Journal Article

Interplay between sarcopenia, GDF-15, and the efficacy of nivolumab plus ipilimumab in patients with mismatch repair deficient metastatic colorectal cancer: final survival analysis of the phase II GERCOR NIPICOL study

Nay, Paula, De La Fouchardière, Christelle, Pigneur, Frédéric, Bennouna, Jaafar, Mazard, Thibault, Depotte, Leonard, Chibaudel, Benoist, Tournigand, Christophe, Meurisse, Aurélia, Henriques, Julie, Borg, Christophe, Vernerey, Dewi, Cohen, Romain, Tougeron, David, Andre, Thierry

2025

Overview

BackgroundSarcopenia and growth differentiation factor 15 (GDF-15) are linked to poor cancer survival. In this exploratory analysis, we evaluated their interaction with nivolumab-ipilimumab efficacy in chemoresistant metastatic colorectal cancer (mCRC) harboring microsatellite instability and/or mismatch-repair deficiency (MSI/dMMR), based on the final survival analysis of the NIPICOL phase II trial.Patients and methods57 patients with MSI/dMMR chemoresistant mCRC received nivolumab-ipilimumab for 3 months (3M), then, nivolumab alone for 9M. Skeletal muscle mass index (SMI) was evaluated by CT scan at baseline and 12M to assess sarcopenia. GDF-15 levels were assessed at baseline and 3M. Main endpoints were overall survival (OS) and immune Response Evaluation Criteria In Solid Tumors progression-free survival (iPFS).ResultsAfter excluding three patients not confirmed as MSI/dMMR by central review, the overall median follow-up was 60.4 months. The 3-year and 5 year iPFS rates were 72.0% and 65.3%, with OS rates of 77.5% and 73.3%, respectively. Among 49 patients with evaluable GDF-15, high-baseline GDF-15 was associated with poorer survival: 3-year iPFS rate of 56.3% for GDF-15≥2500 versus 81.7% for GDF-15<2500 (PFS HR=2.45, 95% CI 0.91 to 6.55), 3-year OS rates of 61.4% versus 84.5% (OS HR=2.08, 95% CI 0.70 to 6.22). Of the 48 evaluable patients for SMI, 31 (65.0%) displayed sarcopenia at baseline. 11 out of 20 (55%) patients with baseline sarcopenia and assessed for SMI at 12M, reversed sarcopenia by 12M. They had higher baseline GDF-15 levels and greater GDF-15 decrease by 3M (delta mean change: −69.8% vs −40.3%) compared with patients who remained sarcopenic.Conclusion1-year nivolumab-ipilimumab demonstrates consistent efficacy after 5-year follow-up in an MSI/dMMR chemoresistant mCRC population. GDF-15 confirms to be a promising biomarker for sarcopenia and survival.Trial registration number NCT03350126.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group
• Subject: Adult / Aged / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Clinical Cancer Immunotherapy / Colorectal Cancer / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - mortality / Colorectal Neoplasms - pathology / DNA Mismatch Repair / Female / Growth Differentiation Factor 15 - metabolism / Humans / Immune Checkpoint Inhibitor / Immunotherapy / Ipilimumab - pharmacology / Ipilimumab - therapeutic use / Male / Microsatellite / Middle Aged / Nivolumab - pharmacology / Nivolumab - therapeutic use / Original Research / Sarcopenia / Survival Analysis