Nivolumab Plus Ipilimumab Improves PFS in Patients with MSI-H/dMMR mCRC

Recent results from the phase 3 CheckMate-8HW trial evaluating nivolumab (Opdivo; Bristol Myers Squibb) with ipilimumab (Yervoy; Bristol Myers Squibb) compared to chemotherapy—mFOLFOX-6 or FOLFIRI with or without bevacizumab or cetuximab—as a first-line treatment for patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) indicated a statistically significant and clinically meaningful improvement in progression-free survival (PFS). The findings indicate that patients treated with nivolumab plus ipilimumab had a 79% reduction in the risk of disease progression or death compared to those treated with chemotherapy alone.

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Nivolumab is a programmed death-1 (PD-1) immune checkpoint inhibitor designed to utilize the body’s immune system to help restore anti-tumor immune response. It was the first PD-1 inhibitor to receive regulatory approval and is approved in more than 65 countries, according to a press release.

Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and is a negative regulator of T-cell activity. The blockage of CTLA-4 augments T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. The inhibition of CTLA-4 signaling can also reduce T-cell regulatory cell function, which potentially contributes to the general increase in T-cell responsiveness, including anti-tumor immune response. In March 2011, ipilimumab 3mg/kg monotherapy was approved by the FDA for the treatment of patients with unresectable or metastatic melanoma. Further, the combination regimen of nivolumab and ipilimumab was the first immune-oncology combination to receive regulatory approval for the treatment of metastatic melanoma.

The CheckMate-8HW (NCT04008030) trial was a randomized, open-label phase 3 trial which evaluated nivolumab plus ipilimumab compared to nivolumab alone or chemotherapy (either mFOLFOX-6 or FOLFIRI with or without bevacizumab or cetuximab) in patients with MSI-H or dMMR mCRC. A total of 830 patients were enrolled in the study and were randomly assigned to received either nivolumab monotherapy (240 mg once every 2 weeks for 6 doses followed by 480mg of nivolumab once every 4 weeks), nivolumab plus ipilimumab (240 mg of nivolumab plus 1mg/kg ipilimumab once every 3 weeks for 4 doses, followed by 480 mg of nivolumab once every 4 weeks), or chemotherapy.

The study’s primary endpoint was PFS and the secondary safety and efficacy endpoints included overall survival (OS). According to the findings, improvements in PFS were noted beginning at the 3-month mark and were sustained through the trial’s duration; however, median PFS was not reached in the nivolumab plus ipilimumab cohort (95% CI: 38.4-NE) versus the chemotherapy cohort, which was 5.9 months (95% CI: 4.4-7.8). Study findings were presented at the 2024 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, which was held January 18, 2024, to January 20, 2024.

“Patients with MSI-H/dMMR metastatic colorectal cancer are less likely to benefit from chemotherapy,” said Thierry Andre, MD, head of the Medical Oncology Department, Sorbonne University and Hospital Saint-Antoine, Paris, France, said in a press release. “An impressive improvement in PFS and sustained benefit beginning at 3 months was observed with [nivolumab] plus [ipilimumab] versus chemotherapy in this trial. These results demonstrate the meaningful efficacy of this combination with practice-changing potential for this patient population.”

In addition, there were no new safety signals identified for the combination of nivolumab plus ipilimumab, which is consistent with prior data. Adverse events were manageable with established protocols. Grades 3 and 4 treatment-related adverse events (TRAEs) occurred in approximately 23% of patients in the nivolumab plus ipilimumab cohort, and 48% of patients in the chemotherapy cohort. TRAE-related discontinuation was approximately 17% in the nivolumab plus ipilimumab cohort and 32% in the chemotherapy cohort.

The CheckMate-8HW trial is ongoing to further assess both the PFS and OS in patients receiving nivolumab plus ipilimumab compared to nivolumab alone across all lines of therapy.

“…Today, with these data from CheckMate-8HW, we showed that [nivolumab] plus [ipilimumab] reduced the risk of disease progression or death by an unprecedented 79%,” said Dana Walker, MD, MSCE, vice president, global program lead, gastrointestinal and genitourinary cancers, Bristol Myers Squibb, said in the press release. “These results build on the benefit of [nivolumab] and [ipilimumab] in MSI-H/dMMR metastatic colorectal cancer as previously demonstrated in CheckMate-142 and reinforce our commitment to exploring the potential of these therapies to help more patients in need."

Reference

Bristol Myers Squibb. 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. January 20, 2024. Accessed January 22, 2024. https://news.bms.com/news/corporate-financial/2024/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-