On June 2, 2023 Novartis reported positive primary endpoint data from the pivotal Phase III NATALEE trial at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Novartis, JUN 2, 2023, View Source [SID1234632401]). Data showed that Kisqali (ribociclib) plus endocrine therapy (ET), compared to ET alone, lowered the risk of cancer recurrence by 25.2% in patients with stage II and III hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (HR=0.748; 95% CI: 0.618, 0.906; p=0.0014) along with a consistent, clinically meaningful invasive disease-free survival (iDFS) benefit across key pre-specified subgroups (see table below)1.
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Kisqali iDFS benefit across key pre-specified subgroups1:
Hazard Ratio 95% CI
Intention-To-Treat Population 0.748 0.618, 0.906 (p=0.0014)
AJCC Tumor Stage II 0.761 0.525, 1.103
AJCC Tumor Stage III 0.740 0.592, 0.925
Node-positive disease 0.771 0.630, 0.944
Node-negative disease 0.630 0.341, 1.165
Pre-menopausal women and men 0.722 0.530, 0.983
Post-menopausal women 0.781 0.613, 0.997
Kisqali data across all secondary efficacy endpoints was also consistent, including distant disease-free survival (DDFS) (26% risk reduction) and recurrence-free survival (RFS) (28% risk reduction), with a trend for improvement in overall survival (OS) (HR=0.759; 95% CI: 0.539, 1.068)*1.
The safety profile of Kisqali at 400 mg was favorable with low rates of symptomatic adverse events (AEs) and limited need for dose modifications when administered up to three years1. The most frequently reported AEs of special interest (grade 3 or higher) were neutropenia (43.8%) and liver-related AEs (e.g. elevated transaminases) (8.3%)1. Grade 3 or higher QT interval prolongation and diarrhea were low for Kisqali at 1.0% and 0.6%, respectively1.
"These landmark results will fundamentally change how we treat patients with stage II and III HR+/HER2- early breast cancer who are in need of new, well-tolerated options that prevent their cancer from coming back," said Dennis J. Slamon, M.D., Director of Clinical/Translational Research, UCLA Jonsson Comprehensive Cancer Center and Chairman and Executive Director of Translational Research In Oncology (TRIO) and NATALEE trial lead investigator. "Addressing this unmet need across such a broad patient population could help streamline treatment decisions for healthcare providers and keep many more at-risk patients cancer-free without disrupting their daily lives."
"Patients diagnosed with HR+/HER2- early breast cancer remain at risk of cancer recurrence, given that one-third of patients diagnosed with stage II and more than half of those diagnosed with stage III will unfortunately experience a return of their cancer," said Shreeram Aradhye, M.D., President, Global Drug Development and Chief Medical Officer, Novartis. "The compelling data from NATALEE highlight the potential of Kisqali to reduce the risk of cancer recurrence in this at-risk population, including node-negative patients, while maintaining a favorable safety profile. These potentially practice-changing results reinforce the unique and well-established profile of Kisqali as a proven treatment in HR+/HER2- metastatic breast cancer."
"After an early breast cancer diagnosis, patients live with a persistent and lifelong worry that their cancer will return," said Fran Visco, President, National Breast Cancer Coalition, and member of the NATALEE Steering Committee. "The National Breast Cancer Coalition partners with industry and scientists to help find treatments that will make certain that does not happen. Educated patient advocate participation in all phases of research, especially in designing and implementing clinical trials, is critical to making certain patients have meaningful options, and we are grateful that Novartis welcomed our collaboration and participation in all aspects of the NATALEE trial."
Novartis plans to submit these Phase III data to regulatory authorities in the US and Europe before end of year.
About NATALEE
NATALEE is a global Phase III multi-center, randomized, open-label trial to evaluate the efficacy and safety of Kisqali with ET as adjuvant treatment versus ET alone in patients with HR+/HER2- EBC, being conducted in collaboration with TRIO1. The adjuvant ET in both treatment arms was a non-steroidal aromatase inhibitor (NSAI; anastrozole or letrozole) and goserelin if applicable1. The primary endpoint of NATALEE is iDFS as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria1. A total of 5,101 adult patients with HR+/HER2- EBC across 20 countries were randomized in the trial1.
