TBCRC 035: randomized phase II pharmacodynamic study of standard and reduced-dose palbociclib with endocrine therapy in hormone receptor (HR)-positive previously treated metastatic breast cancer.

The cyclin-dependent kinase 4/6 inhibitor palbociclib induces neutropenia, resulting in dose delays and reductions. This multicenter phase II trial randomly assigned patients with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer to receive palbociclib 100 mg versus 125 mg with fulvestrant or tamoxifen; cross-over was allowed. Baseline and on-treatment skin and tumor biopsies were analyzed for expression of phosphorylated retinoblastoma protein (pRb), total Rb, and Ki-67. Baseline circulating tumor DNA was collected. The primary endpoint was grade ≥3 neutropenia. Seventy patients with a median of 3 prior treatment lines (range 0-6) were enrolled; 36 received 100 mg and 34 received 125 mg. Grade ≥3 neutropenia occurred in 12 (33%) and 19 (56%) patients in the 100 versus 125 mg groups, respectively (P = 0.04). Median progression-free survival (PFS) was 6.28 versus 9.28 months for 100 versus 125 mg, respectively (hazard ratio 1.697, 95% confidence interval 0.973-2.96, P = 0.0585). Five patients crossed over to 125 mg; two patients were treated for >12 months. Tumor and skin pRb and Ki-67 decreased on treatment, with similar percent changes across palbociclib dose (tumor pRb: -2.16 and -4.64, P = 0.897; tumor Ki-67: -10.27 and -6.7, P = 0.437 for 100 mg and 125 mg, respectively; skin pRb and Ki-67 P < 0.02 at both doses). Baseline mutations in PIK3CA and TP53, and higher baseline Ki-67 were associated with shorter PFS. Changes in pRb and Rb were not associated with PFS. Palbociclib 100 mg was associated with a reduced incidence of ≥grade 3 neutropenia. While PFS was numerically lower at 100 mg, the difference was not statistically significant and was limited by sample size and complicated by varying degrees of pre-treatment. Analysis of skin and tumor pRb or Ki-67 demonstrated robust molecular response at both doses. PIK3CA and TP53 mutations and higher baseline Ki-67 were associated with inferior clinical outcome.