Nivolumab Plus Ipilimumab Improves HRQOL Vs Nivolumab Alone in MSI-H/dMMR mCRC

The addition of ipilimumab (Yervoy) to nivolumab (Opdivo) not only led to a significant improvement in progression-free survival (PFS) over nivolumab alone, but it also resulted in better health-related quality of life (HRQOL) and reduced symptoms in patients with microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC), according to additional analyses from the phase 3 CheckMate 8HW trial (NCT04008030).¹

At the 2025 ESMO Gastrointestinal (GI) Cancers Congress, it was shared that of the 582 total patients treated with the doublet or with nivolumab alone on the trial, questionnaire completion rates ranged from 91% to 95% at baseline. Investigators leveraged the EORTC QLQ-C30, EORTC QLQ-CR29, and EQ-5D-3L instruments to examine mean changes from baseline vs week 21. Improvements in functioning and decreases in symptoms were observed for both treatment groups across all key functional domains and symptoms, with slightly greater improvements in the nivolumab/ipilimumab arm.

When they analyzed the mean change from baseline in global health status (GHS) scores, they found that in both treatment groups, GHS scores showed a trend for improvement starting at week 7. In the doublet arm, GHS scores remained at, or near, the minimally important change from baseline starting at week 21; the nivolumab-alone arm had slightly less improvement.

They also examined the mean change from baseline in fatigue scores. In both treatment groups, fatigue scores demonstrated a trend for improvement starting at week 7. In the doublet arm, fatigue scores exceeded the minimally important change from baseline starting at week 21 vs week 85 in the nivolumab-alone arm. Improvements in fatigue scores from baseline were numerically better in those who received the doublet vs those given the monotherapy starting at week 21; however, the analysis was not designed to formally compare the treatment arms.

When looking at mean change from baseline in ED-5D-3L visual analogue scores, which is a measure of patients’ self-reported health, the score demonstrated a trend for improvement starting at week 7 in both treatment groups. In the doublet arm, the visual analogue scores exceeded the minimally important change from baseline starting at week 21; for the monotherapy arm, the minimally important change from baseline was exceeded starting at week 61.

Lastly, they assessed mean change from baseline in EQ-5D-3L utility index scores. In both treatment groups, these scores indicated a trend for improvement starting at week 7. Those in both the nivolumab/ipilimumab and nivolumab-alone arms exceeded the minimally important change from baseline starting at week 29.

“The addition of nivolumab to ipilimumab significantly improved PFS compared [with] nivolumab immunotherapy while maintaining HRQOL,” Elena Elez MD, PhD, said in a presentation of the data. Elez is a medical oncology consultant at Vall d’Hebron University Hospital and senior investigator at Vall d’Hebron Institute of Oncology in Barcelona, Spain.

Checking Out CheckMate 8HW: Eligibility, Treatment, End Points

The randomized, multicenter, open-label, phase 3 study enrolled patients with histologically confirmed unresectable or mCRC who had MSI-H/dMMR status by local testing, had not been previously exposed to immunotherapy, and had an ECOG performance status of 0 or 1.

They were randomly assigned in a 2:2:1 fashion to receive 240 mg of nivolumab every 2 weeks for 6 doses followed by 480 mg of nivolumab every 4 weeks (n = 353); 240 mg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses followed by 480 mg of nivolumab every 4 weeks (n = 354); or investigator’s choice of chemotherapy in the form of mFOLFOX6 or FOLFIRI with or without bevacizumab (Avastin) or cetuximab (Erbitux; n = 132). Treatment continued until progressive disease, unacceptable toxicity, withdrawn consent, or the maximum treatment duration of 2 years.

Patients were stratified based on number of prior lines of treatment (0 vs 1 vs ≥2) and primary tumor location (right vs left). The trial had dual primary end points: PFS by blinded independent central review (BICR) for the doublet vs chemotherapy in the first-line setting and PFS by BICR for the doublet vs nivolumab alone across all lines—all in those with MSI-H/dMMR mCRC. Other end points included safety, PFS2, objective response rate by BICR, overall survival, and HRQOL.

