In patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer, the addition of ipilimumab to nivolumab significantly improves progression-free survival (PFS) compared to nivolumab alone, while maintaining health-related quality of life (HRQoL).
In the phase III CheckMate 8HW study, nivolumab plus ipilimumab significantly prolonged PFS, improved HRQoL across key functioning domains, and reduced symptom burden compared to chemotherapy in previously untreated patients with MSI-H/dMMR metastatic colorectal cancer.1,2 At ESMO GI 2025, updated HRQoL outcomes comparing nivolumab plus ipilimumab vs nivolumab monotherapy were presented.3
The open-label, multi-centre, phase III CheckMate 8HW study randomised patients with unresectable or metastatic colorectal cancer and MSI-H or dMMR status according to local testing to receive (2:2:1) nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy with or without targeted therapies. Dual primary endpoints included PFS for nivolumab plus ipilimumab vs chemotherapy in the first-line setting, and PFS for nivolumab plus ipilimumab vs nivolumab alone regardless of prior systemic therapy for metastatic disease. HRQoL was a key secondary endpoint, assessed by using the EORTC QLQ-C30, EORTC QLQ-CR29, and EQ-5D-3L questionnaires.
Of 582 patients treated with either nivolumab plus ipilimumab or nivolumab monotherapy, baseline questionnaire completion rates ranged from 91% to 95% and were balanced between treatment arms. Median follow-up was 47.0 months.
Nivolumab plus ipilimumab significantly prolonged PFS compared to nivolumab alone in patients with centrally confirmed MSI-H/dMMR metastatic colorectal cancer across all lines of therapy (median: not reached vs 39.3 months; HR[95% CI]: 0.62[0.48-0.81], p= 0.0003).
HRQoL improvements were observed in both treatment arms across all key EORTC QLQ-C30 functioning domains and symptoms, with numerically greater benefit in the combination arm. Mean improvements from baseline in clinically important scales, including global health status (GHS), physical functioning, and fatigue, were observed with nivolumab plus ipilimumab and nivolumab alone. Patients treated with nivolumab plus ipilimumab group exceeded the prespecified minimally important change (MIC) from baseline for GHS and fatigue starting at week 21, whereas those on nivolumab monotherapy exceeded the MIC for fatigue only from week 85. Similarly, both treatment groups demonstrated mean improvements from baseline in EQ-5D-3L visual analogue scale (VAS) and utility index (UI) scores. The MIC threshold for VAS was reached at week 21 in the combination arm and at week 61 with nivolumab alone. For the UI, both arms exceeded the MIC from week 29 onwards. HRQoL improvements were generally sustained throughout the treatment period.
The addition of ipilimumab to nivolumab not only improved PFS but also maintained HRQoL compared to nivolumab monotherapy in patients with centrally confirmed MSI-H/dMMR metastatic colorectal cancer. Mean improvements from baseline in clinically important EORTC QLQ-C30 scales were observed, exceeding thresholds for MIC in GHS and fatigue by week 21. Additionally, mean improvements from baseline in the EQ-5D-3L VAS and UI scales were observed, exceeding thresholds for MIC in VAS by week 21 and UI by week 29. HRQoL improvements were maintained throughout treatment period.
References
1. André T, Elez E, Van Cutsem E, et al. Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer. N Engl J Med 2024;391(21):2014-26.
2. Lonardi S, André T, Arnold D, et al. 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 S1):S1-S2.
3. Elez E, André T, Lonardi S, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): health-related quality of life (HRQoL) analyses from CheckMate 8HW. Presented at ESMO GI 2025; Abstract 1O.
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