Shom Goel1, Sonia Pernas2, Zhenying Tan-Wasielewski3, William T Barry3, Aditya Bardia4, Rebecca Rees5, Chelsea Andrews5, Rie Kawabori Tahara5, Lorenzo Trippa3, Erica L Mayer5, Eric P Winer5, Laura M Spring4, Sara M Tolaney6. 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA. Electronic address: Shom.goel@petermac.org. 2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medical Oncology, Institut Catala d'Oncologia-H. U. Bellvitge-IDIBELL, Barcelona, Spain. 3. Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA. 4. Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. 5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. 6. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. Electronic address: Sara_Tolaney@dfci.harvard.edu.
Abstract
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 receptor-positive 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 = 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.
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 receptor-positive 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 = 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.
Authors: Maria Chiara Parati; Rebecca Pedersini; Gianluca Perego; Roberto Reduzzi; Tommaso Savio; Mary Cabiddu; Karen Borgonovo; Mara Ghilardi; Andrea Luciani; Fausto Petrelli Journal: Breast Cancer (Dove Med Press) Date: 2022-04-12