Endocrine therapy (ET) is an established first-line treatment for ABC. However, ET resistance and disease progression eventually occur in most patients. Cyclin-dependent kinase (CDK) 4/6 inhibition is a valid treatment strategy for HR+ ABC and may help overcome or delay ET resistance. Here we report interim results from MONALEESA-2 (NCT01958021), a double-blind, randomized, phase 3 trial evaluating the efficacy and safety of first-line ribociclib (a selective CDK4/6 inhibitor) + letrozole in women with HR + , HER2– ABC.
Postmenopausal women (N = 668) with HR + , HER2– ABC with no prior systemic treatment for ABC were randomized (1:1) to receive ribociclib (600 mg/day, 3-weeks-on/1-week-off) + letrozole (2.5 mg/day, continuous) or placebo + letrozole. The primary endpoint was locally assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS; key secondary endpoint), overall response rate (ORR), clinical benefit rate (CBR), and safety. A pre-planned interim analysis was conducted after 243 PFS events (information fraction 80%) had occurred.
Baseline patient characteristics were balanced between treatment arms. The study met its primary objective: at the interim analysis (data cut-off Jan 29, 2016), PFS was significantly improved in the ribociclib arm, with a hazard ratio of 0.556 (95% CI: 0.429–0.720; p = 0.00000329). Median PFS was not reached in the ribociclib arm (95% CI: 19.3–not estimable) vs 14.7 months in the placebo arm (95% CI: 13.0–16.5). In patients with measurable disease at baseline, ORR was 53% vs 37% (ribociclib vs placebo arm; p = 0.00028) and CBR was 80% vs 72% (p = 0.02). Common Grade 3/4 adverse events (≥5% of patients; ribociclib vs placebo arm) were neutropenia (59% vs 1%), leukopenia (21% vs 1%), hypertension (10% vs 11%), elevated alanine aminotransferase (9% vs 1%), lymphopenia (7% vs 1%), and elevated aspartate aminotransferase (6% vs 1%). OS data were immature at data cut-off.
Ribociclib + letrozole was well tolerated and significantly prolonged PFS vs letrozole alone in postmenopausal women with HR + , HER2– ABC who had received no prior therapy for ABC.
Clinical trial identification
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation
Novartis Pharmaceuticals Corporation
G.N. Hortobagyi: Grants and personal fees from Novartis, during the conduct of the study; personal fees from Eli Lilly, LLC, and Pfizer, outside the submitted work. S.M. Stemmer: Advisory boards for Novartis in Hong Kong, Germany and Berlin (June 2016); PI in pharma sponsored trials; travel and hotel expenses for Genomic Health. Y.S. Yap: Consultant/advisory board and honoraria from Novartis. S. Paluch-Shimon: Payment schedule for study costs from Sheba Medical Center, during the conduct of the study; personal fees from Novartis and Roche, consultancy and personal fees from Pfizer, outside the submitted work. M. Campone: Advisory board, grant, and speaker bureau for Novartis; Advisory board for Menarini and Roche; Advisory board speaker bureau for AstraZeneca and Pfizer. K. Blackwell: Institute research support and consultancy fees from Novartis. F. André: Research support from Novartis. W. Janni: Research grants and honoraria from Novartis. S. Verma: Advisory boards for Amgen, AstraZeneca, Eli Lilly, Novartis, Pfizer, Roche. P. Conte: Speaker and advisory boards for AstraZeneca, Celgene, Eli Lilly, Novartis, Obi, and Roche; research grants from Merck-Serono, Novartis, and Roche. C.L. Arteaga: Consultant for AstraZeneca, Clovis, Kiyatek, Lilly, Merrimak, Monogram Bio, Novartis, Provista, Radius, Roche, Susan G. Komen, Symphogen; grants from AstraZeneca, Novartis, PUMA Biotechnology, Symphogen, U3 Pharma-Daichi; stock ownership at Provista. D. Cameron: Institute remuneration for advisory boards for Novartis and Pfizer, and DMC for Lilly. F. Xuan, M. Miller, C. Germa: Employee of Novartis; stock ownership at Novartis. F. Souami: Employee of Novartis. J. O'Shaughnessy: Advisor and honorarium from Novartis. All other authors have declared no conflicts of interest.