Nivolumab Plus Ipilimumab Wins European Approval for MSI-H/dMMR mCRC

The European Commission (EC) has approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the frontline treatment of adult patients with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) unresectable or metastatic colorectal cancer (CRC).1 This combination is the first dual checkpoint inhibitor regimen to be approved in the European Union (EU) for this indication.

The regulatory decision was supported by findings from the phase 3 CheckMate-8HW trial (NCT04008030), in which the combination generated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with investigator’s choice of chemotherapy (P < .001).1,2 At a median follow-up of 31.5 months (range, 6.1-48.4), the median PFS was not reached (95% CI, 38.4%-not evaluable) in the immunotherapy arm vs 5.9 months (95% CI, 4.4-7.8) in the chemotherapy arm.2 Nivolumab plus ipilimumab reduced the risk of disease progression or death by 79% vs chemotherapy per blinded independent central review (BICR).1

The 24-month PFS rate was 72% (95% CI, 64%-79%) with the immunotherapy combination vs 14% (95% CI, 6%-25%) with chemotherapy.2 This PFS benefit with nivolumab plus ipilimumab was seen across all prespecified patient subgroups, including those with KRAS or NRAS mutations (12-month PFS rate with nivolumab/ipilimumab, 76% [95% CI, 56%-88%]; 12-month PFS rate with chemotherapy, 29% [95% CI, 7%-56%]); and those with baseline lung (56% [95% CI, 39%-71%]; 14% [95% CI, 2%-37%]), liver (85% [95% CI, 73%-92%]; 14% [95% CI, 4%-31%]), or peritoneal (74% [95% CI, 62%-83%]; 13% [95% CI, 3%-28%]) metastases.

Furthermore, the estimated restricted mean survival time at 24 months was 19.2 months (95% CI, 17.9-20.5) with the immunotherapy combination vs 8.6 months (95% CI, 6.7-10.4) with chemotherapy, translating to a difference of 10.6 months (95% CI, 8.4-12.9).

“CRC is the second leading cause of cancer death in Europe, and patients are in need of new treatment options that delay disease progression. Approximately 5% to 7% of [patients with] metastatic CRC [mCRC] have MSI-H/dMMR tumors, and these patients are less likely to benefit from conventional chemotherapy and typically have poor prognosis outcomes,” Dana Walker, MD, MSCE, vice president and the Opdivo global program lead at Bristol Myers Squibb, stated in a news release.1 “The EC’s decision to approve [nivolumab] plus [ipilimumab] represents a significant milestone for this patient population in the EU and underscores our commitment to advancing treatment options.”

CheckMate-8HW enrolled 839 patients with MSI-H/dMMR unresectable or metastatic CRC to receive nivolumab alone at 240 mg every 2 weeks for 6 doses then at 480 mg every 4 weeks; nivolumab at 240 mg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab at 480 mg every 4 weeks; or investigator’s choice of chemotherapy with mFOLFOX6 or FOLFIRI with or without cetuximab [Erbitux] or bevacizumab [Avastin].

PFS per BICR for nivolumab plus ipilimumab vs chemotherapy in the frontline setting served as a primary end point of the trial. Secondary end points, including overall survival, were also evaluated.

Adverse effects (AEs) of any cause were observed in 99% and 98% of patients in the nivolumab/ipilimumab and chemotherapy arms, respectively.2 Grade 3/4 treatment-related AEs (TRAEs) occurred in 23% and 48% of patients, respectively. Among evaluable patients (n = 200), the most common TRAEs in the nivolumab/ipilimumab arm were pruritus (any-grade, 22%; grade ≥ 3, 0%), diarrhea (21%; 1%), hypothyroidism (16%; 1%), asthenia (14%; 1%), fatigue (13%; < 1%), rash (10%; 1%), increased alanine aminotransferase levels (10%; 2%), and adrenal insufficiency (10%; 3%).

Further data from CheckMate-8HW are planned to be reported at the 2025 Gastrointestinal Cancers Symposium.1

References

1. Bristol Myers Squibb receives European Commission approval for Opdivo (nivolumab) plus Yervoy (ipilimumab) for the first-line treatment of adult patients with microsatellite instability–high or mismatch repair deficient metastatic colorectal cancer. News release. Bristol Myers Squibb. December 23, 2024. Accessed December 23, 2024. https://news.bms.com/news/corporate-financial/2024/Bristol-Myers-Squibb-Receives-European-Commission-Approval-for-Opdivo-nivolumab-plus-Yervoy-ipilimumab-for-the-First-Line-Treatment-of-Adult-Patients-with-Microsatellite-InstabilityHigh-or-Mismatch-Repair-Deficient-Metastatic-Colorectal-Cancer/default.aspx
2. Andre T, Elez E, Van Cutsem E, et al. Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer. N Engl J Med. 2024;391(21):2014-2026. doi:10.1056/NEJMoa2402141