On October 20, 2023 Novartis reported that it will present late-breaking results from a prespecified exploratory subgroup analysis of invasive disease-free survival (iDFS) from the pivotal Phase III NATALEE trial at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023. After 27.7 months of follow-up, the iDFS benefit with Kisqali (ribociclib) plus endocrine therapy (ET) was consistent across key prespecified subgroups, compared to ET alone, in patients with stage II and III hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC) (see table below) (Press release, Novartis, OCT 20, 2023, View Source [SID1234636184]). Results were also consistent with those in the overall trial population, reinforcing that the benefit was not driven by a specific patient subgroup1,2.

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iDFS results across key prespecified subgroups1:

Subgroup Treatment Arm, n 3-year iDFS rate, % HR (95% CI)
AJCC Stage II ribociclib + ET, 1011
ET alone, 1034 94
91 0.76
(0.53-1.10)
AJCC Stage III ribociclib + ET, 1528
ET alone, 1512 87
84 0.74
(0.59-0.93)
N0 ribociclib + ET, 285
ET alone, 328 94
89 0.63
(0.34-1.17)
N1-N3 ribociclib + ET, 2261
ET alone, 2219 90
87 0.77
(0.63-0.94)
Premenopausal
women & men ribociclib + ET, 1126
ET alone, 1132 91
89 0.72
(0.53-0.98)
Postmenopausal women ribociclib + ET, 1423
ET alone, 1420 90
86 0.78
(0.61-1.00)
<65 years old ribociclib + ET, 2142
ET alone, 2186 90
87 0.77
(0.62-0.94)
≥65 years old ribociclib + ET, 407
ET alone, 366 90
86 0.72
(0.46-1.14)
Ki-67 ≤20% ribociclib + ET, 1199
ET alone, 1236 92
90 0.80
(0.59-1.08)
Ki-67 >20% ribociclib + ET, 920
ET alone, 938 89
84 0.75
(0.56-1.00)
"Subgroup analyses provide a more comprehensive picture of clinical benefit for patients and are critical to guiding treatment decisions, as they help indicate how different breast cancer subgroups might respond to treatment," said Aditya Bardia, M.D., Attending Physician, Medical Oncology, Mass General Cancer Center and Associate Professor, Medicine, Harvard Medical School and NATALEE trial investigator. "Given the outcomes of patients treated with endocrine therapy alone, this analysis outlines the potential benefit of adding ribociclib to endocrine therapy to reduce the risk of recurrence. These data provide important insight into how we think about residual risk in this population and make adjuvant treatment decisions for patients with localized breast cancer."

"Despite endocrine therapy, cancer recurrence remains unpredictable, and too many patients diagnosed with stage II or III HR+/HER2- early breast cancer experience their cancer coming back. This analysis further reinforces the potential of ribociclib to address the need for a new adjuvant option that reduces the ongoing risk of recurrence consistently across many types of at-risk patients," said Jeff Legos, Executive Vice President, Global Head of Oncology Development at Novartis. "These results from the NATALEE trial add to the wealth of efficacy, safety and quality of life data suggesting that ribociclib, if approved, could provide healthcare providers with a new option to help keep their patients living well and cancer-free."

Further analysis of the NATALEE trial is ongoing. Additional data, including the final efficacy analysis of the NATALEE trial, will be shared at upcoming medical meetings.

About NATALEE
NATALEE is a global Phase III multi-center, randomized, open-label trial to evaluate the efficacy and safety of ribociclib with ET as adjuvant treatment versus ET alone in patients with stage II and III HR+/HER2- EBC, being conducted in collaboration with TRIO2. The adjuvant ET in both treatment arms was a non-steroidal aromatase inhibitor (NSAI; anastrozole or letrozole) and goserelin if applicable2. The primary endpoint of NATALEE is iDFS as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria2. A total of 5,101 adult patients with HR+/HER2- EBC across 20 countries were randomized in the trial2.

Results previously announced at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2023 showed ribociclib 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)2. Ribociclib 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).

For these previously announced results, median study duration of follow-up was 34 months (range 21-48 months) with clinical benefits observed after approximately two years2. NATALEE explored a lower starting dose (400 mg) of ribociclib 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 ribociclib at 400 mg was observed to have lower rates of symptomatic adverse events (AEs) and less need for dose modifications when administered up to three years2. 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%).

*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 data.