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

Leonard Depotte ¹, Paula Nay ², Christophe Borg ^3,4

¹Department of Medical Oncology, Univ Paris Est Creteil, INSERM, IMRB, AP-HP, Hopital Henri Mondor, Creteil, Île-de-France, France.
²Department of Medical Oncology, Hôpital Saint-Antoine, Paris, Île-de-France, France.
³Medical Oncology, Hôpital Jean Minjoz, Besancon, France.
⁴TIMc, UMR 1098, Besancon, Bourgogne-Franche-Comté, France.
⁵EFS, INSERM, UMR RIGHT, University of Franche-Comté, Besancon, Bourgogne-Franche-Comté, France.
⁶Methodology and Quality of Life Unit in Oncology, Besançon University Hospital Center, Besancon, France.
⁷Department of Digestive Oncology, University Hospital Centre Nantes, Nantes, Pays de la Loire, France.
⁸Medical Oncology, Centre Leon Berard, Lyon, Rhône-Alpes, France.
⁹Department of Hepato-Gastroenterology, CHU Poitiers, Poitiers, France.
¹⁰Department of Medical Oncology, Institut de Recherche en Cancérologie de Montpellier, Montpellier, Languedoc-Roussillon, France.
¹¹Department of Medical Oncology, Hospital Franco-Britannique, Fondation Cognacq-Jay, Paris, France.
¹²GERCOR, Paris, France.
¹³Department of Radiology, University Hospital of Henri Mondor, Créteil, France.
¹⁴Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de recherche Saint Antoine, Sorbonne Universite, Paris, Île-de-France, France.
¹⁵GERCOR, Paris, France romain.cohen@aphp.fr.

⁰Department of Medical Oncology, Univ Paris Est Creteil, INSERM, IMRB, AP-HP, Hopital Henri Mondor, Creteil, Île-de-France, France.

Journal for Immunotherapy of Cancer +

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May 19, 2025

View abstract on PubMed

Summary

Nivolumab-ipilimumab shows durable efficacy in microsatellite instability-high/mismatch-repair deficient metastatic colorectal cancer. Growth differentiation factor 15 (GDF-15) is a promising biomarker for sarcopenia and survival outcomes in this patient group.

Area Of Science

Oncology
Immunotherapy
Gastroenterology

Background

Sarcopenia and elevated growth differentiation factor 15 (GDF-15) are associated with poor outcomes in cancer patients.
The efficacy of nivolumab-ipilimumab in chemoresistant metastatic colorectal cancer (mCRC) with microsatellite instability and/or mismatch-repair deficiency (MSI/dMMR) needs further investigation.
This study explores the interaction between sarcopenia, GDF-15, and nivolumab-ipilimumab treatment in this specific mCRC population.

Purpose Of The Study

To evaluate the efficacy of nivolumab-ipilimumab in patients with chemoresistant MSI/dMMR mCRC.
To assess the prognostic role of sarcopenia and GDF-15 levels in this patient cohort.
To investigate the relationship between GDF-15, sarcopenia, and treatment response.

Main Methods

The NIPICOL phase II trial included 57 patients with MSI/dMMR chemoresistant mCRC.
Patients received nivolumab-ipilimumab for 3 months, followed by nivolumab monotherapy for 9 months.
Sarcopenia was assessed by skeletal muscle mass index (SMI) via CT scan, and GDF-15 levels were measured at baseline and follow-up points.

Main Results

After a median follow-up of 60.4 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 65.3% and 73.3%, respectively.
High baseline GDF-15 levels (≥2500) were linked to poorer 3-year PFS (56.3% vs. 81.7%) and OS (61.4% vs. 84.5%).
Sarcopenia was present in 65.0% of patients at baseline; 55% of those with sarcopenia reversed it by 12 months, showing higher baseline GDF-15 and greater GDF-15 decrease.

Conclusions

Nivolumab-ipilimumab demonstrates sustained efficacy in chemoresistant MSI/dMMR mCRC after 5 years.
GDF-15 is a promising biomarker for predicting sarcopenia and survival in this population.
The findings support GDF-15 as a valuable prognostic marker in advanced colorectal cancer treated with immunotherapy.

Keywords:

Colorectal Cancer Immune Checkpoint Inhibitor Immunotherapy Microsatellite