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

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) >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.

MONALEESA Clinical Program: A Review of Ribociclib use in Different Clinical Settings

“…Preliminary results from the initial 1008 patients with any menopausal status enrolled with 56 days of follow-up demonstrated a safety profile of ribociclib plus letrozole consistent with that of the MONALEESA-2 trial of postmenopausal women receiving first-line treatment for HR+, HER2-ABC [35]. Another ongoing trial, the TRINITI-1 trial (ClinicalTrials.gov identifier: NCT02732119), is investigating the effects of continuing a CDK4/6 inhibitor through triplet therapy (ribociclib plus everolimus plus exemestane) in patients with disease progression on a CDK4/6 inhibitor [36]. Furthermore, the disposition of ribociclib in the CNS is also being investigated in preclinical and early clinical studies.…”

Real-World Evaluation of Disease Progression After CDK 4/6 Inhibitor Therapy in Patients With Hormone Receptor-Positive Metastatic Breast Cancer

“… 38 , 54-60 Emerging studies support a strategy for suppression of CDK4/6 activity combined with inhibition of PI3K/AKT/mTOR signaling to overcome CDKi resistance; however, no single gene alteration in the PI3K pathway has proven predictive of survival, suggesting that redundancies in the PI3K signaling network influence oncogenic potency. 6 , 37 , 38 , 50 , 51 , 54 , 55 , 58-61 Mutational profiling available in a subset of our cohort revealed a preponderance of mutations in constituents of the FGFR/FGF and PI3K/AKT/mTOR pathways, which have known crosstalk mediating CDKi and endocrine resistance. 13 , 62 Particularly, we observed that patients harboring a PTEN mutation before initiation of CDKi had significantly shorter post-CDKi PFS and 6 times the odds of experiencing rapid disease progression.…”

Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2− Breast Cancer

“…TRINITI-1 was a phase II trial combining ribociclib with everolimus and exemestane in patients who experienced progression on CDK 4/6 inhibition with AI. 54 An appreciable clinical benefit rate of 39.5% was seen. Further randomized trials studying this strategy are ongoing.…”