What Came Before

Previous data indicated that nivolumab plus ipilimumab (n = 296) yielded to a statistically significant and clinically meaningful improvement in PFS vs nivolumab alone (n = 286) in those with centrally confirmed MSI-H/dMMR mCRC across all lines of therapy. The median PFS was not reached (95% CI, 53.8-not evaluable [NE]) with the doublet vs 39.3 months (95% CI, 22.1-NE) with nivolumab alone (HR, 0.62; 95% CI, 0.48-0.81; P = .0003).² The 12-, 24-, and 36-month PFS rates in the doublet arm were 76%, 71%, and 67%, respectively; in the monotherapy arm, these respective rates were 62%, 55%, and 51%.

Elez noted that the PFS benefit with the combination vs the nivolumab alone also proved to be consistent in all randomly assigned patients, at a median of 54.1 months vs 18.4 months, respectively (HR, 0.64; 95% CI, 0.52-0.79).¹

In April 2025, the FDA granted accelerated approval to nivolumab plus ipilimumab for the treatment of adult and pediatric patients at least 12 years of age with dMMR or MSI-H unresectable or mCRC based on CheckMate 8HW data.³ The combination was also cleared in the European Union and other countries for this indication.¹ Elez added that previously, first-line nivolumab plus ipilimumab improved HRQOL in key functioning scales and reduced symptoms compared with chemotherapy.

Breaking Down the Basics of the Current Analysis

For the analysis shared during the 2025 ESMO GI Cancers Congress, Elez shared HRQOL findings for nivolumab plus ipilimumab compared with nivolumab alone across all lines of treatment. The data cutoff was August 28, 2024, and the median follow-up was 47.0 months (range, 16.7-60.5).

These analyses included those with centrally confirmed MSI-H/dMMR mCRC who had received at least 1 dose of the combination or nivolumab monotherapy. They were evaluated with EORTC QLQ-C30, EORTC QLQ-CR29, and EQ-5D-3L questionnaires, which were answered at baseline, defined as before day 1 of cycle 1; day 1 cycle 2; day 1 cycle 3; then every other cycle thereafter, or every 8 weeks. “As a reminder, the C30 refers to [patients with] cancer, the CR29 is specifically for [patients with] CRC, and the EQ-5D-3L refers to all illness beyond patients with cancer,” Elez explained.

The questionnaires were scored per their scoring instructions, and data were summarized through descriptive analyses, which included mean scores and changes from baseline, standard deviation of the means, medians, interquartile range, and minimum and maximum values at each time point.

Disclosures: Elez disclosed serving in consulting or advisory roles for Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cureteq, Jannsen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Repare Therapeutics, RIN Institute, Roche-Genentech, Sanofi, Seagen, Servier, and Takeda. Honoraria was received from Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cureteq, Janssen, Lilly, Medscape, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Pierre Fabre, Repare Therapeutics, RIN Institute, Roche-Genentech, Sanofi, Seagen, Servier, and Takeda. Research funding (institution) was provided by AbbVie, Amgen, Array BioPharma, AstraZeneca, Bayer, BeiGene, Biontech, BioNTech, Boehringer Ingelheim, Boehringer Ingelheim (Spain), Bristol Myers Squibb, Celgene, Daiichi Sankyo, Debiopharm Group, Gercor, HailoDx, Huchison MediPharma, Iovance Biotherapeutics, Janssen-Cilag, Janssen R&D, MedImmune, Menarini, Merck, Merck Sharp & Dohme, Merus NV, Mirati, Novartis, Nouscom, PharmaMar, Pfizer, PledPharma, RedX Pharma, Pierre Fabre, Roche-Genentech, Sanofi, Scandion Oncology, Seagen, Servier, Sotio, Taiho, and WntResearch. Travel or accommodation expenses were provided by Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cureteq, Janssen, Lilly, Medscape, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Pierre Fabre, Repare Therapeutics, RIN Institute, Roche-Genentech, Sanofi, Servier, Seagen, and Takeda. The study was funded by Bristol Myers Squibb.

References

1. Elez E, Andre T, Lonardi S, et al. Nivolumab plus ipilimumab vs nivolumab monotherapy for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: health-related quality of life analyses from CheckMate 8HW. Presented at: 2025 ESMO Gastrointestinal Cancers Congress; July 2-5, 2025; Barcelona, Spain. Abstract 1O.
2. Lonardi S, André T, Arnold D, et al. 2O Health-related quality of life (HRQoL) with first-line (1L) nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC): CheckMate 8HW. Ann Oncol. 2024;35(suppl 1):S1-S2. doi:10.1016/j.annonc.2024.05.013
3. FDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancer. FDA. April 8, 2025. Accessed July 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancer