EMA Validates MAA for Frontline Nivolumab/Ipilimumab for MSI-H/dMMR mCRC


The European Medicines Agency has validated an application for nivolumab plus ipilimumab for frontline MSI-H/dMMR metastatic colorectal cancer.

Dana Walker, MD, MSCE

Dana Walker, MD, MSCE

The European Medicines Agency (EMA) has validated a Type II variation application for nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the frontline treatment of adult patients with microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC).1

This application is supported by findings from the phase 3 CheckMate-8HW trial (NCT04008030), which demonstrated that nivolumab plus ipilimumab generated a statistically significant and clinically meaningful 79% progression-free survival (PFS) improvement vs investigator’s choice of chemotherapy (HR, 0.21; 95% CI, 0.14-0.32; P < .0001).2 This PFS improvement was observed beginning at approximately 3 months.

The median PFS was not yet reached (NR; 95% CI, 38.4 months-NR) in the combination arm compared with 5.9 months (95% CI, 4.4-7.8) in the chemotherapy arm. This PFS benefit was noted across all prespecified patient subgroups, regardless of KRAS or NRAS mutation status or the presence of baseline lung, peritoneal, or liver metastases. The 12- and 24-month PFS rates were 79% and 72%, respectively, in the combination arm vs 21% and 14%, respectively, in the chemotherapy arm.3

“CRC is the third most commonly diagnosed cancer in the world, and more options are needed specifically for patients with MSI-H/dMMR mCRC, who are less likely to benefit from treatment with chemotherapy,” Dana Walker, MD, MSCE, vice president and global program lead of gastrointestinal and genitourinary cancers at Bristol Myers Squibb, stated in a news release.1 “We look forward to working with the EMA to discuss bringing the dual immunotherapy combination of [nivolumab] and [ipilimumab] to patients with MSI-H/dMMR mCRC across Europe.”

The open-label CheckMate-8HW trial assessed nivolumab plus ipilimumab vs nivolumab monotherapy or investigator’s choice of mFOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) or FOLFIRI (leucovorin, fluorouracil, and irinotecan) with or without bevacizumab (Avastin) or cetuximab (Erbitux) in approximately 830 patients with histologically confirmed unresectable or metastatic MSI-H/dMMR mCRC with an ECOG performance status of 0 or 1. Patients were stratified by number of prior lines of therapy (0 vs 1 vs ≥2) and primary tumor location (right vs left).3

In the combination arm, nivolumab was administered at 240 mg in combination with ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks. In the monotherapy arm, nivolumab was administered at 240 mg every 2 weeks for 6 doses and then increased to 480 mg every 4 weeks. Patients in all arms received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. Patients in the nivolumab combination and monotherapy arms received treatment for a maximum of 2 years.

The dual primary end points were PFS per blinded independent central review (BICR) for nivolumab plus ipilimumab vs chemotherapy in the frontline setting and PFS per BICR for the combination vs nivolumab monotherapy across all lines of therapy. Secondary end points included safety, overall survival, overall response rate by BICR, and patient-reported outcomes.

The safety profile of nivolumab plus ipilimumab was consistent with prior reports of the combination and was manageable with no new safety signals.2 Grade 3/4 treatment-related adverse effects (TRAEs) were observed in 23% and 48% of patients in the combination and chemotherapy arms, respectively. Seventeen percent and 32% of patients in the combination and chemotherapy arms, respectively, discontinued treatment because of any-grade TRAEs.

CheckMate-8HW is ongoing to evaluate the other dual primary end point, as well as secondary end points.1


  1. European Medicines Agency validates Bristol Myers Squibb’s application for Opdivo (nivolumab) plus Yervoy (ipilimumab) for the first-line treatment of adult patients with microsatellite… News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024.
  2. Opdivo (nivolumab) plus Yervoy (ipilimumab) reduced the risk of disease progression or death by 79% versus chemotherapy in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer in CheckMate -8HW trial. News release. Bristol Myers Squibb. January 20, 2024. Accessed May 6, 2024.
  3. Andre T, Elez E, Van Cutsem E, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): first results of the CheckMate 8HW study. J Clin Oncol. 2024;42(suppl 3). doi:10.1200/JCO.2024.42.3_suppl.LBA768
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