Original Study Ribociclib Plus Trastuzumab in Advanced HER2-Positive Breast Cancer: Results of a Phase 1b/2 Trial Shom Goel, 1,2 Sonia Pernas, 1,4 Zhenying Tan-Wasielewski, 3 William T. Barry, 3 Aditya Bardia, 5 Rebecca Rees, 1 Chelsea Andrews, 1 Rie Kawabori Tahara, 1 Lorenzo Trippa, 3 Erica L. Mayer, 1 Eric P. Winer, 1 Laura M. Spring, 5 Sara M. Tolaney 1 Abstract Preclinical studies have demonstrated that cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors can resensitize HER2-positive breast cancers to anti-HER2 therapies. We conducted a phase 1b/2 study of ribociclib (400 mg per day) plus trastuzumab in heavily pretreated patients with advanced HER2-positive disease. Continuous low-dose ribociclib plus trastuzumab was safe, but only 1 of 12 patients experienced stable disease. These findings suggest that further study of CDK4/6 inhibitor/anti-HER2 combinations should focus on a less pre- treated population. Background: Signaling through the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway can mediate therapeutic resistance in HER2-positive breast cancer. Preclinical studies have demonstrated that CDK4/6 inhibitors can resensitize resistant HER2-positive breast cancer to anti-HER2 therapies. Patients and Methods: We conducted a phase 1b/2 study of ribociclib (400 mg per day on a continuous schedule) plus trastuzumab (6 mg/kg every 3 weeks) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. There were no restrictions on the number of prior therapy lines. Primary objective was clinical benefit rate at 24 weeks, and secondary objectives included safety, objective response, rate and progression-free survival. The study was enrolled at ClinicalTrials.gov as NCT02657343. Results: From March 2016 to March 2017, 13 patients were enrolled. One patient was found to have HER2-negative disease and did not receive treatment. Median number of prior lines in the metastatic setting was 5 (range, 0-14); 67% had hormone receptorepositive disease. No dose-limiting toxicities were observed during the safety run-in phase, and ribociclib was thus dosed at 400 mg per day continuously for the expansion cohort. Grade 3 adverse events were observed in 4 patients (33.3%) and included neutropenia (n ¼ 2) as well as fatigue and pain in 1 patient each. No grade 4/5 adverse events or QTc prolongation were observed. One patient (8.3%) experienced stable disease > 24 weeks; no objective responses were observed, and median progression-free survival was 1.33 months (95% confidence interval, 0.92-2.57). Conclusion: Continuous low-dose ribociclib (400 mg) plus trastuzumab is safe, with no new safety concerns. The limited activity observed in this study suggests that further study of CDK4/6 inhibitor/anti-HER2 combinations should focus on a less pretreated population. Clinical Breast Cancer, Vol. -, No. -, --- ª 2019 Elsevier Inc. All rights reserved. Keywords: CDK4/6 inhibitors, Continuous daily low-dose, HER2-positive, Ribociclib, Trastuzumab Presented in part at the San Antonio Breast Cancer Symposium (SABCS), San Antonio, TX, December 2018. S.G. and S.P. contributed equally to this work as first authors. Current addresses for Shom Goel: Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia; and The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Australia. 1 Department of Medical Oncology 2 Department of Cancer Biology 3 Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 4 Department of Medical Oncology, Institut Catala d’Oncologia-H. U. BellvitgeeIDIBELL, Barcelona, Spain 5 Department of Medical Oncology, Massachusetts General Hospital, Boston, MA Submitted: Apr 18, 2019; Revised: May 20, 2019; Accepted: May 21, 2019 Address for correspondence: Shom Goel, MD, PhD, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; and Sara M. Tolaney, MD, MPH, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 Fax: (617) 632-3000; e-mail contact: Shom.goel@petermac.org; Sara_Tolaney@dfci. harvard.edu 1526-8209/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clbc.2019.05.010 Clinical Breast Cancer Month 2019 - 1