Results showed Kisqali plus ET, compared to ET alone, lowered the risk of cancer recurrence by 25.2% (HR=0.748; 95% CI: 0.618, 0.906; p=0.0014), along with consistent clinically meaningful iDFS benefit across key pre-specified subgroups: AJCC Tumor Stage II (HR=0.761; 95% CI: 0.525, 1.103), AJCC Tumor Stage III (HR=0.740; 95% CI: 0.592, 0.925), node-negative disease (HR=0.630; 95% CI: 0.341, 1.165), node-positive disease (HR=0.771; 95% CI: 0.630, 0.944), pre-menopausal women and men (HR=0.722; 95% CI: 0.530, 0.983), post-menopausal women (HR=0.781; 95% CI: 0.613, 0.997)1. Kisqali data across all secondary efficacy endpoints was also consistent, including DDFS (26% risk reduction) and RFS (28% risk reduction), with a trend for improvement in OS (HR=0.759; 95% CI: 0.539, 1.068)*1.
Median study duration of follow up was 34 months (range 21-48 months) with clinical benefits observed after approximately two years1. NATALEE explored a lower starting dose (400 mg) of Kisqali than the dose approved for treatment in metastatic breast cancer (MBC) (600 mg) with the goal to minimize disruptions to patient quality of life without compromising efficacy. The safety profile of Kisqali at 400 mg was favorable with low rates of symptomatic AEs and limited need for dose modifications when administered up to three years1. The most frequently reported AEs of special interest (grade 3 or higher) were neutropenia (43.8%) and liver-related AEs (e.g. elevated transaminases) (8.3%)1. Grade 3 or higher QT interval prolongation and diarrhea were low for Kisqali at 1.0% and 0.6%, respectively1.
*Results based on pre-specified interim analysis for OS at time of primary iDFS analysis; additional follow up is planned to obtain more mature OS data1.
About Early Breast Cancer
More than 90% of patients diagnosed with breast cancer have EBC3. Despite standard-of-care adjuvant therapy, approximately one-third of those diagnosed with stage II and more than half of those diagnosed with stage III HR+/HER2- EBC experience cancer recurrence4,5. The risk of recurrence continues over decades with more than half of breast cancer recurrences occurring five or more years after diagnosis4,6. For many of these patients, there are currently no targeted therapeutic options outside of the standard chemotherapy and ET7.
About Kisqali (ribociclib)
Kisqali has consistently demonstrated OS benefit while preserving or improving quality of life across three Phase III trials in MBC8-19. Updates to the NCCN Guidelines for breast cancer, released in January 2023, recommend ribociclib (Kisqali) as the only Category 1 preferred CDK4/6 inhibitor for first-line treatment of patients with HR+/HER2- MBC when combined with an aromatase inhibitor (AI)20. Additionally, Kisqali has the highest rating of any CDK4/6 inhibitor on the ESMO (Free ESMO Whitepaper) Magnitude of Clinical Benefit Scale, achieving a score of five out of five for first-line pre-menopausal patients with HR+/HER2- advanced breast cancer21. Further, Kisqali in combination with either letrozole or fulvestrant has uniquely, among other CDK4/6 inhibitors, received a score of four out of five for post-menopausal patients with HR+/HER2- advanced breast cancer treated in the first line22.
Kisqali has been approved in 99 countries worldwide, including by the United States Food and Drug Administration (FDA) and the European Commission. In the U.S., Kisqali is approved for the treatment of adult patients with HR+/HER2- advanced or MBC in combination with an AI as initial ET or fulvestrant as initial ET or following disease progression on ET in post-menopausal women or in men. In the EU, Kisqali is approved for the treatment of women with HR+/HER2- advanced or MBC in combination with either an AI or fulvestrant as initial ET or following disease progression. In pre- or peri-menopausal women, the ET should be combined with a luteinizing hormone-releasing hormone agonist19.
Novartis is committed to continuing to study Kisqali in breast cancer. Novartis is collaborating with SOLTI, which is leading the HARMONIA study to test whether Kisqali changes tumor biology to enable a better response to ET compared to Ibrance** (palbociclib) for patients with HR+/HER2-, HER2-enriched subtype23 MBC, and with the Akershus University Hospital in Norway on the NEOLETRIB trial, a neoadjuvant Phase II trial studying the effects of Kisqali in HR+/HER2- EBC to discover the potentially unique underlying mechanism of action24.
Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.
Please see full Prescribing Information for Kisqali, available at www.Kisqali.com