In the phase III CheckMate 8HW trial, previously untreated patients with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) metastatic colorectal cancer derived significant benefit from an immunotherapy doublet of nivolumab plus ipilimumab in the first-line setting, which reduced the risk of disease progression or death by 79% compared with chemotherapy. Investigators reported these findings at the 2024 ASCO Gastrointestinal Cancers Symposium (Abstract LBA768).
The first results from the prespecified interim analysis for nivolumab plus ipilimumab vs chemotherapy as a first-line approach were presented by Thierry André, MD, 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. Dr. André, who led the pivotal KEYNOTE-177 trial that established pembrolizumab monotherapy as the first-line standard of care, acknowledged that better therapies are still needed in this patient population.
Thierry André, MD
“An unmet need still exists for these patients,” he said.
“CheckMate 8HW met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival with nivolumab/ipilimumab over chemotherapy,” said Dr. André. 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). “There was an early and sustained separation of the progression-free survival curve, starting at about 3 months. The 24-month progression-free survival rate was 72% vs 14%,” Dr. André reported.
He described the benefit as being “robust and consistent” across all the sensitivity analyses, including progression-free survival by blinded independent central review in all randomly assigned first-line patients (hazard ratio = 0.32). He further noted the consistent benefit across all subgroups, including patients with KRAS or NRAS mutations and those with baseline liver, lung, or peritoneal metastases.
More About CheckMate 8HW
CheckMate 8HW 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. A third cohort received nivolumab alone; this comparison will be presented at a later date, upon the occurrence of the required number of events, Dr. André said.
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 and Adverse Events
“Nivolumab plus ipilimumab had a different safety profile as compared with chemotherapy, with fewer grade 3/4 treatment-related adverse events, and safety was consistent with the established profiles of each individual drug,” Dr. André said. There were, however, two treatment-related deaths in the nivolumab/ipilimumab arm: one was cardiac-related and one remains mostly unexplained, he added. 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.
“It remains crucial to identify predictive factors that can aid in the clinical decision-making process when choosing between immune checkpoint inhibitor monotherapy or combination [therapy].... Identifying patients who would benefit from a dual immunotherapy combination aligns with optimizing treatment choices to help deliver the best possible outcome for these patients,” concluded Dr. André.
The CheckMate 8HW study is currently ongoing to assess the additional dual primary endpoint of progression-free survival for the nivolumab/ipilimumab combination vs nivolumab alone.
ASCO Expert Perspective
“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.
Disclosure: Dr. Andre reported financial relationships with Amgen, Bristol Myers Squibb, GlaxoSmithKline, Merck, Merck Serono, Pierre Fabre, Roche/Genentech, Sanofi, Seagen, Servier, Ventana Medical Systems, Aptitude Health, Astellas, AstraZeneca/Medimmune, GamaMabs Pharma, Gilead Sciences, Gritstone Bio, Kaleido Biosciences, MSD Oncology, Nordic Bioscience, Takeda/Lundbeck, Tesaro, Transgene, and Inspirna.
