544P - Nivolumab plus ipilimumab in microsatellite instability high (MSI)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC): Final survival analysis and prognostic evaluation of GDF-15 in the phase II GERCOR NIPICOL study

Background

The NIPICOL phase 2 study evaluated 1-year therapy with nivolumab plus ipilimumab for MSI/dMMR mCRC patients (pts). GDF-15 is a cancer-associated cachexia biomarker that has been associated with poor survival and immunotherapy failure in melanoma and lung cancer. Here, we report the final survival results and GDF-15 evaluation analysis.

Methods

A total of 57 MSI/dMMR mCRC chemoresistant pts received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W for 4 cycles, then nivolumab 3 mg/kg Q2W until progression or a maximum of 20 cycles. GDF-15 levels were assessed at baseline and week 12 and skeletal muscle mass index (SMI) was determined via CT-scans at baseline and month 12 (M12) to assess sarcopenia following Martin’s criteria. Objectives were to evaluate disease control rate at 12 weeks (primary endpoint), progression-free survival per iRECIST (iPFS), and overall survival (OS).

Results

Overall median follow-up was 60.4 months (95%CI 59.0-63.1). The 1-, 3-, and 5-year iPFS rates were respectively 75.4% (95%CI 62.0-84.6), 70.0% (95%CI 56.2-80.1), and 61.3% (95%CI 46.8-72.9), with OS rates of 84.1% (95%CI 71.7-91.4), 75.1% (95%CI 61.6-84.4), and 71.1% (95%CI 57.2-81.2). 31 out of 48 (65%) pts evaluable for SMI displayed sarcopenia at baseline, with no detrimental survival impact. Of the 20 sarcopenic pts evaluable for SMI at M12, nine (45%) still had sarcopenia. GDF-15, at a 2500pg/mL threshold, was associated with survival: the 1-year iPFS and OS rates were 84.8% and 90.8% for GDF-15 <2500, compared to 68.8% and 75.0% for GDF-15 >2500, respectively. Sarcopenic pts had higher median GDF-15 at baseline: 2206.1 vs 1434.4pg/mL for non-sarcopenic pts. Pts who reversed sarcopenia by M12 experienced a significant decrease in GDF-15 levels (-69.8%), suggesting a direct correlation between changes in GDF-15 and sarcopenia.

Conclusions

Nivolumab plus ipilimumab demonstrates consistent efficacy after 5 years of follow-up in MSI/dMMR mCRC pts, despite sarcopenia. GDF-15 confirms to be a promising prognostic biomarker for cachexia and survival, making it a potential target for future therapies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Gercor.

Funding

Gercor; Bristol-Myers Squibb.

