Abstract P2-12-29: A randomized clinical trial comparing ctDNA-directed therapy change with standard of care in patients with metastatic triple negative breast cancer (mTNBC)

Abstract Background: Despite treatment advances in mTNBC, most patients presenting for first-line therapy will require cytotoxic chemotherapy (CT). Sacituzumab govitecan (SG) is an antibody-drug conjugate to the Trop-2 antigen that is expressed in the majority of TNBCs. SG is approved as second- or third-line therapy for patients with mTNBC per the phase III ASCENT trial, but its utility as a first-line treatment is unknown. ctDNA correlates with cancer burden and response to local and systemic therapies, but there is not an approved use for quantitatively monitoring patients’ ctDNA levels during treatment. Previous studies showed a direct correlation between a patient’s ctDNA mean variant allele frequency (VAF) and tumor burden as well as response or resistance to treatment. We hypothesize that a lack of a significant decrease in ctDNA VAFs shortly after initiating a first-line CT for mTNBC could serve as a biomarker of de novo resistance and could warrant a change of therapy earlier than conventional imaging studies would normally dictate. This study therefore evaluates switching to SG in mTNBC patients without a 50% decrease in ctDNA VAFs less than one month after starting a first-line CT with the goal of improving progression-free survival (PFS) and overall survival (OS) and of decreasing toxicity by stopping an ineffective treatment earlier. Methods: In this two-arm randomized clinical trial, 120 patients will receive standard of care (SOC) physician’s choice CT. Patients will be randomized 1:1; one group will undergo SOC treatment with conventional staging imaging to guide treatment decisions, while the other group will undergo ctDNA evaluation on cycle (C) 1 days (D) 1 and 15 of treatment. If the mean ctDNA VAF on-treatment does not decrease by 50% on C1D15, patients will change SOC CT to SG. Both groups will undergo radiological assessment every 9 weeks. ctDNA will be banked on C4D1, C7D1, and at the end of treatment. Patients with a biopsy-confirmed new diagnosis of mTNBC that is PD-L1 negative (CPS <10) or who are otherwise not eligible for immune checkpoint inhibitor therapy are eligible for this study. Patients will not have received prior treatment for mTNBC and must have an ECOG PS of 0-2 as well as measurable disease by RECIST. The primary endpoint is PFS. This study has 80% power to detect a 2-month difference in PFS between patients treated with a ctDNA-guided therapeutic approach compared to patients assessed by conventional imaging alone (one-sided type 1 error of 10%). Key secondary endpoints include evaluating the overall response rate (RECIST v1.1), PFS2, and OS. Correlative studies include assessing ctDNA-defined clonal mutation profiles and their predictive value and correlating changes in ctDNA with standard imaging. This study (NCT05770531) is open at Vanderbilt University Medical Center and will open at 7 other sites through the ACCRU network. Six patients have been enrolled as of 6/2024. Citation Format: Jessica Sharpe, Ben H. Park, Vandana G. Abramson. A randomized clinical trial comparing ctDNA-directed therapy change with standard of care in patients with metastatic triple negative breast cancer (mTNBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-12-29.