Abstract CT107: Ribociclib in combination with everolimus and exemestane in men and postmenopausal women with HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: Efficacy and safety results from phase II of the TRINITI-1 study
Authors: Moulder Stacy , Karuturi Megan , Yardley Denise A. , Wright Gail Shaw , Hurvitz Sara , Moroose Rebecca , Sanft Tara , Ma Cynthia , Zelnak Amelia , DeMichele Angela , Clark Amy , Purkayastha Das , Khullar Alisha , Caria Nicola , Bardia Aditya 
Published: August 2018

Abstract
Background: Combining endocrine therapy (ET) with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor significantly improves progression-free survival (PFS) over ET alone in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, optimal management of disease that progresses on this therapy is not established. In Phase 1 of the TRINITI-1 study (ClinicalTrials.gov identifier: NCT02732119), continuous ribociclib 300 mg/d + everolimus (EVE) 2.5 mg/d + exemestane (EXE) 25 mg/d, the recommended Phase 2 dose, resulted in 1 dose-limiting toxicity. Clinical benefit at week 24 was found in 3 of 6 patients whose disease had progressed on a CDK4/6 inhibitor. Here we report Phase 2 efficacy and safety in patients whose disease progressed on a CDK4/6 inhibitor.
Methods: Men and postmenopausal women with HR+, HER2− ABC whose disease progressed on ≤3 lines of therapy for ABC (1-3 lines of ET and ≤1 line of chemotherapy) and had measurable disease and/or lytic/mixed bone lesions were eligible. Progression on 1 CDK4/6 inhibitor, as the last therapy before enrollment, after ≥4 months of treatment for ABC was required. Dexamethasone mouthwash was required for the first 8 weeks. The primary objective of clinical benefit at 24 weeks in Phase 2 would be met if ≥9 of 42 patients had clinical benefit at 24 weeks. Secondary objectives included PFS, tumor response, safety, and tolerability.
Results: Of 46 enrolled patients, 44 were evaluable; among 42 evaluable for efficacy, 6 had prior chemotherapy, 13 had ≥2 prior lines of therapy (median, 1 line), and 13 were on therapy on December 15, 2017. At week 24, 17 patients (40.5%) had clinical benefit by local assessment; the overall response rate was 7.1% (n=3; all had partial response at week 24). Median PFS was 8.8 months (95% CI, 1.9 months-not evaluable). In the safety set (n=44), there was 1 on-treatment death unrelated to study drug; 1 patient discontinued with Grade 4 hypophosphatemia. Common (≥25%) any-grade adverse events were neutropenia (68.2%), stomatitis (45.5%), fatigue (38.6%), nausea (34.1%), thrombocytopenia (34.1%), diarrhea (29.5%), and anemia (25.0%). Seven patients (15.9%) had Grade 1/2 pneumonitis, 23 (52.3%) had Grade 3/4 neutropenia, 2 (4.5%) had Grade 3/4 increased aspartate aminotransferase, and 1 (2.3%) had Grade 3/4 increased alanine aminotransferase. Febrile neutropenia, Grade 3/4 stomatitis or pneumonitis, and corrected QT interval (Fridericia's formula) &gt;480 ms were not observed.
Conclusion: TRINITI-1 is the first trial to demonstrate promising clinical benefit and tolerability of continuous ribociclib 300 mg/d, EVE 2.5 mg/d, and EXE 25 mg/d following progression on a CDK4/6 inhibitor, warranting further evaluation of this combination.
Citation Format: Stacy Moulder, Megan Karuturi, Denise A. Yardley, Gail Shaw Wright, Sara Hurvitz, Rebecca Moroose, Tara Sanft, Cynthia Ma, Amelia Zelnak, Angela DeMichele, Amy Clark, Das Purkayastha, Alisha Khullar, Nicola Caria, Aditya Bardia. Ribociclib in combination with everolimus and exemestane in men and postmenopausal women with HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: Efficacy and safety results from phase II of the TRINITI-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT107.