First-line treatment with nivolumab plus ipilimumab has shown a significant benefit in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer, according to results from the phase III CheckMate 8HW trial. The study demonstrated a 79% reduction in the risk of disease progression or death compared to chemotherapy.
The findings, presented at the 2024 ASCO Gastrointestinal Cancers Symposium, highlight the potential of this immunotherapy doublet as a new first-line option for this patient population. "An unmet need still exists for these patients," said Dr. Thierry André, Professor of Medical Oncology at the Sorbonne Université in Paris and Head of the Medical Oncology Department at the Saint Antoine Hospital, Assistance Publique Hôpitaux de Paris.
Progression-Free Survival Benefit
CheckMate 8HW met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival with nivolumab/ipilimumab over chemotherapy. At a median follow-up of 24.3 months, median progression-free survival was not reached in the nivolumab/ipilimumab arm and was 5.9 months with chemotherapy, resulting in a hazard ratio of 0.21 (P < .0001). The 24-month progression-free survival rate was 72% vs 14%.
The benefit was described as "robust and consistent" across all sensitivity analyses, including progression-free survival by blinded independent central review (hazard ratio = 0.32). Consistent benefit was also observed across all subgroups, including patients with KRAS or NRAS mutations and those with baseline liver, lung, or peritoneal metastases.
Study Design
The CheckMate 8HW trial randomly assigned 303 previously untreated patients with MSI-H/dMMR metastatic colorectal cancer 2:1 to receive nivolumab plus ipilimumab (n = 202) or chemotherapy (n = 101). MSI-H/dMMR status was centrally confirmed in 255 patients (84%) and balanced between the arms. The nivolumab/ipilimumab regimen included nivolumab at 240 mg every 2 weeks for six doses, followed by nivolumab at 480 mg every 4 weeks. The chemotherapy cohort received investigator’s choice of modified FOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan); 75% of these patients also received bevacizumab or cetuximab.
At data cutoff, 21% of patients in the nivolumab/ipilimumab arm and 7% of those in the chemotherapy arm were still on treatment. For 19% vs 69%, respectively, treatment was discontinued because of disease progression.
Safety Profile
The safety profile of nivolumab plus ipilimumab was distinct from chemotherapy, with fewer grade 3/4 treatment-related adverse events. There were two treatment-related deaths in the nivolumab/ipilimumab arm: one was cardiac-related and one remains mostly unexplained. Patients receiving immunotherapy had more pruritus and hypothyroidism, whereas those on chemotherapy had more gastrointestinal complaints, neutropenia, alopecia, neuropathy, and other toxicities commonly related to chemotherapy.
Expert Commentary
"This is the first phase III study demonstrating that combination immunotherapy with nivolumab plus ipilimumab is better than chemotherapy for patients with MSI-H/dMMR metastatic colorectal cancer. With fewer serious adverse events that are different than the standard chemotherapy-associated side effects, this treatment combination may offer a new first-line treatment option," added Pamela Kunz, MD, an ASCO Expert.
