findings from] a subgroup analysis [showed] a benefit [with the combination] for all subgroups of patients. For this reason, it’s difficult to know if there is a population where monotherapy is still [appropriate]. It’s an important question, but it’s difficult to answer [based on] these data.

How could these findings affect the treatment landscape of MSI-H/dMMR mCRC?

At this time, for [patients with] MSI-H/dMMR mCRC, there is no place for chemotherapy or other therapy. Immunotherapy is now the SOC for MSI-H/dMMR mCRC. The question is [should they receive] monotherapy or combination therapy, and the conclusion of this trial makes nivolumab plus ipilimumab a SOC in this situation.

References

1. Andre T, Elez E, Lenz HJ, et al. First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. J Clin Oncol. 2025;43(suppl 4):LBA143. doi:10.1200/JCO.2025.43.4_suppl.LBA143
2. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s supplemental biologics license application for Opdivo Plus Yervoy for patients with unresectable or metastatic microsatellite instability-high or mismatch repair deficient... News release. Bristol Myers Squibb. February 24, 2025. Accessed February 27, 2025. https://news.bms.com/news/corporate-financial/2025/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Supplemental-Biologics-License-Application-for-Opdivo-Plus-Yervoy-for-Patients-with-Unresectable-or-Metastatic-Microsatellite-Instability-High-or-Mismatch-Repair-Deficient/default.aspx