ESMO 2016 Press Release: Ribociclib Improves Progression-free Survival in Advanced Breast Cancer

LUGANO-COPENHAGEN – The addition of the CDK4/6 inhibitor ribociclib to letrozole therapy significantly improves progression-free survival in postmenopausal women with hormone receptor-positive advanced breast cancer, researchers reported today at the ESMO 2016 Congress in Copenhagen.

The first interim analysis of data from the randomized, double-blind MONALEESA2 study showed a 44% improvement in progression-free survival with ribociclib plus letrozole as a first-line treatment combination.

“This was THE definitive study to demonstrate the superiority of the combination of ribociclib and letrozole over letrozole alone,” said principle investigator, Professor Gabriel Hortobagyi, from the University of Texas MD Anderson Cancer Center in Houston, Texas, US.

 Kaplan–Meier Analysis of Progression-free Survival

Let, letrozole; NR, not reached

Researchers randomized 668 postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, who had not undergone any prior systemic treatment, to ribociclib (600 mg/day, 3 weeks on/1 week off) and letrozole (2.5 mg/day, continuous), or letrozole plus placebo.

In the ribociclib arm, there was a 44% improvement in the primary objective of progression-free survival compared to the placebo arm (HR: 0.556, p = 0.00000329). Median progression-free survival was 14.7 months in the placebo arm, but was not reached in the ribociclib arm at data cut-off.

“The results of this trial represent a compelling proof of principle, and suggest a paradigm shift in metastatic, HR+ breast cancer. They also suggest that testing combinations of ribociclib with other inhibitors of various signaling pathways might lead to additional progress in the management of several subtypes of breast cancer,” Hortobagyi said.

Patients with measurable disease at baseline showed a significantly higher objective response rate to ribociclib plus letrozole compared to letrozole alone (53% vs. 37%; p=0.00028), and improved clinical benefit rate (80% vs. 72% p=0.02).

Subgroup Analysis of Progression-free Survival

NSAI, non-steroidal aromatase inhibitor.
*Excludes patients who had received tamoxifen.

Serious adverse events occurred in fewer than 5% of patients in both arms but other adverse events were significantly more common in the ribociclib arm. Neutropenia occurred in 59% of patients in the ribociclib arm compared to 1% of the placebo arm; leukopenia occurred in 21% vs 1%; lymphopenia in 7% vs. 1%, and patients in the ribociclib arm had a higher incidence of elevated alanine aminotransferase and elevated aspartate aminotransferase.

The number of deaths in the study was too low to enable a reliable analysis of the impact of ribociclib therapy on overall survival.

Commenting on the findings, Professor Giuseppe Curigliano, Director of the New Drugs and Early Drug Development for Innovative Therapies Division at the European Institute of Oncology, Milan, Italy, said, “I believe the results of this study are significant because now we have a new CDK4/6 inhibitor for patients with estrogen-receptor positive metastatic breast cancer, in addition to palbociclib (already FDA approved) and abemaciclib (under development).”

“The addition of ribociclib to letrozole does increase the rate of toxicity, but overall, if we evaluate the magnitude of clinical benefit, there is definitely a benefit to be gained from adding ribociclib.”

Curigliano also suggested that further studies of ribociclib should examine the use of cancer biomarkers to better identify patients who would respond to the combination.

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Notes to Editors

References

Abstract LBA1_PR ‘Ribociclib + letrozole for postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer who received no prior therapy for advanced disease’ will be presented by Professor Gabriel Hortobagyi during the Presidential Symposium 1: on Saturday, 8 October, 16:30 to 18:00 (CEST) in Room Copenhagen. 

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Abstract for LBA1_PR

First-line ribociclib + letrozole for postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2–), advanced breast cancer (ABC)

G.N. Hortobagyi1, S.M. Stemmer2, H.A. Burris3, Y.S. Yap4, G.S. Sonke5, S. Paluch-Shimon6, M. Campone7, K. Blackwell8, F. André9, E.P. Winer10, W. Janni11, S. Verma12, P. Conte13, C.L. Arteaga14, D. Cameron15, F. Xuan16, F. Souami17, M. Miller16, C. Germa16, J. O'Shaughnessy18

1Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 2Davidoff Center, Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel, 3Drug Development Unit, Sarah Cannon Research Institute, Nashville, TN, USA, 4Division of Medical Oncology, National Cancer Center, Singapore, 5Department of Medical Oncology, Netherlands Cancer Institute and BOOG Study Center, Amsterdam, Netherlands, 6The Oncology Institute, Sheba Medical Center, Ramat Gan, Israel, 7Institut de Cancérologie de l’Ouest, René Gauducheau, Saint-Herblain, France, 8Department of Medicine, Duke University Medical Center, Durham, NC, USA, 9Department of Medical Oncology, Institut Gustave Roussy, Université Paris Sud, Villejuif, France, 10Breast Oncology Center, Dana-Farber Cancer Institute, Boston, MA, USA, 11Department of Gynecology and Obstetrics, University of Ulm, Ulm, Germany, 12Department of Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada, 13University of Padova, Istituto Oncologico Veneto IRCCS, Padua, Italy, 14Center for Cancer Targeted Therapies, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA, 15Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK, 16Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 17Oncology, Novartis Pharma AG, Basel, Switzerland, 18Texas Oncology-Baylor Charles A. Sammons Cancer Center, The US Oncology Network, Dallas, TX, USA

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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: MONALEESA-2/NCT01958021

Legal entity responsible for the study: Novartis Pharmaceuticals Corporation

Funding: Novartis Pharmaceuticals Corporation

Disclosure:
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.

Keywords: Ribociclib, Advanced breast cancer, MONALEESA-2, CDK4/6