Abstract OT3-05-11: Palbociclib after CDK inhibitor and endocrine therapy (PACE): A randomized phase II study of fulvestrant versus palbociclib plus fulvestrant, with and without avelumab, for CDK inhibitor pre-treated HR+/HER2- metastatic breast cancer

Abstract

Background: CDK4/6 inhibition (CDK4/6i) has a significant role in contemporary management of hormone receptor positive/HER2 negative (HR+/HER2-) metastatic breast cancer (MBC). The addition of a CDK4/6i to endocrine therapy (ET) in HR+/HER2- MBC leads to prolongation of progression-free survival in previously untreated and pre-treated HR+/HER2- MBC. Mechanisms of resistance to CDK4/6i are not well described, and it is not known if continuation of CDK4/6i with subsequent lines of ET improves outcomes over ET alone. Further, preclinical data suggest combination therapy with ET, CDK4/6i, and anti-PDL1 may provide synergistic efficacy. The PACE trial was designed to determine the optimal subsequent line of therapy in patients (pts) with HR+ /HER2- MBC that has progressed despite prior CDK4/6 inhibition and endocrine therapy. Methods: PACE (NCT03147287) is a multicenter phase II trial randomizing pts 1:2:1 to Arm A: fulvestrant alone (with option for Palbociclib (P) monotherapy crossover at time of progression); Arm B: fulvestrant + P; or Arm C: fulvestrant + P + avelumab. The primary objective is to evaluate progression-free survival (PFS) with the combination of fulvestrant + P vs. fulvestrant alone; secondary objectives include overall response (OR), safety and tolerability, and PFS comparisons of avelumab containing arm vs other arms. Exploratory objectives include assessment of outcomes in predefined molecular subgroups (i.e. ESR mutation, PI3K mutation, and loss of Rb); and comparing OR by RECIST vs irRECIST in the avelumab cohort. Extensive molecular profiling of tissue, ctDNA, and CTCs for markers of response and resistance to therapy is also planned. Eligible pts have HR+/HER2- MBC, with prior response to and subsequent progression on any CDK4/6i and ET, defined as at least 6 months of prior treatment, with confirmed subsequent progression, and no more than one prior P dose reduction for toxicity. Pts may have had 1-2 prior ET (aromatase inhibitor or tamoxifen), and 0-1 prior lines of chemotherapy. A sample size of 220 patients is planned. Citation Format: Mayer EL, Wander SA, Regan MM, DeMichele AM, Forero A, Rimawi MF, Ma CX, Cristofanilli M, Anders CK, Huang Bartlett C, Koehler M, Winer EP, Burstein HJ. Palbociclib after CDK inhibitor and endocrine therapy (PACE): A randomized phase II study of fulvestrant versus palbociclib plus fulvestrant, with and without avelumab, for CDK inhibitor pre-treated HR+/HER2- metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-11.

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

“…This difference could reflect the different endocrine sensitivity of patients enrolled as well as the prevalence of PIK3CA and SR1 mutations which were present in 30% of patients enrolled in TRINITI-1 trial [118]. Two phase II trials, MAINTAIN (NCT02632045) and PACE (NCT03147287), are evaluating the efficacy of CDK4/6i (ribociclib and palbociclib, respectively) plus fulvestrant in HR-positive BC patients who progressed after a CK4/6i regimen; the PACE study is also exploring the synergistic effect of addition of avelumab (anti-PD-L1) [119,120].…”

CDK4/6 Inhibitors—Overcoming Endocrine Resistance Is the Standard in Patients with Hormone Receptor-Positive Breast Cancer

“…This resulted in an OS of 27.5 and 24.6 months in the fulvestrant and fulvestrant + palbociclib arms, and a total of 42.5 months in the fulvestrant + palbociclib + avelumab arm. Rates of immune-related toxicities under avelumab were low [ 88 ]. Other studies with abemaciclib and pembrolizumab, palbociclib and nivolumab, or ribociclib and spartalizumab demonstrated high grade 3 AE rates, especially for enhanced transaminases and inflammatory lung disease/pneumonitis, indicating that such combinations cannot be developed further.…”

Sequencing of Endocrine and Targeted Therapies in Hormone-Sensitive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

“…In contrast to these results, the recently presented PACE trial did not show benefit in continuing CDK 4/6 inhibition with palbociclib versus placebo, combined with switching the ET to fulvestrant. 9 The PACE study was a three-arm randomized phase II trial where patients who had previously progressed on CDK 4/6 inhibitor and ET were randomly assigned 1:2:1 to fulvestrant alone, fulvestrant and palbociclib, or fulvestrant, palbociclib, and avelumab (a PD-L1 inhibitor). PFS was not improved with fulvestrant plus palbociclib compared with fulvestrant alone (mPFS, 4.6 v 4.8 months; HR, 1.11; 90% CI, 0.79 to 1.55; P 5 .62).…”