CHMP Recommends Approval of Nivolumab/Ipilimumab in MSI-H/dMMR mCRC

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of nivolumab (Opdivo) plus ipilimumab (Yervoy) for the first-line treatment of adult patients with microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) unresectable or metastatic colorectal cancer (mCRC).¹

The positive opinion is based on data from the phase 3 CheckMate-8HW trial (NCT04008030), which demonstrated that treatment with the combination in the first line led to a 79% reduction in the risk of disease progression or death vs chemotherapy in this patient population (HR, 0.21; 95% CI, 0.14-0.32; P <.0001). The combination also reduced the risk of disease progression or death vs nivolumab monotherapy, meeting the other dual primary end point of the trial.

The European Commission (EC) will now review the recommendation and determine whether the regimen will be approved for use in the European Union.

“Approximately 5% to 7% of patients with mCRC have dMMR or MSI-H tumors, and current treatment options often do not provide sufficient benefit,” Dana Walker, MD, MSCE, vice president, global program lead, gastrointestinal and genitourinary cancers, Bristol Myers Squibb, stated in a news release. “This is the first dual checkpoint inhibitor treatment for first-line mCRC, delivering a transformative benefit for MSI-H/dMMR patients in this population. We are focused on bringing [nivolumab] plus [ipilimumab] to these patients in the European Union and look forward to EC’s upcoming decision.”

The combination of nivolumab and ipilimumab has been approved for use in the United States in patients with MSI-H/dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan since 2018 under the FDA’s accelerated approval pathway. The indication was based on data from the phase 2 CheckMate-142 trial (NCT02060188), in which the combination led to an overall response rate (ORR) of 46% (95% CI, 35%-58%).²

The randomized, open-label phase 3 CheckMate-8HW trial is evaluating nivolumab plus ipilimumab vs nivolumab alone or investigator’s choice of mFOLFOX-6 or FOLFIRI with or without bevacizumab (Avastin) or cetuximab (Erbitux) in patients with MSI-H/dMMR unresectable or mCRC.³

A total of 839 patients were randomly assigned to receive either 240 mg of nivolumab every 2 weeks for 6 doses, followed by 480 mg every 4 weeks; 240 mg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by 480 mg of nivolumab every 4 weeks; or investigator’s choice of chemotherapy.¹

The dual primary end points of the study are progression-free survival (PFS) per blinded independent central review (BICR) for the combination vs investigator’s choice of chemotherapy in the first-line setting and PFS per BICR for the combination vs nivolumab alone across all lines of therapy. Secondary end points include ORR and overall survival (OS).³

Expanded efficacy data were presented at the 2024 ASCO Annual Meeting with a median follow-up of 31.5 months (range, 6.1-48.4).4 At this cutoff, the combination retained its PFS benefit with a median PFS that was not reached (95% CI, 38.4–not evaluable) vs 5.9 months (95% CI, 4.4-7.8) with chemotherapy (HR, 0.21; 97.91% CI, 0.13-0.35; P <.0001). The 12- and 24-month PFS rates with the combination were 79% and 72%, respectively, compared with 21% and 14% with chemotherapy. The time to progression after second-line therapy (PFS2) was also prolonged with the combination (HR, 0.27; 95% CI, 0.17-0.44), with 12- and 24-month PFS2 rates of 89% and 83% with the combination, respectively, vs 65% and 52% with chemotherapy.

Subgroup efficacy and expanded safety analyses were subsequently presented at the 2024 ESMO Congress.⁵ Findings showed that the combination improved PFS vs chemotherapy regardless of age, ECOG performance status, BRAF/RAS mutation status, and baseline liver metastasis.

In terms of safety, any grade and grade 3/4 treatment-related adverse effects (TRAEs) were less common in the combination arm compared with the chemotherapy arm. The most frequent any-grade TRAEs that occurred in at least 10% of patients in the combination arm were pruritis (23%), diarrhea (21%), and hypothyroidism (16%), vs diarrhea (51%), nausea (47%), and asthenia (35%) in the chemotherapy arm. Additionally, most non-endocrine immune-mediated AEs resolved with a median time to resolution ranging from 6.7 weeks to 16.1 weeks.

The trial is ongoing and will continue to evaluate secondary safety and efficacy end points, including OS.¹

References

1. Bristol Myers Squibb receives positive CHMP opinion 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. November 15, 2024. Accessed November 15, 2024. https://news.bms.com/news/corporate-financial/2024/Bristol-Myers-Squibb-Receives-Positive-CHMP-Opinion-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. FDA grants accelerated approval to ipilimumab for MSI-H or dMMR metastatic colorectal cancer. FDA. July 11, 2018. Accessed November 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ipilimumab-msi-h-or-dmmr-metastatic-colorectal-cancer
3. A study of nivolumab, nivolumab plus ipilimumab, or investigator’s choice chemotherapy for the treatment of participants with deficient mismatch repair (dMMR)/microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC) (CheckMate 8HW). ClinicalTrials.gov. Updated September 19, 2024. Accessed November 15, 2024. https://clinicaltrials.gov/study/NCT04008030
4. Lenz HJ, Lonardi S, Elez 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): expanded efficacy analysis from CheckMate 8HW. J Clin Oncol. 2024;42(suppl 16):3503. doi:10.1200/JCO.2024.42.16_suppl.3503
5. André T, Lonardi S, Lenz HJ, 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): subgroup efficacy and expanded safety analyses from CheckMate 8HW. Ann Oncol. 2024;35(suppl 2):S451-S452. doi:10.1016/j.annonc.2024.08.610