A phase II trial of an alternative schedule of palbociclib and embedded serum TK1 analysis

Abstract

Palbociclib 3-weeks-on/1-week-off, combined with hormonal therapy, is approved for hormone receptor positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer (MBC). Neutropenia is the most frequent adverse event (AE). We aim to determine whether an alternative 5-days-on/2-days-off weekly schedule reduces grade 3 and above neutropenia (G3 + ANC) incidence. In this single-arm phase II trial, patients with HR+/HER2- MBC received palbociclib 125 mg, 5-days-on/2-days-off, plus letrozole or fulvestrant per physician, on a 28-day cycle (C), as their first- or second-line treatment. The primary endpoint was G3 + ANC in the first 29 days (C1). Secondary endpoints included AEs, efficacy, and serum thymidine kinase 1 (sTK1) activity. At data-cutoff, fifty-four patients received a median of 13 cycles (range 2.6-43.5). The rate of G3 + ANC was 21.3% (95% CI: 11.2-36.1%) without G4 in C1, and 40.7% (95% CI: 27.9-54.9%), including 38.9% G3 and 1.8% G4, in all cycles. The clinical benefit rate was 80.4% (95% CI: 66.5-89.7%). The median progression-free survival (mPFS) (95% CI) was 19.75 (12.11-34.89), 33.5 (17.25-not reached [NR]), and 11.96 (10.43-NR) months, in the overall, endocrine sensitive or resistant population, respectively. High sTK1 at baseline, C1 day 15 (C1D15), and C2D1 were independently prognostic for shorter PFS (p = 9.91 × 10-4, 0.001, 0.007, respectively). sTK1 decreased on C1D15 (p = 4.03 × 10-7), indicating target inhibition. Rise in sTK1 predicted progression, with the median lead time of 59.5 (inter-quartile range: -206.25-0) days. Palbociclib, 5-days-on/2-days-off weekly, met its primary endpoint with reduced G3 + ANC, without compromising efficacy. sTK1 is prognostic and shows promise in monitoring the palbociclib response. ClinicalTrials.gov#: NCT3007979.

Trial registration: ClinicalTrials.gov NCT03007979.

Conflict of interest statement

J.K. holds consulting or advisory roles from Abbvie, Pfizer, Sanofi, Rigel, Guidepoint Global, Gerson Lehrman Group, and AstraZeneca. A.F. reports stock and ownership interests in Athenex and research funding from Menarini, Seagen, and Daiichi Sankyo/Lilly. M.B. is employed by Biovica Inc and has stock and ownership interests in Biovica Inc. C.M. holds consultant or advisory roles from Novartis, Seattle Genetics, Agendia, AstraZeneca, Athenex, Bayer HealthCare Pharmaceuticals, Biovica Inc, Eisai, Olaris Inc, Philips Electronics North America, Puma Biotechnology and Sanofi-Genzyme, in addition to, research funding from Pfizer and Puma Biotechnology. All authors not listed declare no potential conflicts of interest.

© 2022. The Author(s).

Figures

Fig. 1. Progression-free survival (PFS) of all treated patients.

a the overall population, and b by endocrine sensitivity.

Fig. 2. Serum TK1 activity over time.

a Box plot of log (sTK1 Du/L) along the 5-time points indicated. b Time to progression by TK1 increase from the previous time point (sTK1 PD) or by RECIST/investigator decision (Clinical PD). c The lead time from TK1 progression to clinical/RECIST progression. BL baseline, C1D15 cycle 1 day 15, C2D1 cycle 2 day 1, Progression PFS events that included RECIST progression (n = 17) and investigator decision (n = 7). The center horizontal line of the box plot indicates the median, while the box limits indicate the upper and lower quartiles. The box-plot whiskers show a 1.5× interquartile range. Those points outside the whisker line are indicated as outliers. *p < 0.05, ***p < 0.001.

Fig. 3. PFS by sTK1 and time points of baseline (BL), C1D15, C2D1, C4D1.

sTK1 cutoff for high versus low is 200 at BL (a) and 20 at time points C1D15 (b) and C2D1 (c). Shown in legends are even/n (number of events/total samples), median PFS, 95% CI by group, log rank test P, and HR (hazard ratio: high sTK1 vs. low sTK1) with 95% CI. The number of patients at risk is indicated at the bottom of each plot.