Leveraging circulating tumor DNA sequencing for first-line cancer treatment: Insights from two prospective precision medicine studies

BackgroundUtilizing circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) marks a transformative approach to personalizing therapy for cancer patients (pts). This study aims to evaluate the clinical efficacy of ctDNA in guiding treatment decisions for newly diagnosed locally advanced/metastatic cancers.MethodsPts enrolled in prospective molecular screening programs at two participating French centers (Institut Gustave Roussy, Villejuif, NCT04932525, and Institut Bergonié, Bordeaux, NCT02534649) underwent ctDNA CGP using the 324-gene FoundationOneLiquid®CDx prior to initiating first-line systemic treatment. The primary objective was to assess the proportion of pts for whom CGP led to molecularly guided therapy at the first-line. Proportions and descriptive analyses were conducted.ResultsBetween Sept 1st, 2020, and Dec 1st, 2023, 736 eligible pts were enrolled. Predominant cancers were lung (231, 31%), prostate (91, 12%), and colorectal (70, 10%). The median time to ctDNA results was 13 days (Interquartile (IQR) 9-19), significantly faster than tissue screening (median 38 days, IQR 31-46). 65.2% of pts (N=480) presented actionable molecular alterations. Oriented treatment was recommended for 266 pts, with 17.7% treated at 1st line based on ctDNA results (25% of them in the context of a clinical trial). In this group, EGFR was the most frequently altered gene (21.3%). The best objective response rate (defined as a sum of complete response and partial response) was 59.5% (95% confidence interval (CI) [44.3-73.6]). For this subgroup, after a median follow-up of 33.5 months, the median PFS was 16.1 months (95% CI 15.5-19.4). 14.5% of pts received ctDNA-based 2nd line treatment (40% of them in the context of a clinical trial).ConclusionsctDNA CGP efficiently matches pts with advanced cancer to targeted therapies in the first-line of metastatic disease. Its rapid turnaround time compared to tissue screening underscores its potential in expediting treatment initiation, enhancing clinical trial enrollment, and mitigating biopsy-related limitations.Clinical trial identificationNCT04932525, NCT02534649.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureV. Debien: Non-Financial Interests, Personal and Institutional, Membership or affiliation: EORTC; Non-Financial Interests, Personal, Member: ASCO, AACR. S. Cousin: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, Lilly, Roche; Non-Financial Interests, Principal Investigator: AstraZeneca, Daiichi Sankyo, Gilead, Takeda, Sanofi, MSD, GSK, BMS. A. Bayle: Financial Interests, Personal, Advisory Board, ASCO 2022 & ESMO 2023: Sanofi; Financial Interests, Personal, Invited Speaker, Health Economics conference: Roche; Financial Interests, Personal, Other, Expert at the Commission for the Evaluation of Diagnostic, Prognostic and Predictive Health Technologies: HAS (French National Authority for Health); Other, Transportation and accommodation support for the ASCO 2023 Congress: Pfizer. D. Vasseur: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche. L. Blouin: Other, Unfunded public speaking (JEPO conference): AstraZeneca. I. Soubeyran: Financial Interests, Institutional, Invited Speaker, congress; meeting: AstraZeneca; Financial Interests, Institutional, Funding, research funding: AstraZeneca. C.P. Massard: Other, Christophe Massard: Consultant/Advisory fees from Amgen, Astellas, AstraZeneca, Bayer, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, Netcancer, PegascyPrincipal/sub-Investigator of Clinical Trials for AbbVie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, BeiGene, Blueprint, BMS, Boehringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor: Company. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. All other authors have declared no conflicts of interest.