Disclosure

C. Borg: Financial Interests, Advisory Board: Bayer, Roche; Financial Interests, Invited Speaker: MSD, Pierre Fabre. J. Bennouna: Financial Interests, Personal, Advisory Board: Roche, MSD, AstraZeneca, AMGEN, Bristol Myers Squibb, Servier; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, MSD, AstraZeneca, Bristol Myers Squibb, Servier, Janssen-Cilag; Financial Interests, Institutional, Coordinating PI: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Local PI: AMGEN, Sanofi, Daiichi Sankyo, MSD, Brsitol Myers Squibb; Non-Financial Interests, Member: Institut Francophone de Cancérologie Thoracique, GERCOR. C. de la Fouchardiere: Financial Interests, Personal, Advisory Board: Merck, Roche, Lilly, Bayer, Amgen, MSD, Servier, Pierre Fabre Oncologie, Bristol-Myers Squibb, Incyte, Daiichi Sankyo, Astellas; Financial Interests, Personal, Invited Speaker: Ipsen, Eisai, Servier, MSD, Daichi Sankyo; Financial Interests, Institutional, Coordinating PI: Pierre Fabre Oncologie, Servier; Non-Financial Interests, Principal Investigator: Amgen, Daichi Sankyo, MSD. D. Tougeron: Financial Interests, Personal, Advisory Board: AstraZeneca, Sanofi, AMGEN, MSD, Roche, Servier, Pierre Fabre, BMS, Bayer; Non-Financial Interests, Member of Board of Directors: Federation francophone de cancerologie digestive. T. Mazard: Financial Interests, Personal, Advisory Board: PIERRE FABRE, PIERRE FABRE, SERVIER; Financial Interests, Personal, Invited Speaker: SERVIER, SANOFI, PIERRE FABRE; Financial Interests, Personal, Other, Development of clinical cases for regional meetings: MERCK SERONO; Financial Interests, Personal, Writing Engagement: GALAPAGOS; Financial Interests, Institutional, Coordinating PI: AMGEN; Non-Financial Interests, Advisory Role, development of guidelines about molecular testing in colorectal cancers: INCA; Other, travel grant: PIERRE FABRE, MERCK SERONO, SANOFI, MSD. B. Chibaudel: Financial Interests, Personal, Advisory Board: Amgen, Bayer, BeiGene, Biocartis, Lilly, Merck, MSD, Pfizer, Pierre Fabre, Roche, SeqOne, Sanofi, Servier, Takeda. C. Tournigand: Non-Financial Interests, Leadership Role: GERCOR; Non-Financial Interests, Advisory Role: Fondation APHP. T. André: Financial Interests, Personal, Advisory Board, Advosiry Board on February 12, 2021: Astellas pharma; Financial Interests, Personal, Advisory Board, Advisory Board on February 2021: Kaleido Biosciences; Financial Interests, Personal, Invited Speaker, and advisory board 2021: Amgen; Financial Interests, Personal, Invited Speaker, Ivited speaker in a symposuim december 2020: AstraZeneca; Financial Interests, Personal, Advisory Board, and consultant fees and consultant contract 2021 and 2022: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory board in Janaury 2020: Clovis; Financial Interests, Personal, Advisory Board, Advisory board in january 2020: Gritstone Oncology; Financial Interests, Personal, Advisory Board, Advisory board 2020: Haliodx; Financial Interests, Personal, Advisory Board, and consultant fees/consultant contract and invited speaker: MSD Oncology; Financial Interests, Personal, Invited Speaker, and other: Pierre Fabre; Financial Interests, Personal, Invited Speaker, in an symposuim in 2020: Roche; Financial Interests, Personal, Invited Speaker, in a meeting in 2019: Ventana; Financial Interests, Personal, Invited Speaker, In a educational meeting in 2019: Sanofi; Financial Interests, Personal, Advisory Board, in a symposuim in 2020: Servier; Financial Interests, Personal, Advisory Board, Consultant with personnal fees and invited speaker: Servier; Financial Interests, Personal, Advisory Board, in 2019: GSK; Financial Interests, Personal, Invited Speaker, in 2020 and 2021: GSK; Financial Interests, Personal, Invited Speaker, Virtual symposuimLecture: 1 MSI-H CRC: Implementation of Immunotherapy in clinical practice (30 minutes) – (this will be pre-recorded)Q&A – Live Q&A – (10 minutes) (on July 2, 2021): MSD Oncology; Financial Interests, Personal, Invited Speaker, June 2022: Sanofi; Financial Interests, Personal, Advisory Board, Contract 2021, 2022, 2023: Merck & Co., Inc; Financial Interests, Personal, Advisory Board, Contrat 2019, 2020, 2021, 2022: BMS; Financial Interests, Personal, Advisory Board, Contract 2021: Gritstone Oncologie; Financial Interests, Personal, Invited Speaker, June 2022 and June 2023 during ESMO GI meeting: Seagen; Financial Interests, Personal, Writing Engagement, Contract of