Ribociclib extends progression-free survival in pre-menopausal patients with metastatic hormone receptor-positive breast cancer

MD Anderson-led Phase III trial finds CDK4/6 inhibitor superior to hormone therapy alone

MD Anderson News Release December 06, 2017

The addition of ribociclib, an inhibitor of the cell cycle, to standard hormone therapy significantly improved progression-free survival (PFS) in pre-menopausal patients with advanced hormone receptor-positive (HR+) breast cancer, according to results of the MONALEESA-7 Phase III clinical trial led by researchers at The University of Texas MD Anderson Cancer Center.

The trial results, presented today at the 2017 San Antonio Breast Cancer Symposium by Debu Tripathy, M.D., chair of Breast Medical Oncology, also show a greater overall response rate (ORR), a delay in patient-reported quality-of-life (QOL) deterioration and manageable treatment side effects with ribociclib compared to hormone therapy alone.

Ribociclib is one of a class of drugs that inhibit cyclin-dependent kinases 4/6 (CDK4/6), proteins necessary for progression of the cell cycle. Three CDK4/6 inhibitors have been approved by the Food and Drug Administration (FDA) for combination treatment with standard hormone therapies, known as aromatase inhibitors, in post-menopausal women with advanced HR+ breast cancer. Previously, these patients were treated with hormone therapy alone.

“This is the first study that tells us we can reliably use CDK inhibitors in pre-menopausal patients, which represent about 20 percent of all breast cancer patients in the U.S.,” said Tripathy. “This study confirms that the benefits of these drugs are similar in both pre- and post-menopausal patients with advanced hormone receptor-positive breast cancers, and I think this will change practice.”

Pre-menopausal patients also have been treated with hormone therapy and CDK4/6 inhibitors, in addition to drugs that suppress ovarian production of estrogen, but there previously was a lack of data to confirm the utility of this approach, explained Tripathy.

The international, randomized Phase III clinical trial enrolled 672 metastatic breast cancer patients, all of whom were pre- or peri-menopausal (ceased having periods within the last year) at diagnosis with HR+, HER2-negative disease. Participants could not have had prior hormone therapy for advanced disease or more than one cycle of chemotherapy for advanced disease.

This trial is also unique in that it allowed the use of either tamoxifen or aromatase inhibitors, which can be tolerated differently in some patients, noted Tripathy.

Patients were randomized to receive either ribociclib (335) or placebo (337) in combination with tamoxifen or a nonsteroidal aromatase inhibitor (NSAI), and goserelin, an ovarian suppression drug. In the ribociclib arm, 87 patients (26 percent) received tamoxifen, compared with 90 patients (26.7 percent) in the placebo arm.

“The trial met its primary endpoint of progression-free survival, which was nearly doubled in the ribociclib arm, and it didn’t seem to matter whether patients received tamoxifen or an aromatase inhibitor,” said Tripathy.

Median PFS in the ribociclib arm was 23.8 months compared to 13.0 months in the placebo arm. Among those taking tamoxifen, median PFS was 22.1 months and 11.0 months in the ribociclib and placebo arms, respectively. Patients taking NSAI had median PFS of 27.5 months in the ribociclib arm compared with 13.8 months in the placebo arm. The PFS benefit was consistent across all subgroups.

In patients with measurable disease, the ORR, or percentage of patients with tumor shrinkage, was 50.9 percent among patients receiving ribociclib compared to 36.4 percent in patients in the placebo group.

The most common adverse event was neutropenia, which occurred in 75.8 percent of patients in the ribociclib arm compared to 7.7 percent of patients in the placebo arm. Grade 3/4 neutropenia occurred in 60.6 percent and 3.6 percent of patients on ribociclib and placebo, respectively. However, consequences of this were rare; febrile neutropenia, or development of a fever, occurred in just 2 percent and 1 percent of patients in the ribociclib and placebo arms, respectively. Additional side effects included hot flushes, nausea, leukopenia and arthralgia.

Patient-reported QOL measures revealed a significant improvement in time to deterioration and a clinically meaningful improvement from baseline in pain score.

“This trial showed significant clinical benefits for patients treated with ribociclib and a manageable safety profile,” said Tripathy. “I think this is an important step forward for pre-menopausal patients, as we see they receive similar benefits from CDK inhibitors as post-menopausal patients.”

Going forward, the study leaders plan to share the trial data with the FDA for consideration of an amendment to the drug’s label requirements. Overall survival will be available in the future as the data matures.

The study was sponsored by Novartis Pharmaceuticals Corporation, which markets ribociclib (Kisqali). Tripathy serves as a paid consultant for Novartis, and MD Anderson received funds from Novartis to conduct this study.

In addition to Tripathy, co-investigators on the study are: Joohyuk Sohn, M.D., Ph.D., Severance Hospital of Yonsei University Health System, Seoul; Seock-Ah Im, M.D., Ph.D., Seoul National University Hospital, Seoul; Marco Colleoni, M.D., Unità di Ricerca in Senologia Medica – Istituto Europeo di Oncologia, Milan, Italy; Fabio Franke, M.D., Hospital de Caridade de Ijuí, CACON, Ijuí, Brazil; Aditya Bardia, M.D., Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Nadia Harbeck, M.D., Ph.D., University of Munich (LMU), Munich, Germany; Sara Hurvitz, M.D., UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA; Louis Chow, M.D., Organisation for Oncology and Translational Research, Hong Kong; Keun Seok Lee, M.D., Ph.D., Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea; Saul Campos-Gomez, M.D., Centro Oncológico Estatal, Instituto de Seguridad Social del Estado de México y Municipios, Toluca, Mexico; Rafael Villanueva Vazquez, M.D., Institut Català d’Oncologia, Hospital Moisès Broggi, Barcelona, Spain; Kyung Hae Jung, M.D., Ph.D., Asan Medical Center, University of Ulsan College of Medicine, Seoul; Gary Carlson, Caroline Germa, M.D., Samit Hirawat, M.D., all of Novartis Pharmaceuticals Corporation, East Hanover, NJ; Gareth Hughes, Ph.D. and Ivan Diaz-Padilla, M.D., Ph.D. both of Novartis Pharma AG, Basel, Switzerland; and Yen-Shen Lu, M.D., Ph.D. National Taiwan University Hospital, Taipei, Taiwan.