TKa and Palbociclib

A phase II trial of an alternative schedule of palbociclib and embedded serum TK1 analysis
NPJ Breast Cancer. 2022 Mar 21;8(1):35.

Study Type
Single-arm phase II trial, patients with HR+/HER2− MBC from multiple U.S. sites (University of Nebraska, Omaha, Washington University, St. Louis), n = 54

Background
CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, have gained FDA approval based on the significant improvement in progression-free survival (PFS) when added to endocrine therapy in patients with advanced disease as front-line therapy or following disease progression on prior endocrine therapy. These agents have now become the standard of care in combination with an endocrine therapy partner for HR+/HER2− metastatic breast cancer (MBC). However, treatment-related neutropenia is a common adverse event (AE), leading to dose interruption, reduction, and at times discontinuation. An alternative palbociclb dosing schedule of 5-days-on/2-days-off weekly was investigated to determine if it could reduce grade 3 and above neutropenia.

Objective
We assessed sTK1 (TKa) dynamics for target inhibition and examined its potential prognostic value and utility in disease monitoring.

Results
We assessed treatment-induced pharmacodynamics effect: All patients with high sTK1 (TKa) at C1D15 (≥20 Du/L) had high TKa at baseline (>200 Du/L, predefined cut point for high baseline TKa). Among the 24 patients who progressed with TKa available, an TKa increase from the prior time point was detected at the time of progression in nine patients, and at an earlier time point in 13 patients.

We then assessed the prognostic significance of baseline and early on-treatment TKa:

• There was no association between levels of TKa either at baseline or C1D15 with the presence of visceral metastasis or endocrine sensitivity defined by ESMO criteria
• However, TKa at both BL and C1D15 time points were significantly correlated with clinical benefit versus not
• Baseline TKa was higher in patients with PD as the best response
• Progression within 6 months (not achieving clinical benefit) was negatively correlated with high TKa at baseline (p = 0.000419) and C1D15 (p = 8.4 × 10−5)
• High TKa at baseline (>200 Du/L), C1D15 (>20 Du/L) or C2D1 (>20 Du/L) predicted progression within 3 (or 6) months
• TKa at BL, C1D15, and C2D1 remained an independent predictor of PFS in the multivariate analysis that included age, endocrine sensitivity, and sites of metastases

Conclusions

• Our study demonstrated the potential utility of sTK1 activity (TKa) at baseline and on-treatment as a prognostic marker and in monitoring disease status for patients with MBC receiving a CDK4/6 inhibitor. High TKa at baseline or early on-treatment time point (C1D15 or C2D1), especially at C1D15, had high degrees of accuracy in predicting progression within 6 months (84% accuracy for C1D15).
• In addition, we demonstrated that a rise in TKa predicted subsequent clinical/RECIST progression. Our data demonstrate TKa a promising biomarker of prognosis and disease monitoring in patients receiving CDK4/6 inhibitors.