Abstract P4-01-22: Serum Thymidine Kinase as a Biomarker for Response Beyond Progression in First-line CDK 4/6 Inhibitors: Insights from the Randomized Phase II MAINTAIN Trial

Le résumé fourni par la source

Abstract Background: There are multiple therapeutic strategies for patients (pts) with hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) following progression on a first-line cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and endocrine therapy (ET). There is an unmet need for predictive and prognostic biomarkers to identify HR+, HER2- MBC pts likely to benefit from continued CDK4/6i therapy beyond progression. Thymidine kinase (TK), an enzyme involved in DNA synthesis, represents a promising biomarker due to the association of elevated serum TK activity (sTKa) with greater tumor cell division and poorer clinical outcomes. We investigated sTKa as a potential biomarker of response to continued CDK4/6i therapy beyond progression in the MAINTAIN trial. Methods: MAINTAIN was the first randomized controlled trial to demonstrate a significant progression-free survival (PFS) benefit for HR+, HER2- MBC patients who switched ET (fulvestrant or exemestane) and received the CDK4/6i ribociclib compared to ET plus placebo after progressing on prior CDK4/6i and ET. We evaluated the association between sTKa and PFS. In this exploratory analysis, sTKa levels were analyzed from blood samples collected at baseline and cycle 2 day 1 (C2D1) by Biovica using the Divitum® TKa assay. Patients were categorized into low (<250 Divitum® unit of Activity [DuA]) and high (≥250 DuA) sTKa groups for PFS analysis. The cut-off point of 250 DuA is a clinically validated and FDA 510(k) cleared reference value for prognosis in HR+ MBC. Log-rank test and Cox regression models were used to assess the association between sTKa levels and PFS as well as calculate hazard ratios (HR) and 95% confidence intervals (CI). The database was locked on Jan 4, 2022. Results: Of the 119 MAINTAIN participants, 90 had samples available for analysis. Forty (44%) in the placebo+ET group and 50 (56%) in the ribociclib+ET group. Eighty-one pts had baseline sTKa, 73 had C2D1 sTKa, and 69 had sTKa at both timepoints. Fifty-three percent (43/81) of pts had high baseline TKa and 37% (27/73) of pts had high C2D1 TKa. Pts with low baseline sTKa exhibited a non-significant trend towards improved PFS compared to those with high baseline sTKa (median PFS [mPFS] 5.6 vs 3.0 mo; HR 0.73, 95% CI 0.45-1.18, p=0.198). In contrast, pts with low C2D1 sTKa demonstrated a statistically significant PFS benefit compared to those with high C2D1 sTKa (mPFS 5.7 vs 2.7 mo; HR 0.30, 95% CI 0.17-0.52, p<0.001). Notably, the mPFS in the ribociclib+ET group was 10.9 mo for pts with low C2D1 sTKa compared to 2.7 mo for those with high C2D1 sTKa (HR 0.15, 95% CI 0.06-0.37, p<0.001). The placebo+ET group did not show a statistically significant PFS benefit for those with low C2D1 sTKa versus high C2D1 sTKa (mPFS 4.8 vs 2.5 mo; HR 0.51, 95% CI 0.23-1.13, p=0.098). Among 69 pts evaluated for sTKa dynamics, the longest PFS was seen in 13 pts (19%) who transitioned from high baseline to low C2D1 sTKa (mPFS 8.2 mo; 95% CI 5.6-16.6). Twenty-one (30%) pts who maintained high sTka levels from baseline to C2D1 had the shortest PFS (mPFS 2.7 mo; 95% CI 2.1-3.0). Conclusions: In the phase II MAINTAIN trial, sTKa was a predictive biomarker for response to switching ET + continuing CDK4/6i in HR+, HER2- MBC pts following progression on CDK4/6i and ET. Low (<250 DuA) C2D1 sTKa levels predicted a positive treatment response, especially among those receiving ribociclib+ET. sTKa dynamics from baseline to C2D1 were prognostic, providing insights into PFS outcomes. Our analysis supports C2D1 as a critical timepoint for sTKa in assessing continued benefit of CDK4/6i and risk of progression. Further research in a larger trial evaluating sTKa dynamics and clinical outcomes is warranted. Citation Format: Ruth Sacks, Codruta Chiuzan, Melissa K. Accordino, Elizabeth Sakach, Amy Williams, Prabhjot S. Mundi, Claire Sathe, Meghna S. Trivedi, Naomi Sender, Yelena Novik, Amy Tiersten, George Raptis, Lea N. Baer, Sun Y. Oh, Amelia B. Zelnak, Kari B. Wisinski, Eleni Andreopoulou, Williams J. Gradishar, Erica Stringer-Reasor, Sonya A. Reid, Anne O'Dea, Ruth O'Regan, Katherine D. Crew, Dawn L. Hershman, Kevin Kalinsky. Serum Thymidine Kinase as a Biomarker for Response Beyond Progression in First-line CDK 4/6 Inhibitors: Insights from the Randomized Phase II MAINTAIN Trial [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 P4-01-22.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.