Abstract 116P
Background
STRATEGIC-1 GERCOR-PRODIGE trial, a landmark randomized phase III study, compares multi-line standard treatment strategies in patients (pts) with KRAS/NRAS/BRAF wt mCRC. The treatment starting with FOLFIRI-cetuximab, followed by mFOLFOX6-bev showed higher response rates and a trend toward better median overall survival (OS) exceeding 3 years. However, the median disease control duration (DDC) was similar in both arms. Biomarkers to stratify treatment options are warranted. Here, we conducted an exploratory study of the impact of ANG-2 protein levels in clinical outcomes in pts enrolled in STRATEGIC-1.
Methods
263 mCRC pts were randomized 1:1 to FOLFIRI-cetuximab followed by mFOLFOX6-bev (Arm A) or OPTIMOX-bev followed by FOLFIRI-bev followed by EGFR-mab +/- irinotecan (Arm B). ANG-2 was measured via ELISA in plasma collected at baseline.
Results
ANG-2 was assessable in 131 pts (71/60 in Arm A/B). The baseline characteristics of the biomarker cohort resembled the overall cohort. Median ANG-2 value was 3331pg/mL (range: 31–24823), with similar levels between Arm A and B (Wilcoxon test P=0.994). Using restricted cubic spline analysis, a cutoff of 6000ng/mL was determined. Pts with ANG-2 levels above 6000pg/mL (ANG-2high; n=40) had median OS enhanced compared to those with ANG-2low (n=91; HR=2.62 95%Cl 1.71-4, P<0.001). In the ANG-2low group, Arm A/B had objective response rates (ORR) of 81.6%/77.5% (P=0.630). In the ANG-2high group, Arm B had a lower ORR (47.4%) than Arm A (83.3%; P=0.022). An interaction test between baseline ANG-2 and allocated strategies revealed a differential effect on PFS across ANG-2 levels subgroups. The benefit effect of anti-EGFR first-line therapy on PFS was more important in pts with ANG-2high (HR=0.60, 95%Cl 0.30-1.22) than in pts with ANG-2low (HR=1.23, 95%Cl 0.79-1.93, P=0.038). Median OS for arm A/B was 22.8/15.4 months in the ANG-2high group and 43.4/41.5 months in the ANG-2low group.
Conclusions
Baseline ANG-2 level is a promising biomarker to guide anti-EGFR or bev prescription in RAS/BRAF wt unresectable mCRC.
Clinical trial identification
EudraCT 2013-001928-19; NCT01910610.
Editorial acknowledgement
Editorial assistance was provided by Magdalena Benetkiewicz, with funding from GERCOR.
Legal entity responsible for the study
GERCOR.
Funding
Roche, GERCOR.
Disclosure
C. Borg: Financial Interests, Personal and Institutional, Research Grant: Roche, Bayer, Molecular Partner; Financial Interests, Personal, Advisory Board: Bayer, Servier, Molecular Partner; Financial Interests, Personal, Invited Speaker: Pierre Fabre, MSD, Servier, AstraZeneca. T. André: Financial Interests, Personal, Advisory Board, Advisory 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, Invited 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 an educational meeting in 2019: Sanofi; Financial Interests, Personal, Advisory Board, in a symposuim in 2020: Servier; Financial Interests, Personal, Expert Testimony, 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 symposium, Lecture 1, MSI-H CRC: Implementation of Immunotherapy in clinical practice (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, Invited Speaker, Contract of consulting 2021 and 2022 and 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, September 2022: GSK, Seagen; Financial Interests, Personal, Invited Speaker, Contract of consulting 2022 and 2023: GSK; Financial Interests, Personal, Invited Speaker, Contract of consulting 2022: Nordic Pharma; Financial Interests, Personal, Invited Speaker, October 2022: Merck Serono; Financial Interests, Personal, Other, Educational 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 before the board (6h)Participation of the Board on September 2022 in Paris, September 10, 2022 MOUNTAINEER-03 Steering Committee Meeting during ESMO: Seagen; Financial Interests, Personal, Other, Consultant like 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 interview 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 Takeda Contract between 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, Invited Speaker, PI Garnet study: GSK; Financial Interests, Institutional, Invited Speaker, Keynote 164 and 171 and 811 and C08: MSD; Financial Interests, Institutional, Invited Speaker, BMS CA209-8HW, BMS CA209-142, BMS CA209-577: BMS; Financial Interests, Institutional, Invited Speaker, SPOTLIGHT study: Astellas; Financial Interests, Personal, Invited Speaker, and international PI (trial chair Solstice study): Servier; Financial Interests, Personal, Invited Speaker, MOUNTAINEER and MOUNTAINEER-03 study (PI for France) 2022, 2023: Seagen; Financial Interests, Institutional, Invited Speaker, 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, Invited Speaker, Study wuith traztuzumab derxtecan in mCRC C study: Daiichi; 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 committee of A randomized Phase 2 Study of ompenaclid versus placebo in combination with FOLFIRI plus bevacizumab in patients with previously treated RAS mutant advanced or metastatic colorectal cancer (RGX-202-002): Inspira. V. Bourgeois: Financial Interests, Personal, Advisory Role: Servier; Financial Interests, Personal, Speaker’s Bureau: Servier; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Servier. C. Louvet: Financial Interests, Personal, Advisory Board: MSD, Roche, Amgen; Financial Interests, Personal, Invited Speaker: Servier. C. Tournigand: Non-Financial Interests, Leadership Role: GERCOR; Non-Financial Interests, Advisory Role: Fondation APHP. E. Shacham Shmueli: Financial Interests, Personal, Advisory Role: MSD, Medison; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Merck Serono. F. Ghiringhelli: Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Institutional, Funding: AstraZeneca, MedImmune; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Amgen, Roche/Genentech. B. Chibaudel: Financial Interests, Personal, Expert Testimony: Amgen, BeiGene, Biocartis, Lilly, Merck, MSD, Pfizer, Pierre Fabre, Roche, SeqOne, Sanofi, Servier, Takeda; Financial Interests, Personal, Advisory Board: Bayer. All other authors have declared no conflicts of interest.