Abstract CT239: IND.241: A Canadian cancer trials group liquid-biopsy informed platform trial to evaluate treatment in CDK4/6-inhibitor resistant ER+/HER2- metastatic breast cancer

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Abstract Introduction: The combination of CDK4/6 inhibitor+endocrine therapy (CDK4/6i+ET) is standard 1st-line (1L) systemic treatment for patients with ER+/HER2-negative metastatic breast cancer (MBC). Numerous agents are available / in development for subsequent lines of treatment. Circulating tumor DNA (ctDNA) via liquid biopsy presents a promising, non-invasive approach for blood-based tumor genotyping, patient stratification and response assessment with the potential to enhance biomarker-driven strategies and aid in development of new therapeutics. Experimental Procedures: IND.241 is a master protocol platform design consisting of independent substudies monitoring patients with ER+/HER2- MBC prior to progression (PD) on CDK4/6i+ET and investigating novel agents or drug combinations in 2nd/3rd lines (2L, 3L) after progression on CDK4/6i+ET. The primary objective of the novel drug/combination substudies is to centrally interrogate ctDNA (Tempus xF+, a 523-gene liquid biopsy panel) and evaluate whether biomarker selection improves ORR or CBR (RECIST 1.1). Secondary objectives include safety and toxicity profile, PFS, and OS. The monitoring substudy (Substudy A) enrolls patients currently on CDK4/6i+ET treatment and aims to characterize molecular profile, clinical features, and ctDNA dynamics of acquired resistance. This platform trial enables creation and maintenance of a tissue and data bank including clinical data, genomics, and radiomics to evaluate surrogates of treatment outcomes and potential biomarkers of response, resistance, and disease progression. Results: Patients with specific biomarkers detected in ctDNA will be enrolled to corresponding biomarker positive cohorts of substudies. Patients with no substudy-specific biomarkers are randomized to biomarker negative cohorts of available substudies. Treatment substudies follow a 2-stage design. Currently, the monitoring substudy A is actively accruing. Substudy B is evaluating lunresertib (PKMYT1 inhibitor) + gemcitabine in patients +/-CCNE1 overexpression / amplification. Substudy C is evaluating niraparib (PARP inhibitor) + fulvestrant (ET) in patients +/- alterations in BRCA1/2 (germline/somatic) or PALB2 (germline). These latter two substudies have now closed to accrual, with efficacy and safety evaluation ongoing. Substudy D, recently added, is evaluating lunresertib + camonsertib (ATR inhibitor) in patients +/- CCNE1 overexpression/amplification, FBXW7 or PPP2R1A alterations. Additional substudies are in development for this platform trial. Conclusions: IND.241 employs a biomarker-driven platform trial designed to evaluate CDK4/6i resistant ER+/HER2- MBC, using non-invasive ctDNA tumor genotyping to select patients for biomarker-driven substudies with the goal of defining the ctDNA landscape across 1L to 3L treatments. Citation Format: Moira Rushton, Dave W. Cescon, Nathalie Levasseur, Michelle B. Nadler, Daniel Rayson, Brooke E. Wilson, Sara K. Taylor, Rossanna Pezo, Arif Awan, Zahi Mitri, Vikaash Kumar, Jennifer Melvin, John Hilton, Stephen Chia, Philippe L. Bedard, Spencer Finn, Wei Tu, Courtney Coschi, Philippe Jamme, Elia Aguado-Fraile, Lesley Katie Seymour, Laura Pearce. IND.241: A Canadian cancer trials group liquid-biopsy informed platform trial to evaluate treatment in CDK4/6-inhibitor resistant ER+/HER2- metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT239.

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