Thymidine kinase activity (TKa) as independent predictor of outcome in metastatic breast cancer (MBC) patients in the GEICAM/2013-02 PEARL trial.

Abstract

1066 Background: TKa is a proliferation biomarker measurable in blood via the DiviTum™ TKa assay. Levels of TKa before and during treatment can provide prognostic, predictive and monitoring information in MBC. The PEARL trial (NCT02028507) was a phase III, multicenter, open-label, randomized study that compared endocrine therapy (ET) + CDK4/6 inhibitor Palbociclib (Palbo) vs. Capecitabine (Cape) in aromatase inhibitor-resistant HR+/HER2- MBC patients (pts). ET + Palbo did not improve median progression-free survival (mPFS 17.8 vs. 17.3 months (m.), p = 0.9) or overall survival (mOS 31.1 vs. 32.8 m., p = 0.5) over Cape. We explored whether TKa levels could predict better response to ET + Palbo vs Cape. Methods: Plasma from 555 pts (92%) was collected at baseline (BL) and on treatment (C1D15, C2D15). 1129 samples were analyzed using the DiviTum TKa assay (FDA approved/CE labelled, Biovica, Sweden). Cutoffs: 250/400 DiviTum units of Activity (DuA) for BL, 50 DuA or fold change (C1,C2/BL) > 2 for on-treatment. The Kaplan-Meier method estimated median PFS and OS. Adjusted hazard ratio (HR) with 95% confidence interval (CI) were calculated using Cox proportional hazards regression model, considering relevant prognostic clinical variables. Results: BL TKa ≤ 250 DuA predicted better mPFS (11.4 vs. 4.04 m., aHR 2.1; 95% CI 1.7-2.6, p < 0.0001) and mOS (38.47 vs. 17.31 m., aHR 3.2; 95% CI 2.45-4.19, p < 0.0001) regardless of therapy. After starting therapy, Cape and ET + Palbo elicited distinct TKa responses due to their different mechanisms. At C1, C2, pts on Cape had higher mTKa vs ET + Palbo (448 vs. 28 DuA, p < 0.0001). In the CT arm, an increase of TKa at C1 or C2 greater than 2-fold from BL predicted for better mPFS (13.04. vs. 6.34 m., aHR 0.59; 95% CI 0.43-0.81, p = 0.0013) and mOS (39.26 vs. 23.23 m., aHR 0.31; 95% CI 0.2-0.5, p < 0.0001). In the ET + Palbo arm, a TKa at C1 or C2 > 50 DuA predicted a shorter mPFS (3.68 v 11.27 m, aHR 2.81; 95% CI 2.08-3.8, p < 0.0001) and mOS (18.73 vs. 45.11 m., aHR 3.44; 95%CI 2.34-5.06, p < 0.0001). Similar results are observed regardless of BL TKa value. Exploring a BL TKa > 400 DuA demonstrated a better response to Cape compared to ET+ Palbo, despite overall very poor outcomes: mPFS 4.04 m on Cape vs 2.01 on ET + Palbo, (aHR 1.72; 95% CI 1.14-2.59, p < 0.0096), and showed a similar trend in mOS, 15.4 m on Cape vs 14.6m on ET+Palbo, (aHR 1.29 95% CI 0.84-1.99, p = 0.24). Conclusions: These data demonstrate that CT vs a CDK4/6 inhibitor influence TKa response differently, and the direction and magnitude of the TKa response can predict for benefit to a specific therapy. The original PEARL study analysis showed no outcome differences between Cape vs ET + Palbo in HR+/HER2- MBC pts, however assessment of TKa before and during therapy identified which patients had the highest probability of responding. Utilization of TKa as a predictive biomarker may allow for better personalized treatment selection. Clinical trial information: NCT02028507 .