consulting 2021 and 2022 and 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, September 2022: GSK, Seagen; Financial Interests, Personal, Writing Engagement, Contract of consulting 2022 and 2023: GSK; Financial Interests, Personal, Writing Engagement, Contract of consulting 2022: Nordic Pharma; Financial Interests, Personal, Invited Speaker, October 2022: Merck Serono; Financial Interests, Personal, Other, Educationnal in 2022: Roche; Financial Interests, Personal, Other, Contract of consulting 2020, 2021, 2022,2023: Servier; Financial Interests, Personal, Advisory Board, Gilead Sciences Global GI Advisory Board on January 18, 2023: Aptitude Health, Glilead; Financial Interests, Personal, Other, Consultant like member of the SGNTUC-029 Steering Committee (the “Steering Committee”) Services related to the Company’s Study titled “An Open-label Randomized Phase 3 Study of Tucatinib in Combination with Trastuzumab and mFOLFOX6 versus mFOLFOX6 given with or without either Cetuximab or Bevacizumab as First-line Treatment for Subjects with HER2+ Metastatic Colorectal Cancer” (collectively, the “Services”).Including teleconferences and board preparation befor the board (6h)Participation of the Board on September 2022 inParis, September 10, 2022 MOUNTAINEER-03 Steering Committee Meeting during ESMO: Seagen; Financial Interests, Personal, Other, Consultant like member of the to be a member of the Colorectal Program Scientific Advisory Committee (SAC). In charges for reviewing V940 Pembro on Engagezone (as per your contract in ref).and also an inrtview about Pembrolizumab for MSI/dMMR Metastaic colo-rectal 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, but also formation for the takeda team, and consultant for TakedaContract beetween 1 sept 2023 and 15 october 2024: Takeda; Financial Interests, Personal, Advisory Board, Board Meeting (October 19, 2023): Abbvie; Financial Interests, Personal, Invited Speaker, Emerging Role of Biomarkers in Gastrointestinal Cancers Webcast Engagement reference : Wenibar: MSD; Financial Interests, Personal, Invited Speaker, Preparation and resentation at the Seagen ESMO GI 2023 Scientific Exchange HER2 as an emerging target for the treatment of mCRC in the context MOUNTAINEER03: Seagen; Financial Interests, Personal, Advisory Board, Fruquitinib: Takeda; Financial Interests, Personal, Invited Speaker, Oral speaker in a Symposuim 2 and 3 February 2024, GI ancer MSI: MSD; Financial Interests, Personal, Invited Speaker, Management of CRC: Aptitude Health; Financial Interests, Personal, Invited Speaker, symposuim JFHOD GI CancerPARIS15 03-2024: Servier; Financial Interests, Institutional, Coordinating PI, PI Garnet study: GSK; Financial Interests, Institutional, Coordinating PI, Keynote 164 and 171 and 811 and C08: MSD; Financial Interests, Institutional, Coordinating PI, BMS CA209-8HW, BMS CA209-142, BMS CA209-577: BMS; Financial Interests, Institutional, Coordinating PI, SPOTLIGHT study: Astellas; Financial Interests, Personal, Steering Committee Member, and internationnal PI (trial chair Solstice study): Servier; Financial Interests, Personal, Steering Committee Member, MOUNTAINEER and MOUNTAINEER-03 study (PI for France) 2022, 2023: Seagen; Financial Interests, Institutional, Local PI, A RANDOMIZED, OPEN-LABEL, PHASE 2 STUDY OF BOTENSILIMAB (AGEN1181) AS MONOTHERAPY AND IN COMBINATION WITH BALSTILIMAB (AGEN2034) OR INVESTIGATOR’S CHOICE STANDARD OF CARE (REGORAFENIB OR TRIFLURIDINE AND TIPIRACIL) FOR THE TREATMENT OF REFRACTORY METASTATIC COLORECTAL CANCER: Agenus; Financial Interests, Institutional, Local PI, Study wuith traztuzumab derxtecan in mCRC C study: Daichi; Non-Financial Interests, Member of Board of Directors, Investigator: Gercor group; Non-Financial Interests, Member of Board of Directors, President since october 2022: ARCAD Foundation; Other, DMC Meeting by Teleconference on November 7, 2023 5member of steering comittee of A randomized Phase 2 Study of ompenaclid versus placebo in combination with FOLFIRI plus bevacizumab in patients withpreviously treated RAS mutant advanced or metastatic colorectal cancer (RGX-202-002): Inspira. R. Cohen: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Exeliom Biosciences, Enterome Biosciences; Financial Interests, Personal, Invited Speaker: Pierre Fabre, MSD Oncology, Servier, AstraZeneca; Financial Interests, Personal, Research Grant: Servier Institute. All other authors have declared no conflicts of interest.