Patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) had better progression-free survival (PFS) with first-line combination immunotherapy consisting of nivolumab plus ipilimumab compared with chemotherapy. Results from the phase 3 CheckMate 8HW study show that nivolumab plus ipilimumab reduced the risk of disease progression or death by 79% compared with chemotherapy with or without a targeted agent and support this immunotherapy combination as a new standard-of-care first-line treatment option, according to lead investigator Thierry André, MD, who presented the data at the 2024 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.
These exciting results from the CheckMate 8HW study have potentially practice-changing implications for previously untreated patients with MSI-H/dMMR mCRC.
Patients with MSI-H/dMMR mCRC have poor outcomes with standard chemotherapy with or without additional targeted therapies. Despite global approval of pembrolizumab monotherapy in the first-line setting for patients with MSI-H/dMMR mCRC, the 2-year and 5-year progression-free survival (PFS) rates are 48% and 34%, respectively, so better treatment options represent an unmet need, said Dr André, of the Sorbonne Université and Hôpital Saint Antoine, Assistance Publique Hôpitaux de Paris. “These exciting results from the CheckMate 8HW study have potentially practice-changing implications for previously untreated patients with MSI-H/dMMR mCRC,” he said. In many countries, nivolumab alone or in combination with ipilimumab has already been approved in previously treated patients with MSI-H/dMMR mCRC, based on the phase 2 CheckMate 142 study, he noted.
Although the study compared agents across different lines of therapy, the data reported were from a prespecified interim analysis in the first-line setting. Eligible patients had histologically confirmed unresectable or metastatic CRC. They were randomized 2:2:1 to:
- nivolumab, 240 mg every 2 weeks for 6 doses; followed by nivolumab, 480 mg every 4 weeks
- nivolumab, 240 mg, plus ipilimumab, 1 mg/kg every 3 weeks for 4 doses; followed by nivolumab, 480 mg every 4 weeks
- investigator’s choice of chemotherapy (FOLFOX or FOLFIRI) with or without bevacizumab or cetuximab
Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or a maximum treatment duration of 2 years.
Of the 839 patients enrolled, 303 were randomized in the first-line setting to nivolumab plus ipilimumab (n=202) or chemotherapy (n=101). Median patient age was 62 years in the immunotherapy combination arm and 65 years in the chemotherapy arm. About 85% overall had centrally confirmed MSI-H/dMMR disease; about one-fourth in each arm had a BRAF, KRAS, or NRAS mutation. Nearly 90% had a prior surgery related to their current cancer. Sites of metastases were liver in 38% and 42%, lung in 22% and 25%, and peritoneum in 42% and 43% of the nivolumab/ipilimumab and chemotherapy arms, respectively.
The median duration of treatment was 13.5 months in the nivolumab plus ipilimumab arm versus 4.0 months in the chemotherapy arm. In the nivolumab plus ipilimumab arm, median duration of treatment for each component was 13.5 months for nivolumab and 2.1 months for ipilimumab. Among patients randomized to chemotherapy, 66 (75%) received a biologic agent (56 received bevacizumab and 10 received cetuximab). Treatment is ongoing in 21% of the nivolumab/ipilimumab arm and 7% of the chemotherapy arm. Some 31% and 0%, respectively, completed treatment.
At a median follow-up of 24.3 months, median PFS had yet to be reached with nivolumab/ipilimumab compared with 5.9 months with chemotherapy (P<.0001). The separation of the PFS curves between the 2 treatment arms occurred early and was sustained throughout the follow-up. The 24-month PFS rates were 72% for nivolumab plus ipilimumab versus 14% for chemotherapy.
Nivolumab plus ipilimumab had a different safety profile compared with chemotherapy, with fewer grade 3/4 treatment-related adverse events (23% vs 48% with chemotherapy), and safety was consistent with the established profiles of each individual drug. Grade 3/4 nonendocrine immune-mediated adverse events (IMAEs) in the immunotherapy group included diarrhea/colitis (5%), hepatitis (3%), and rash and pneumonitis (2% each). Endocrine IMAEs included adrenal insufficiency (4%), hypothyroidism/thyroiditis (2%), and hypophysitis (3%). No new safety signals were identified.
“This is the first phase 3 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,” agreed Pamela Kunz, MD, from Smilow Cancer Hospital at Yale-New Haven, CT.