In the phase III CheckMate 8HW trial, previously untreated patients with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) nonresectable or metastatic colorectal cancer derived significant benefit from an immunotherapy doublet, with nivolumab plus ipilimumab reducing the risk of disease progression or death by 79%, as compared with chemotherapy, in the first-line setting. These initial results were reported at the 2024 ASCO Gastrointestinal Cancers Symposium.¹

“The study met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival with nivolumab plus ipilimumab over chemotherapy with or without cetuximab or bevacizumab in the population of patients with centrally confirmed MSI-H/dMMR tumoral status,” said Thierry André, MD, Professor of Medical Oncology at the Sorbonne Université, Paris, and Head of the Medical Oncology Department at the Saint Antoine Hospital, Assistance Publique Hôpitaux de Paris.

Thierry André, MD

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 (HR) 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%,” he said.

The benefit of combination immunotherapy was “robust and consistent” across all the sensitivity analyses, Dr. André added, including progression-free survival by blinded independent central review in all randomly assigned first-line patients with locally determined MSI-H/dMMR tumoral status (HR = 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.

“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 from the standard chemotherapy-­associated side effects, this treatment combination may offer a new first-line treatment option,” said Pamela Kunz, MD, an ASCO Expert.

Pamela Kunz, MD

Need for Better Treatment

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 KEYNOTE-177, the progression-free survival rate was 48% at 2 years and 34% at 5 years.^2,3 “Less progression-free survival benefit was seen with pembrolizumab monotherapy vs chemotherapy with or without targeted therapy in patients with KRAS or NRAS mutations, compared with the overall study population. An unmet need still exists for these patients,” he commented.

Based on the previous phase II CheckMate 142 study,⁴ nivolu­mab alone or with ipilimumab is approved in many countries for previously treated patients with MSI-H/dMMR metastatic colorectal cancer. The 64-month follow-up of CheckMate 142 in first-line treatment was also presented at the 2024 ASCO Gastrointestinal Cancers Symposium, showing that median progression-free survival has still not been reached.⁵ At 5 years, 55% of patients were progression-free, and 67% were alive, the investigators reported.

The current phase III CheckMate 8HW study, evaluating nivolumab plus ipilimumab, vs nivolumab alone and vs chemotherapy with or without cetuximab or bevacizumab, in previously untreated patients with metastatic MSI-H/dMMR colorectal cancer. Dr. André reported the first results from the prespecified interim analysis for the combination vs chemotherapy in the first-line setting. The comparison to nivolumab alone will be presented once the required number of events has occurred.

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 was balanced between the arms. (A third arm received nivolumab alone, for a comparison of nivolumab plus ipilimumab vs nivolumab monotherapy; data are still being collected for that comparison.)

Nivolumab at 240 mg and ipilimumab at 1 mg/kg were given every 3 weeks for four doses, then nivolumab was given at 480 mg every 4 weeks. The chemotherapy-alone cohort received investigator’s choice of modified FOLFOX6 (fluorouracil, leucovorin, oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, irinotecan); 75% of this arm also received bevacizumab or cetuximab.

At data cutoff, 21% of the nivolumab/ipilimumab arm and 7% of the chemotherapy arm remained on treatment; for 19% vs 69%, respectively, treatment was discontinued because of disease progression. The median duration of treatment was 13.5 months in the combination arm and 4.0 months in the chemotherapy arm.

“Nivolumab plus ipilimumab had a different safety profile as compared with chemotherapy, with fewer grade 3 or 4 treatment-related adverse events, and safety was consistent with the established profiles of each individual drug,” Dr. André reported. There were, however, two treatment-related deaths in the nivolumab/ipilimumab arm: one from cardiac toxicity and the other related to pneumonitis, he added. Patients receiving immunotherapy had more pruritus and hypothyroidism, whereas those on chemotherapy had more gastrointestinal complaints, neutropenia, alopecia, and neuropathy.

In closing, Dr. André shared these comments: “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.” 

DISCLOSURE: Dr. André reported financial relationships with Amgen, Aptitude Health, Astellas, AstraZeneca/MedImmune, Bristol Myers Squibb, Gilead Sciences, Gritstone Oncology, GlaxoSmithKline, Merck & Co, Merck Serono, Seagen Nordics, Servier, Takeda, and Inspirna. Dr. Kunz has had a consulting or advisory role with BMS, HUTCHMED, Ipsen, Isotope Technologies Munich SE (ITM), and Novartis (Advanced Accelerator Applications); and has received research funding from Novartis (Advanced Accelerator Applications) and RayzeBio.

REFERENCES

1. André T, Elez E, Van Cutsem E, et al: Nivolumab plus ipilimumab vs chemotherapy as first-line treatment for microsatellite instability–high/mismatch repair–deficient metastatic colorectal cancer: First results of the CheckMate 8HW study. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract LBA768. Presented January 20, 2024.

2 André T, Shiu KK, Kim TW, et al: Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 383:2207-2218, 2020.

3. Shiu K, André T, Kim TW, et al: Pembrolizumab versus chemotherapy in microsatellite instability–high/mismatch repair–deficient metastatic colorectal cancer: 5-year follow-up of the randomized phase III KEYNOTE-177 study. ESMO Congress 2023. Abstract LBA32. Presented October 22, 2023.

4. Lenz HJ, Van Cutsem E, Limon LM, et al: First-line nivolumab plus low-dose ipilimumab for microsatellite instability–high/mismatch repair–deficient metastatic colorectal cancer: The phase II CheckMate 142 study. J Clin Oncol 40:161-170, 2022.

5. Lenz HJ, Overman MJ, Van Cutsem E, et al: First-line nivolumab + ipilimumab in patients with microsatellite instability–high/mismatch repair–deficient metastatic colorectal cancer: 64-month follow-up from CheckMate 142. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract 97. Presented January 20, 2024.