Metastatic colorectal cancer (mCRC), particularly the microsatellite instability (MSI-H) and/or are deficient in mismatch repair (MSI-H/dMMR) subtype, poses significant treatment challenges due to limited curative options and resistance to standard therapies. Recent advances focus on biomarker-driven approaches, with dual immunotherapy showing promise. In April 2025, the US Food and Drug Administration (FDA) approved this combination of OPDIVO (nivolumab; PD-1 inhibitor) and YERVOY (ipilimumab; CTLA-4 inhibitor) for adults and children (≥12 years) with MSI-H/dMMR mCRC, based on the Phase III CheckMate-8HW trial, which demonstrated superior PFS versus chemotherapy. This approval also converts the combination’s earlier accelerated approval to full approval for patients who progressed after prior standard treatment.

Among all randomized 1L patients with centrally confirmed MSI-H/dMMR mCRC, NIVO + IPI (Nivolumab plus ipilimumab) achieved a median PFS of 54.1 months, compared to 5.9 months for chemotherapy, a nearly five-fold improvement. Median PFS2 was also notably longer with immunotherapy. When considering all lines of therapy, NIVO + IPI continued to outperform NIVO alone. Median PFS was not reached in the combination immunotherapy arm versus 39.3 months for NIVO monotherapy. The superior benefit of dual immunotherapy was further supported by PFS2. 

Median PFS2 was not reached in the combination immunotherapy arm (171 patients), compared with 30.3 months in the chemotherapy arm (84 patients)—with a 72% reduction in the risk of death or progression after first subsequent therapy (HR 0.28, 95% CI [0.18, 0.44]). Importantly, fewer patients needed subsequent therapy after 1L NIVO + IPI (16%) versus chemotherapy (73%), and fewer required further immunotherapy. No new safety signals were observed, with grade 3/4 treatment-related adverse events in 22% (NIVO + IPI) and 14% (NIVO) of treated patients.

KOL insights

Even though the CheckMate 8HW trial was not powered to compare various subpopulations of CRC, between the nivolumab/ipilimumab vs nivolumab (monotherapy) arms, there was consistent benefit observed across (subgroups with the combination). This gives us the confidence to use dual immune checkpoint blockade as an FDA-approved option for patients with untreated MSI-H mCRC. – Expert Opinion

Nivolumab and ipilimumab showed improved time to second objective disease progression (PFS2) and manageable safety profiles, reinforcing its role as a standard first-line treatment for MSI-H/dMMR mCRC.” – Expert Opinion

Conclusion

As of 2024, mCRC remains a significant clinical burden in the US, with approximately 79,500 total cases. Among these, the MSI-H/dMMR subtype accounts for about 11,900 cases, making it the second most prevalent molecular subset after KRAS mutations. 

Conventional chemotherapy usually has a poor outcome for patients with MSI-H/dMMR mCRC. Over the past several years, investigators have learned the role of administering immune checkpoint inhibitors in this subset. Even though KEYTRUDA (pembrolizumab) was approved in international markets to treat patients with MSI-H/dMMR mCRC who had not previously received treatment, some of these patients still have unmet needs. In the approved treatment landscape for MSI-H/dMMR mCRC, the combination of nivolumab and ipilimumab has emerged as a cornerstone immunotherapy. This combo is the first dual immunotherapy regimen to demonstrate a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy as first-line treatment in MSI-H/dMMR mCRC. 

Latest data from the CheckMate 8HW data confirmed that the combination immunotherapy arm (NIVO + IPI) provides robust and sustained clinical benefit compared to both chemotherapy and single-agent immunotherapy in MSI-H/dMMR mCRC. The results are particularly striking in first-line patients, with more than four years of median PFS and durable responses observed. PFS2 outcomes reinforce the benefit of initial dual immunotherapy, even after subsequent therapies. Given these findings and a manageable safety profile, NIVO + IPI should now be considered a standard of care for patients with MSI-H/dMMR mCRC.