Nivolumab Plus Ipilimumab Shows Sustained PFS Benefit in MSI-H/dMMR mCRC

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Nivolumab (Opdivo) in combination with ipilimumab (Yervoy) demonstrated a significant improvement in terms of progression-free survival (PFS) vs chemotherapy or nivolumab monotherapy in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer, according to data from the phase 3 CheckMate-8HW trial (NCT04008030) presented during the 2025 ASCO Annual Meeting.1

At the August 28, 2024, data cutoff, with a median follow-up of 47 months (range, 16.7-60.5), first-line nivolumab plus ipilimumab (n = 171) yielded a median PFS of 54.1 months (95% CI, 54.1-not evaluable) compared with 5.9 months (95% CI, 4.4-7.8) with chemotherapy (n = 84; HR, 0.21; 95% CI, 0.14-0.31). The benefit of combination immunotherapy extended beyond first-line treatment, outperforming both chemotherapy and nivolumab monotherapy in PFS and PFS after subsequent therapy (PFS2) across all lines of therapy.

These updated findings not only reinforce the combination’s position as the preferred first-line therapy in this biomarker-defined patient population, but also provide confirmatory evidence following its FDA approval in April 2025 for adult and pediatric patients aged 12 and older with MSI-H/dMMR mCRC. Notably, PFS2 remained significantly improved in the combination arm, even in the setting of high crossover from chemotherapy (46%) to immunotherapy.2

“First-line nivolumab/ipilimumab continued to demonstrate improved PFS and PFS2 vs chemo with longer follow-up in patients with mismatch repair-deficient metastatic colorectal cancer. Nivolumab plus ipilimumab also demonstrated a superior PFS vs nivolumab,” Heinz-Josef Lenz, MD, said during the presentation. "[We] also showed that nivolumab/ipilimumab demonstrated an improved PFS2 vs nivolumab across all lines of therapy in patients with mismatch repair-deficient metastatic colon cancer.”

About the CheckMate-8HW Trial

CheckMate-8HW randomly assigned 839 patients with histologically confirmed MSI-H/dMMR mCRC to receive either nivolumab plus ipilimumab, nivolumab alone, or investigator’s choice of chemotherapy. Random assignment followed a 2:2:1 ratio.3 Patients were enrolled based on local confirmation of MMR deficiency, with 84% to 86% centrally confirmed across arms.

Eligible patients had histologically confirmed recurrent or metastatic MSI-H/dMMR colorectal cancer, an ECOG performance status of 0 or 1, and no surgical treatment options. In part 1 of the study, patients could have received prior systemic therapy; in part 2, they were treatment naive.

The dual primary end points were PFS per blinded independent central review (BICR) for nivolumab/ipilimumab vs chemotherapy in the first-line setting, and for nivolumab plus ipilimumab vs nivolumab monotherapy across all treatment lines. Additional end points included PFS2, overall response rate (ORR) by BICR, health-related quality of life, and overall survival.

According to Lenz, a professor of medicine in the University of Southern California Norris Comprehensive Cancer Center Departments of Medicine and Preventive Medicine, the section head of gastrointestinal oncology in the Division of Medical Oncology at Keck School of Medicine, “the baseline characteristics shown were well balanced among all 3 cohorts.”

The median age of patients in the nivolumab/ipilimumab arm was 62 years (range, 21-86), 63 years in the nivolumab arm (range, 20-87), and 65 years in the chemotherapy arm (range, 26-87).1 Across these arms, 54%, 52%, and 46%, respectively, of patients had an ECOG performance status of 0. A substantial proportion of patients (57% in the nivolumab plus ipilimumab and nivolumab arms, and 77% in the chemotherapy arm) were treatment naive. The median duration of treatment was longest for the nivolumab plus ipilimumab group at 20.5 months, compared with 16.4 months for nivolumab and 5.1 months for chemotherapy.

Additional Efficacy and Safety Data

In the first-line subgroup, only 16% of patients treated with nivolumab plus ipilimumab required subsequent systemic therapy, compared with 73% of patients in the chemotherapy arm. Even with high crossover from chemotherapy to immunotherapy, PFS2 significantly favored the combination arm. Across all treatment lines, median PFS for nivolumab plus ipilimumab was not reached compared with 39.3 months for nivolumab alone (HR, 0.62; 95% CI, 0.48-0.81; P =.0003), and PFS2 showed a 43% reduction in risk of progression or death for the combination regimen. The 3-year PFS2 rate was 80% with the combination compared with 66% with nivolumab alone.

The ORR was higher with nivolumab/ipilimumab (71%) than with nivolumab alone (58%). A statistically significant improvement in ORR was seen in the nivolumab/ipilimumab arm combination arm vs nivolumab alone arm (difference in ORR, 13% [95% CI, 5%-21%]; P = .0011).

In terms of safety, 22% of patients in the combination arm and 14% in the monotherapy arm experienced grade 3 or 4 treatment-related adverse events (TRAEs). Most TRAEs emerged within the first 6 months of therapy and were manageable. No new safety signals were observed in the extended follow-up and overall, the safety profile of the combination remained consistent with previous reports and the known safety profiles of each agent.

These data from the expanded analyses of CheckMate-8HW strengthen the case for the immunotherapy combination as a new standard of care for this patient population.

“Putting these results together, they provide further evidence to support nivolumab/ipilimumab as the standard of care treatment option for patients with mismatch repair-deficient colorectal cancer,” Lenz concluded.

References

1. Lenz HJ, Lonardi S, Elez E, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) or NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): expanded analyses from CheckMate 8HW. J Clin Oncol. 2025;43(suppl 17):3501. doi:10.1200/JCO.2025.43.16_suppl.3501
2. FDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancer. News release. FDA. April 8, 2025. Accessed May 31, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancer?utm_medium=email&utm_source=govdelivery
3. A study of nivolumab, nivolumab plus ipilimumab, or investigator's choice chemotherapy for the treatment of participants with deficient mismatch repair (dMMR)/microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC) (CheckMate 8HW). ClinicalTrials.gov. Updated October 27, 2023. Accessed May 31, 2025. https://www.clinicaltrials.gov/study/NCT04008030