Abstract
The efficacy of a CDK4/6 inhibitor (i) with an aromatase inhibitor (AI) or fulvestrant (ful) as frontline therapy for hormone receptor positive (HR+) human epidermal growth factor receptor 2- (HER2-) metastatic breast cancer (MBC) is limited by the onset of resistance mutations. For breast cancer, the prognostic value of ctDNA has been validated; however, the clinical utility of serial ctDNA monitoring remains unclear. Results from PADA-1 support the utility of serial ctDNA monitoring to guide an early switch in frontline therapy based on molecular progression (MP) in patients (pts) with HR+HER2- MBC. This strategy led to improvements in median progression free survival (mPFS) of 7 months and time to second progression (PFS2) of 15.4 months. This is a randomized phase 2 study conducted in pts receiving an AI or ful and a CDK4/6i as first-line therapy for HR+HER2- MBC evaluating the efficacy of switching a frontline regimen upon detection of a molecular signal, rise in ctDNA, suggesting MP prior to clinical progression (CP). Compared to PADA-1, this study is utilizing a more comprehensive biomarker, ctDNA ratio>1. The calculated ctDNA ratio (ctDNA value at time of assessment over baseline value) corresponds to mutant allele abundance (mutant copies/ml of plasma) at a given timepoint relative to baseline quantification. Use of this ratio as a dynamic marker of response has been validated by O’Leary et al and Darrigues et al. This study design also includes pts with de novo HR+HER2- MBC, a prior history of breast cancer and those who progressed on adjuvant endocrine therapy. In Step 1, enrolled pts will receive frontline therapy with a CDK4/6i and AI or ful. ctDNA will be serially monitored. When a ctDNA ratio >1 is detected and there is no synchronous CP, pts will be randomized in Step 2 to continue the same therapy until CP, which is the current standard of care (SOC), or switch to an alternative second-line regimen. The primary endpoint is PFS in Step 2. Secondary endpoints include the number and percentage of pts with events of MP and no CP and the median time from enrollment to this event, overall response rate, clinical benefit rate, PFS2, overall survival and patient-reported outcomes. Study feasibility will be evaluated based on the number of pts with MP events (ctDNA ratio>1 and no synchronous CP). Trial accrual will be suspended if <15% of the first 25-30 pts have MP without synchronous CP. To date, 24 pts have enrolled, with follow up < 12 months in all pts. Seventeen pts are in Step 1 and two are in Step 2. Two had CP prior to MP and are off study. Two had MP without CP and proceeded to Step 2 and were randomized to an early switch in therapy or maintenance of frontline therapy. Another 3 have been censored and are off study not related to progressive disease. Plasma samples (n=43) were ctDNA-positive (detectable somatic events), with actionable findings (BRCA2, PIK3CA, ESR1, PTEN variants) and biologically relevant findings (ARID1A, NOTCH3, MSH3, FANCM, NOTCH1, MAP3K1 variants) detected by the BostonGene Liquid Biopsy test in 7 and 6 samples, respectively. At screening/baseline, 20/29 pts (70%) had detectable levels of ctDNA. As expected for pts in Step 1 responding to frontline therapy, ctDNA abundance and cfDNA yield decreased during treatment, with a median pre-treatment and median on-treatment ctDNA abundance of 17.8 mutant copies/ml and 3.3 mutant copies/ml (P<0.01), respectively, for cases with ctDNA-positive baseline timepoints. This pilot serves to document the feasibility of serial ctDNA monitoring and the early switch approach to then expand to phase II. The overall aim is to validate the utility of serial ctDNA monitoring as a predictive biomarker, and identify a strategy to extend duration of disease control and prolong survival in pts with MBC.
Citation Format: Frances Valdes, Carmen Calfa, Mauricio Escobar, Lawrence Negret, Aleksei Efremov, Dmitry Tabakov, Egor Savin, Kelley Lauziere, Alexander Bagaev, Elisa Krill, Alejandra Perez. Levels of Circulating Tumor DNA as a Predictive Marker for Early Switch in Treatment for Patients with Metastatic Breast Cancer: A Phase 2 Randomized, Open-Label Study [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 P4-08-15.