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.

Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor–Positive (HR+)/HER2-Negative Metastatic Breast Cancer

“…For these patients, plasma samples collected at the timepoints immediately prior to clinical progression were also included in this analysis. The results of the primary endpoint (rate of grade 3 or 4 neutropenia), and clinical response were reported previously ( 40 ). The study was approved by the institutional review board at each site and conducted according to the ethical guidelines set forth in the Declaration of Helsinki.…”

“…Serial ctDNA testing was performed retrospectively on samples collected from a prospective clinical trial of palbociclib in combination with ET (letrozole or fulvestrant) (40). Two-hundred sixty-five samples from 51 evaluable patients with HR+/HER2-negative MBC were analyzed using Predicine liquid biopsy NGS platforms (Figure 1A).…”

Identifying cooperative genes causing cancer progression with dynamic causal inference

“…To name a few of the novel non-mutated cancer drivers discovered by the proposed method, CXCL12 (specifically the CXCL12/CXCR4 signal pathway) has been found to promote several aspects of breast cancer tumorigenesis, such as proliferation, cell motility, and distant metastasis [39, 40, 41]. TK1 and MDK have also been linked to advanced/metastatic stages of breast cancer [42, 43, 44, 45, 46], while CIB1 is a promising therapeutic target gene that drives cancer cell death [47, 48]. The relevance of the discovered genes to cancer provides strong support for the effectiveness of the proposed method in identifying mutated and non-mutated drivers of cancer.…”

The CDK4/6 Inhibitor Palbociclib Inhibits Estrogen-Positive and Triple Negative Breast Cancer Bone Metastasis In Vivo

“…However, all the animals in the palbociclib treated group developed skeletal tumours by the end of the experiment, suggesting that this schedule only delayed, rather than prevented, tumour progression in bone. The 5 day-on/2 day-off regimen may improve adverse events, as has been assessed in a phase II trial (NCT03007979), demonstrating reduced neutropoenia grades [ 47 ]; however no data exist on survival and disease progression using this treatment regimen. Other trials have demonstrated significant improvements in overall survival (OS) and progression free survival (PFS), with few adverse events, in response to 3 week-on/1 week-off palbociclib treatment cycles [ 44 ].…”