Abstract P6-18-10: A phase 1b/2 study of ribociclib plus trastuzumab for the treatment of advanced, treatment-refractory HER2-positive breast cancer
Authors: Goel S , Spring L , Rees R , Andrews C , Tahara RK , Mayer EL , Bardia A , Winer EP , Tolaney SM 
Published: May 2019

Abstract
Introduction:
Despite the success of anti-HER2 therapy, acquired resistance usually develops in the metastatic setting. CDK4/6 pathway activity has been identified as a mediator of this resistance, and in preclinical studies the combination of CDK4/6 and HER2 blockade can be more effective than either therapy alone. We conducted a single-arm phase 1b/2 study of the CDK4/6 inhibitor ribociclib given with trastuzumab or T-DM1 to subjects with advanced, treatment-refractory HER2-positive breast cancer. The results of the trastuzumab cohort are presented below. The primary objective was to determine the clinical benefit rate (CBR) at 24 weeks, and secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and adverse events.
Methods: Individuals with locally advanced or metastatic, measurable HER2-positive breast cancer were eligible. All subjects must have previously received trastuzumab, pertuzumab, and T-DM1 as (neo)adjuvant or metastatic therapy. There was no limit on the number of prior lines of treatment. Patients with previous CDK4/6 inhibitor exposure, QTcF &gt; 450msec on EKG, or without stable brain metastases were excluded. An initial safety run-in phase (with dose-limiting toxicity (DLT) monitoring) included six subjects who received trastuzumab (8mg/kg loading then 6mg/kg IV three-weekly) and ribociclib 400mg PO daily on a continuous schedule (cycle length 21 days). The study had a two-stage design. The first stage required 20 patients, at least 6 of whom must have demonstrated clinical benefit (CR+PR+ SD&gt;24 weeks) in order to recruit 15 more patients to the second stage. All patients with accessible disease underwent metastatic tumor biopsies at baseline and C2D1.
Results: 13 patients were enrolled (6 in the safety run-in and 7 in the expansion cohort). One patient was found to have HER2-negative disease and did not receive treatment. Patient characteristics are shown in Table 1 No DLTs were observed during the safety run-in phase, and ribociclib was thus used at 400mg po daily for the expansion cohort. Grade 3/4 toxicities were observed in 5 patients (41.7%) and included neutropenia (n=2), and fatigue, pain, and muscle weakness (all n=1). No patient demonstrated QTc prolongation &gt;480 msec, or grade 3/4 LFTs. 1/12 patients ((8.3%); 95% CI 0.2%-38.5%) achieved stable disease&gt;24 weeks; no objective responses were observed, and median PFS was 41.5 days. The trastuzumab portion of study was closed early due to limited clinical activity observed (the T-DM1 with ribociclib cohort remains open).
Table 1Age (median, range)50.5 (42 - 71)Number of prior lines of systemic therapy for metastatic disease (median, range)5.5 (0-14)Number with Hormone receptor-positive disease (%)8 (67 %)Number of metastatic sites (median, range)2.5 (2 - 5)
Conclusions: The combination of trastuzumab and ribociclib (400mg daily continuous schedule) is safe, with no new safety signals observed. The limited activity seen in this heavily pretreated population suggests that future efforts to incorporate CDK4/6 inhibition should be limited to a less extensively treat population.
Citation Format: Goel S, Spring L, Rees R, Andrews C, Tahara RK, Mayer EL, Bardia A, Winer EP, Tolaney SM. A phase 1b/2 study of ribociclib plus trastuzumab for the treatment of advanced, treatment-refractory HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-10.