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. 2024 Oct 4;23(1):221.
doi: 10.1186/s12943-024-02134-4.

Deciphering resistance mechanisms in cancer: final report of MATCH-R study with a focus on molecular drivers and PDX development

Damien Vasseur #  1   2 , Ludovic Bigot #  3 , Kristi Beshiri #  4 , Juan Flórez-Arango  3 , Francesco Facchinetti  3 , Antoine Hollebecque  4   5 , Lambros Tselikas  6 , Mihaela Aldea  5 , Felix Blanc-Durand  5 , Anas Gazzah  4 , David Planchard  5 , Ludovic Lacroix  1   2 , Noémie Pata-Merci  2 , Catline Nobre  3 , Alice Da Silva  3 , Claudio Nicotra  4 , Maud Ngo-Camus  4 , Floriane Braye  3 , Sergey I Nikolaev  3 , Stefan Michiels  7   8 , Gérôme Jules-Clement  9 , Ken André Olaussen  3 , Fabrice André  3   5 , Jean-Yves Scoazec  1   2 , Fabrice Barlesi  5 , Santiago Ponce  3   5 , Jean-Charles Soria  3   5 , Benjamin Besse  3   5 , Yohann Loriot  10   11   12 , Luc Friboulet  13
Affiliations

Deciphering resistance mechanisms in cancer: final report of MATCH-R study with a focus on molecular drivers and PDX development

Damien Vasseur et al. Mol Cancer. .

Abstract

Background: Understanding the resistance mechanisms of tumor is crucial for advancing cancer therapies. The prospective MATCH-R trial (NCT02517892), led by Gustave Roussy, aimed to characterize resistance mechanisms to cancer treatments through molecular analysis of fresh tumor biopsies. This report presents the genomic data analysis of the MATCH-R study conducted from 2015 to 2022 and focuses on targeted therapies.

Methods: The study included resistant metastatic patients (pts) who accepted an image-guided tumor biopsy. After evaluation of tumor content (TC) in frozen tissue biopsies, targeted NGS (10 < TC < 30%) or Whole Exome Sequencing and RNA sequencing (TC > 30%) were performed before and/or after the anticancer therapy. Patient-derived xenografts (PDX) were established by implanting tumor fragments into NOD scid gamma mice and amplified up to five passages.

Results: A total of 1,120 biopsies were collected from 857 pts with the most frequent tumor types being lung (38.8%), digestive (16.3%) and prostate (14.1%) cancer. Molecular targetable driver were identified in 30.9% (n = 265/857) of the patients, with EGFR (41.5%), FGFR2/3 (15.5%), ALK (11.7%), BRAF (6.8%), and KRAS (5.7%) being the most common altered genes. Furthermore, 66.0% (n = 175/265) had a biopsy at progression on targeted therapy. Among resistant cases, 41.1% (n = 72/175) had no identified molecular mechanism, 32.0% (n = 56/175) showed on-target resistance, and 25.1% (n = 44/175) exhibited a by-pass resistance mechanism. Molecular profiling of the 44 patients with by-pass resistance identified 51 variants, with KRAS (13.7%), PIK3CA (11.8%), PTEN (11.8%), NF2 (7.8%), AKT1 (5.9%), and NF1 (5.9%) being the most altered genes. Treatment was tailored for 45% of the patients with a resistance mechanism identified leading to an 11 months median extension of clinical benefit. A total of 341 biopsies were implanted in mice, successfully establishing 136 PDX models achieving a 39.9% success rate. PDX models are available for EGFR (n = 31), FGFR2/3 (n = 26), KRAS (n = 18), ALK (n = 16), BRAF (n = 6) and NTRK (n = 2) driven cancers. These models closely recapitulate the biology of the original tumors in term of molecular alterations and pharmacological status, and served as valuable models to validate overcoming treatment strategies.

Conclusion: The MATCH-R study highlights the feasibility of on purpose image guided tumor biopsies and PDX establishment to characterize resistance mechanisms and guide personalized therapies to improve outcomes in pre-treated metastatic patients.

Keywords: Biopsy; Cancer; Metastatic; PDX; Resistance; Targeted therapy.

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Conflict of interest statement

