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Clinical Trial
. 2025 May 19;13(5):e011220.
doi: 10.1136/jitc-2024-011220.

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 , Aurélia Meurisse  5   6 , Julie Henriques  5   6 , Jaafar Bennouna  7 , Christelle De La Fouchardière  8 , David Tougeron  9 , Thibault Mazard  10 , Benoist Chibaudel  11 , Christophe Tournigand  1   12 , Dewi Vernerey  5   6 , Frédéric Pigneur  13 , Thierry Andre  12   14 , Romain Cohen  15   14
Affiliations
Clinical Trial

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 et al. J Immunother Cancer. .

Abstract

Background: Sarcopenia 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 methods: 57 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).

Results: After 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.

Conclusion: 1-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.

Keywords: Colorectal Cancer; Immune Checkpoint Inhibitor; Immunotherapy; Microsatellite.

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Conflict of interest statement

Competing interests: RC declares honoraria from AstraZeneca, Bristol Myers Squibb, MSD Oncology, Mylan Medical, Pierre Fabre, Servier, and travel fees from Amgen, Bristol Myers Squibb, MSD Oncology, Mylan Medical and Servier. TA reported attending advisory board meetings and/or receiving consulting fees from AbbVie, Aptitude Health, Bristol Myers Squibb, Gritstone Oncology, Gilead, GlaxoSmithKline, Merck & Co. Inc., Nordic Oncology, Seagen, Servier, Takeda, and Transgène; honoraria for lectures, presentations, or speakers bureaus from Bristol Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Merck Serono, Pierre Fabre, Roche, Sanofi, Seagen, Servier, and Takeda; support for meetings from Merck & Co. Inc., and a DMC member role for Inspirna. DT declares honoraria from AstraZeneca, Bristol Myers Squibb, Takeda, MSD Oncology, BMS, Roche, AMGEN, Merck Serono, Pierre Fabre, Servier, and travel fees from MSD Oncology, Pierre Fabre, Roche and Servier.

Figures

Figure 1
Figure 1. Study flowchart. GDF-15, growth differentiation factor 15; MSI/dMMR, microsatellite instability and/or mismatch-repair deficiency; M3, 3 months; M12, 12 months; N, number of patients.
Figure 2
Figure 2. Swimmer plot. BRAF, BRAF V600E mutation; PD, disease progression.
Figure 3
Figure 3. Progression-free survival by iRECIST (A) and overall survival (B) in the MSI/dMMR population. iPFS, iRECIST progression-free survival; iRECIST, immune Response Evaluation Criteria In Solid Tumors; MSI/dMMR, microsatellite instability and/or mismatch-repair deficiency; OS, overall survival.
Figure 4
Figure 4. Progression-free survival (A) and overall survival (B) in the sarcopenic (red) and non-sarcopenic group (blue) at baseline. iPFS, iRECIST progression-free survival; iRECIST, immune RECIST; OS, overall survival; RECIST, Response Evaluation Criteria In Solid Tumors.
Figure 5
Figure 5. Progression-free survival (A) and overall survival (B) according to baseline GDF-15 levels. GDF-15, growth differentiation factor 15; iPFS, iRECIST progression-free survival; iRECIST, immune RECIST; OS, overall survival; RECIST, Response Evaluation Criteria In Solid Tumors.
See this image and copyright information in PMC

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