Abstract 514P
Background
Detecting acquired resistance to targeted therapies with liquid biopsy is a promising, non-invasive strategy to monitor therapeutic efficacy in real time. We explored the landscape of clinically validated resistance mutations across gastrointestinal cancers.
Methods
In this single institution study, patients with gastrointestinal cancers who received standard of care as well as experimental EGFR-, HER2-, FGFR-, MET, IDH1, BRAF- and other MAPK pathway directed therapy for at least 60 days were retrospectively evaluated. Patients with no prior targeted therapy and an available liquid biopsy (Guardant 360® assay) after clinical progression on targeted therapy, prior to the start of next line of systemic therapy, were included in the analysis.
Results
116 patients met the inclusion criteria. The main tumor types identified were colorectal (n=49), biliary (n=46), gastroesophageal (n=16) and others (n=5). Clinically validated resistance mutations were mainly detected in patients receiving therapy targeting BRAF (11/18, 61%), EGFR (15/27, 55%), FGFR (22/42, 52%) and HER2 (3/12, 25%). 55/116 (47%) had at least 1 and 29/116 (25%) had 2 or more acquired resistance mutations detected. Overall, 152 mutations were detected; 119/152 (78%) were point mutations, 31/152 (21%) were gene amplifications, 2/152 (1%) were indels. 78/152 (51%) were the result of bypass activation and 74/152 (49%) were on-target mutations. The main method of bypass resistance was downstream MAPK- pathway activation (63/78, 81%), the rest were alternate receptor tyrosine kinase activations (15/78, 19%). In the FGFR treatment group, there was a high frequency of on-target alterations (55/78, 71%) and point mutations (75/78, 96%).
Conclusions
ctDNA can identify heterogenous clinically relevant resistance alterations. Understanding the real-world landscape of these mutations not only improves our understanding of resistance mechanisms guiding subsequent treatment strategies but is also critical to designing therapies capable of overcoming such resistance alterations.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
P.S. Pathak: Financial Interests, Personal, Research Grant: Robert Winn Diversity in Clinical Trials Career Development Award. B. Caughey: Financial Interests, Personal, Invited Speaker: Foundation Medicine Inc. S.J. Klempner: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Merck, Eli Lilly, Astellas, Daiichi Sankyo, Pieris, Natera, Novartis, AstraZeneca, Mersana, Sanofi-Aventis, Servier, Coherus; Financial Interests, Personal, Stocks/Shares: Turning Point Therapeutics, Nuvalent. A. Parikh: Financial Interests, Personal, Advisory Board: Eli Lilly, Mirati, Pfizer, Inivata, Biofidelity, Checkmate Pharmaceuticals, FMI, Guardant, AbbVie, Bayer, Delcath, Taiho, CVS, Value Analytics Lab, Seagen, Saga, AZ, Scare Inc., Illumina, Taiho, Hookipa, Kahar Medical, Xilio Therapeutics, Sirtex, Takeda, a; Financial Interests, Personal and Institutional, Funding: PureTech, PMV Pharmaceuticals, Plexxicon, Takeda, BMS, Mirati, Novartis, Erasca, Genentech, Daiichi Sankyo, Syndax, Revolution Medicine and Parthenon. R.B. Corcoran: Financial Interests, Personal, Member of Board of Directors: Alterome Therapeutics, Sidewinder Therapeutics; Financial Interests, Personal, Funding: Lilly, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Avidity Biosciences, C4 Therapeutics, Cogent Biosciences, Erasca, Nested Therapeutics, Interline Therapeutics, nRichDx, Kinnate Biopharma, Remix Therapeutics, Revolution Medicines, Theonys; Financial Interests, Personal, Advisory Role: AbbVie, Array Biopharma, Astex Pharmaceuticals, Asana Biosciences, BMS, C4 Therapeutics, Cogent Biosciences, Elicio, FOG Pharma, Guardant Health, Ipsen, Kinnate Biopharma, Mirati Therapeutics, Navire, Nested Therapeutics, N-of-One, nRichDx, Remix Therapeu. All other authors have declared no conflicts of interest.