D. Vasseur: speaker for Roche and Astra Zeneca JC. Soria: Full time employee of Amgen. Share-holder of Amgen. LF: Research funding from Debiopharm, Incyte, Relay Therapeutics, Sanofi and Nuvalent. F. Facchinetti : personal fees from BeiGene outside the submitted work. Y. Loriot : personal fees, nonfinancial support, and other support from Janssen during the conduct of the study, as well as personal fees, nonfinancial support, and other support from MSD, Pfizer, Merck KGaA, Astellas, Gilead, Bristol Myers Squibb, and Roche, nonfinancial support and other support from Incyte, other support from Exelixis, and personal fees and other support from Taiho outside the submitted work. S. Michiels : personal fees from DSMB or scientific committee study membership for Kedrion, Biophytis, Servier, IQVIA, Yuhan, and Roche outside the submitted work. L. Tselikas : personal fees from Incyte during the conduct of the study, as well as personal fees from GE Healthcare, Quantum Surgical, and Boston Scientific outside the submitted work. B. Besse : other support from AbbVie, BioNTech SE, Bristol Myers Squibb, Chugai Pharmaceutical, CureVac AG, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, PharmaMar, Regeneron, Sanofi-Aventis, and Turning Point Therapeutics, other support from AbbVie, Eli Lilly and Company, Ellipses Pharma Ltd, F.Hoffmann-La Roche Ltd, Genmab, Immunocore, Janssen, MSD, Ose Immunotherapeutics, Owkin, and Taiho oncology, other support from AstraZeneca, BeiGene, Genmab A/S, GlaxoSmithKline, Janssen, MSD, Ose Immunotherapeutics, PharmaMar, Roche-Genentech, Sanofi, and Takeda, and other support from AbbVie, AstraZeneca, Chugai Pharmaceutical, Daichii Sankyo, Hedera Dx, Janssen, MSD, Roche, Sanofi-Aventis, and Springer Healthcare Ltd during the conduct of the study. F. André : grants from AstraZeneca, Guardant Health, Novartis, Owkin, Pfizer, Eli Lilly and Company, Roche, and Daiichi Sankyo, other support from Boston Pharmaceutics, Gilead, and Servier, and grants and other support from N-Power medicine outside the submitted work. A. Hollebecque : personal fees and nonfinancial support from Amgen, personal fees from Basilea, Bristol Myers and Squibb, Servier, Relay Therapeutics, Taiho, MSD, Seagen, grants and personal fees from Incyte, and nonfinancial support from Pierre Fabre outside the submitted work, as well as reports being a PI of the TransThera (Tinengotinib) phase III trial. A. Gazzah: travel accommodations, congress registration expenses from Boehringer Ingelheim, Novartis, Pfizer, and Roche. Consultant/Expert role for Novartis. Principal/sub-Investigator of Clinical Trials for Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Exelixis, Forma, Gamamabs, Genentech, Inc., Gilead Sciences, Inc., GlaxoSmithKline, Glenmark Pharmaceuticals, H3 Biomedicine, Inc., Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Iris Servier, Janssen, Kura Oncology, Kyowa Kirin Pharm, Lilly, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Rigontec Gmbh, Roche, Sanofi Aventis, Sierra Oncology, Taiho Pharma, Tesaro, Inc., Tioma Therapeutics, Inc., Xencor. Research Grants from AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi. Non-financial support (drug supplied) from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. D. Planchard: Consulting, advisory role or lectures: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. Honoraria: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. Clinical trials research as principal or co-investigator (Institutional financial interests): AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi Aventis, Taiho Pharma, Novocure, and Daiichi Sanky. Travel, Accommodations, Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. M. Aldea: Expenses from Sandoz. No disclosures were reported by the other authors.

Figures

Fig. 1
Fig. 1
Global patient population. A. Study flow chart. B. Oncoprint depicting 1230 pathogenic alterations identified in the initial biopsy of 563 patients, all of whom exhibited at least 1 pathogenic alteration. C. Frequency of the highest OncoKb alteration in each first biopsy
Fig. 2
Fig. 2
Targeted therapy cohort. A. Sankey diagram depicting the tumor type of origin of the 265 patients harboring a molecular driver and the 594 patients without any molecular driver identified. B. Flow chart representing the resistance mechanisms identified in the 265 patients harboring a molecular driver. C. Pie chart depicting the by-pass resistance mechanisms identified in the 265 patients harboring a molecular driver
Fig. 3
Fig. 3
Resistance mechanisms in EGFR, FGFR2/3 and ALK driven patients. A & B. Sunburst charts representing the EGFR cohorts. The innermost layer depicts the baseline molecular driver and the identified resistance mechanism are presented in the outermost layer. C & D. Sunburst charts illustrating the FGFR2/3 cohorts. The innermost layer depicts the baseline molecular driver and the identified resistance mechanism are presented in the outermost layer. E. Sunburst chart representing the ALK cohort. The innermost layer depicts the baseline molecular driver and the identified resistance mechanism are presented in the outermost layer
Fig. 4
Fig. 4
PDX models available. Illustration of the PDX developed based on the molecular driver and the targeted therapy that led to acquired resistance
Fig. 5
Fig. 5
Pharmacological status of PDX models. In vivo pharmacological evaluation was performed by measuring the tumor volume in vehicle-treated and TKI-treated mice for: A. Two EGFR-resistant PDX models (MR7 and MR441) treated with 25 mg/kg of Osimertinib and vehicle. B. Two ALK-resistant PDX models (MR619, from cholangiocarcinoma, and MR448re, from lung) treated with 50 mg/kg of Alectinib and 20 mg/kg of Lorlatinib, respectively. C. Two FGFR3 bladder PDX models from the same patient: one from a biopsy in a stable disease site (MR86-SD) and one from a resistant disease site (MR86-PD), treated with 15 mg/kg of erdafitinib and vehicle. D. Two FGFR2-resistant cholangiocarcinoma PDX models (MR313 and MR369) treated with 1 mg/kg of Pemigatinib or vehicle
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