Opdivo (nivolumab) plus Yervoy (ipilimumab) improved progression-free survival (PFS) compared to Opdivo alone in patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC), according to the CheckMate 8HW trial presented at the 2025 ASCO GI Cancer Symposium.
Among patients with centrally confirmed MSI-H or dMMR status, data showed a median PFS that was not reached with Opdivo plus Yervoy versus 39.3 months with Opdivo monotherapy, meaning that more than half of patients in the study group had not experienced disease progression. The PFS rates in each respective arm across this population were 76% versus 63% at 12 months, 71% versus 56% at 24 months and 68% versus 51% at 36 months. Among all randomly assigned patients, the median PFS was 54.1 months versus 18.4 months, respectively.
PFS outcomes generally favored the Opdivo/Yervoy arm across all lines of therapy and prespecified patient subgroups based on factors including age, sex, ECOG performance status and liver metastases.
In the MSI-H/dMMR tumor population, the objective response rate (ORR) was 71% using Opdivo plus Yervoy versus 58% using Opdivo alone. Of note, complete responses (CRs) and partial responses (PRs) occurred in 30% and 40% of the Opdivo/Yervoy arm and 28% and 30% of the Yervoy monotherapy arm, respectively. Additionally, the median time to response (TTR) in each arm was 2.8 months versus 2.8 months, and the median duration of response (DOR) was not reached versus not reached.
“[Opdivo] plus [Yervoy] demonstrated statistically significant and clinically meaningful improvement in PFS versus [Opdivo] in patients with centrally confirmed [MSI-H or dMMR metastatic CRC] across all lines [of therapy]. [There were] early and sustained separation of PFS curves after the first scan,” Dr. Thierry André, a 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, France, stated in the presentation. “These results, combined with the previously reported superior PFS with [Opdivo/Yervoy] versus chemotherapy in the first-line setting, establish [Opdivo] plus [Yervoy] as a new standard of care for patients with MSI-H/dMMR metastatic [CRC].”
In the phase 3 trial, patients were randomly assigned to receive Opdivo monotherapy (353 patients), Opdivo plus Yervoy (354 patients) or investigator’s choice of modified folinic acid plus fluorouracil and oxaliplatin (mFOLFOX6) or folinic acid plus fluorouracil and irinotecan (FOLFIRI) with or without Avastin (bevacizumab) or Erbitux (cetuximab; 132 patients).
The trial’s primary end points were PFS for Opdivo/Yervoy versus chemotherapy in the first-line setting and PFS for Opdivo versus Opdivo/Yervoy across all lines of treatment. Secondary end points included ORR, health-related quality of life (HRQOL) and safety.
Patients with histologically confirmed unresectable or metastatic CRC, MSI-H or dMMR status, no prior treatment with immunotherapy and an ECOG performance status of 0 or 1 were eligible for enrollment on the trial.
Of note, 352 patients in the Opdivo/Yervoy arm and 351 in the Opdivo monotherapy arm received study treatment, with ongoing treatment at the time of analysis reported for 6% and 4% of patients, respectively. Additionally, 49% and 57% of patients discontinued treatment, mostly due to disease progression (23% versus 39%). The median duration of treatment in each arm was 20.5 months and 16.4 months, with deaths reported in 29% and 42% of patients.
Data showed HRQOL improvements in the Opdivo/Yervoy arm. The mean changes in HRQOL scores were typically positive in both arms, with outcomes in the Opdivo/Yervoy arm reaching the trial’s prespecified threshold for meaningful change from baseline starting at week 21.
Any-grade treatment-related side effects occurred in 81% and 71% of patients who received Opdivo/Yervoy and Opdivo monotherapy, respectively. Common any-grade treatment-related side effects in each arm included itching (26% versus 18%), diarrhea (20% versus 17%) and underactive thyroid (17% versus 9%). Additionally, the most common grade 3 (severe) or higher treatment-related side effect in each arm was adrenal insufficiency (2% versus less than 1%).
Regarding immune-mediated side effects, the most common any-grade non-endocrine events in the combination and monotherapy arms, respectively, included rash (7% versus 6%), diarrhea or colitis (6% versus 4%), and hepatitis (4% versus 1%). Additionally, the most common endocrine events in each arm included underactive thyroid or inflammation of the thyroid gland (18% versus 9%), overactive thyroid (12% versus 5%) and adrenal insufficiency (10% versus 3%).
Reference:
First results of nivolumab (NIVO) plus ipilimumab (IPI) versus NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. Dr. Thierry André, et al. J Clin Oncol.
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