Nivolumab/Ipilimumab Receive Type II Validation by EMA in MSI-H/dMMR mCRC

The validation is based on results from the phase 3 CheckMate-8HW trial (NCT04008030) assessing the efficacy of nivolumab/ipilimumab in patients with MSI-H/dMMR metastatic colorectal cancer.

Nivolumab (Opdivo) plus ipilimumab (Yervoy) has received Type II variation application validation from the European Medicines Agency as first-line treatment for microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC), according to a press release from Bristol Myers Squibb.¹

With this validation, the submission is complete, and the centralized review process can now begin. The validation is based on results from the phase 3 CheckMate-8HW trial (NCT04008030) assessing the efficacy of nivolumab/ipilimumab in the aforementioned population. Results were presented at the 2024 Gastrointestinal Cancers Symposium.²

Most notable was the statistically significant improvement in progression-free survival (PFS) in the combination arm, which was not reached (95% CI, 38.4 months-not evaluable) at the median follow-up of 24.3 months vs 5.9 months (95% CI, 4.4-7.8) in the chemotherapy arm (HR, 0.21; 95% CI, 0.13-0.34; P <.0001).

“[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, global program lead, gastrointestinal and genitourinary cancers, Bristol Myers Squibb, said in the press release.¹ “We look forward to working with the European Medicines Agency to discuss bringing the dual immunotherapy combination of [nivolumab] and [ipilimumab] to patients with MSI-H/dMMR mCRC across Europe.”

A total of 303 patients were randomly assigned to receive nivolumab plus ipilimumab (n = 202) or chemotherapy (n = 101). Additionally, 171 and 84 patients in each arm, respectively, had centrally confirmed MSI-H/dMMR disease via immunohistochemistry and/or polymerase chain reaction-based tests.

Patients were randomly assigned 2:1:1 and given nivolumab at 240 mg with ipilimumab at 1 mg/kg every 3 weeks for 4 doses, then nivolumab at 480 mg every 4 weeks; nivolumab at 240 mg every 2 weeks for 6 doses, then nivolumab at 480 mg every 4 weeks; or chemotherapy with or without targeted therapies.

The dual primary end points were PFS per blinded independent central review (BICR) in the combination arm in the first-line setting and PFS per BICR in the combination arm compared with nivolumab alone across all lines of therapy.

The trial included 2 parts for those with MSI-H or dMMR status, and patients must have had an ECOG performance status of 0 or 1. In part 1, patients needed to have histologically confirmed recurrent or metastatic CRC that is not amenable to surgery, irrespective of prior treatment history with chemotherapy and/or targeted agents. In part 2, patients needed to have histologically confirmed recurrent or metastatic CRC not amenable to surgery with no prior treatment history with chemotherapy and/or targeted agents for metastatic disease.

Those with active, known, or suspected autoimmune disease; a history of interstitial lung disease or pneumonitis; or a known history of human immunodeficiency virus or known acquired immunodeficiency syndrome could not be enrolled in the study.

“The study met its primary end point demonstrating statistically significant and clinically meaningful improvement in PFS with [nivolumab] plus [ipilimumab] over chemotherapy. The median PFS was not reached in the [nivolumab] plus [ipilimumab] arm and was 5.9 months in the chemo arm with a hazard ratio of 0.21. There was an early separation of the PFS curve starting at approximately 3 months and so the 24 months PFS rates…were 72% vs 14%,” Thierry Andre, MD, professor of medical oncology, University Pierre et Marie Curie, head, Medical Oncology Department, St. Antoine Hospital, Paris, said during a presentation on these findings.²

A total of 80% of patients had any-grade treatment-related adverse effects (TRAEs) in the combination arm vs 94% in the chemotherapy arm, and grade 3/4 toxicities were noted in 23% and 48%. Serious TRAEs were observed in 19% and 19%, respectively, with grade 3/4 toxicity in 16% and 16%.

References

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 instability–high or mismatch repair deficient metastatic colorectal cancer. News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. https://shorturl.at/wzKMY
2. 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. Presented at the 2024 Gastrointestinal Cancers Symposium; San Francisco, CA, January 18-20, 2024. LBA 768.