7P - Molecular targeted therapies based on metastatic site in first-line treatment for colorectal cancer patients: An ARCAD pooled analysis

Background

Targeted therapies (TGTs), inhibiting (i) EGFR or VEGF, are used in first-line (1L) treatment (trt) of metastatic colorectal cancer (mCRC) patients (pts). EGFRi is recommended in RAS wild-type (WT) and left sided primary tumor (LT). There is no predictive biomarker for VEGFi. The magnitude of TGTs effect might differ based on metastatic (met) site. ARCAD database contains individual patient data (IPD) of trials that evaluated TGTs. We evaluated the predictive value of met site for TGTs.

Methods

IPD from 8 trials comparing chemotherapy (CT) ± TGT were pooled. TGTs effect was evaluated in mCRC pts with either single site (SS) or multiple sites (MS) in groups: A) CT ± VEGFi and B) CT ± EGFRi. Endpoints were overall survival (OS) and progression free survival (PFS) assessed using Kaplan-Meier estimates and Cox models stratified by trial.

Results

2728 pts in group A and 3681 pts in group B were pooled. Pts characteristics were well balanced. In group A, 1020 pts had SS and 1708 pts MS. OS and PFS benefit (bnf) of VEGFi was found in the whole population. In SS pts, bnf of VEGFi was not found in pts with non liver metastases (mets). In MS pts, bnf of VEGFi was not found in pts with peritoneal with or without liver mets. In group B, 1173 pts had SS and 2508 pts MS. OS and PFS bnf of EGFRi was found in pts with KRAS WT and LT. However, in this subgroup, bnf of EGFRi was not found in pts with lymph node (LN), peritoneal and SS lung mets. In KRAS mutated (MT) SS pts, OS bnf of EGFRi was found in pts with lung (N=55) and LN (N=26) mets. After adjustment for multiple comparisons, OS benefit remained in lung SS. Table: 7P

HR (95% CI) for OS and PFS comparing TGT+CT vs CT

Conclusions

Efficacy of TGTs in 1L trt of mCRC depended on met sites. Bnf of VEGFi was not found in SS non liver mets and in MS with peritoneal mets. Bnf of EGFRi was not found in KRAS WT and LT with LN, peritoneal and SS lung mets. In KRAS MT, OS bnf of EGFRi was found in pts with SS lung mets based on a limited sample size. Further studies are ongoing to confirm this finding.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Professors Thierry André and Aimery de Gramont from ARCAD Foundation.

Funding

ARCAD Foundation.

Disclosure

R. Cohen: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Exeliom Biosciences, Enterome Biosciences; Financial Interests, Personal, Invited Speaker: Pierre Fabre, MSD Oncology, Servier; Financial Interests, Personal, Research Grant: Servier Institute. B. Chibaudel: Financial Interests, Personal, Advisory Role: Amgen, Bayer, BeiGene, Biocartis, Lilly, Merck, MSD, Pfizer, Pierre Fabre, Revolution Medicines, Roche, SeqOne, Sanofi, Servier, Takeda. H. Hurwitz: Financial Interests, Personal, Stocks/Shares: Roche. N. Tebbutt: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Beigene, MSD, Takeda; Financial Interests, Personal, Invited Speaker: Amgen, Roche. T. Maughan: Financial Interests, Personal, Advisory Role: AstraZeneca, Perspectum, Nordic Pharma, Ground truth labs. E. Van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; Financial Interests, Institutional, Research Grant: Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. C. Bokemeyer: Financial Interests, Personal, Advisory Board, advisory boards and speaker: Merck Serono; Financial Interests, Personal, Invited Speaker: Roche Pharma, AOK Germany; Financial Interests, Personal, Advisory Board: Bayer Healthcare, AstraZeneca, Oncology Drug Consult CRO, Jansen Cilag, BioNTech; Financial Interests, Personal, Advisory Board, Boards attended and lectures given: Sanofi Aventis; Financial Interests, Personal, Advisory Board, and lectures given: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker, organisation for medical education: Med Update; Financial Interests, Institutional, Invited Speaker, our department is involved in several clinical trials sponsored by industry and cooperative groups where we hold participants roles and local PI roles and PI roles: more than 95 clinical trials; Non-Financial Interests, Personal, Member of Board of Directors: DGHO, Northern German Society of Internal Medicine; Non-Financial Interests, Personal, Leadership Role: Hamburg Cancer Society, National Network of German Cancer Centers (DKH); Non-Financial Interests, Personal, Advisory Role, Board of DGHO Advisors: DGHO. R.A. Adams: Financial Interests, Personal, Speaker’s Bureau: Servier, Takeda, Amgen; Financial Interests, Personal, Advisory Role: Takeda, Seagen, Bayer; Financial Interests, Institutional, Funding: AZ, MSD, Jazz Pharma. J.R. Zalcberg: Financial Interests, Personal, Leadership Role: ICON Group, Lipotek, PRAXIS; Financial Interests, Personal, Stocks/Shares: Biomarin, Ophthea, Amarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead, Madrigal Pharmaceuticals, UniQure, Zogenix, Orphazyme, Moderna Therapeutics, TWST, Novavax, Teladoc; Financial Interests, Personal, Other: Gilead Sciences, MSD Oncology, Viatris, MSD Oncology, ICON Group, Praxis; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme, Specialized Therapeutics, CEND, Deciphera, Revolution Medicine, FivePHusion, Genorbio, 1Global, Novatech, Alloplex Biotherapeutics Inc, Oncology Republic; Financial Interests, Personal, Research Grant: BMS, AstraZeneca, Pfizer, Iqvia, Mylan, Ipsen, Eisai, Medtronic, MSD Oncology, Servier. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd., Sanofi K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Amgen K.K., Pfizer Japan Inc., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Roche Diagnostics K.K., FALCO Biosystems Ltd. C. Cremolini: Financial Interests, Personal, Advisory Board: Roche, MSD, Pierre Fabre, Nordic Pharma, Takeda; Financial Interests, Personal, Invited Speaker: Bayer, Servier, Merck Serono; Financial Interests, Personal, Expert Testimony: Amgen; Financial Interests, Institutional, Invited Speaker: Roche, Bayer, Servier, Merck, Seagen, Hutchinson. Q. Shi: Financial Interests, Personal, Advisory Board: Regeneron Pharmaceuticals, Inc., Kronos Bio; Financial Interests, Personal, Advisory Board, DSMB: Hoosier Cancer Research Network, Yiviva Inc., Mirati Therapeutics Inc; Financial Interests, Institutional, Research Grant: Genentech, BMS, Novartis, Johnson & Johnson. 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 symposium 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 January 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 symposium 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 symposium in 2020: Servier; Financial Interests, Personal, Expert Testimony, Consultant with personal 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 (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, Contract 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, Gilead; 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 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 interview about Pembrolizumab for MSI/dMMR Metastatic colorectal 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, 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; Non-Financial Interests, Personal, Member of Board of Directors, Investigator: Gercor group; Non-Financial Interests, Personal, Member of Board of Directors, President since October 2022: ARCAD Foundation. All other authors have declared no conflicts of interest.