Latest Novartis Kisqali® NATALEE analysis reinforces 25% reduction in risk of recurrence across broad population of patients with early breast cancer; supports regulatory submissions

• With 5.6 months of additional follow-up and 78.3% of patients having completed Kisqali® (ribociclib) investigational treatment, the updated analysis shows sustained iDFS benefit and stability in secondary endpoints including overall survival (OS)1,2

• iDFS benefit remains consistent across key patient subgroups; among patients with stage II and stage III tumors, Kisqali lowered risk by 30% and 24.5%, respectively1,2

• Latest analysis continues to show a well-tolerated safety profile in line with previously reported results, and quality of life for Kisqali patients preserved vs. endocrine therapy (ET) alone1,2,3

• Risk of recurrence remains a short and long term concern; one in eight women treated with ET alone in NATALEE likely to experience invasive disease at 3 years1,2

• Kisqali is currently approved in the metastatic setting, where it has consistently demonstrated statistically significant OS benefit across three Phase III trials4-15; Novartis has filed NATALEE results with EMA and will submit these latest EBC data to the FDA by end of year

Basel, December 8, 2023 – Novartis today announced results from an updated invasive disease-free survival (iDFS) analysis of the pivotal Phase III NATALEE trial, with a median follow-up of 33.3 months and following Kisqali® (ribociclib) treatment completion by 78.3% of patients. Results reinforce the benefit seen at the earlier interim analysis, with a 25.1% (HR=0.749; 95% CI: 0.628, 0.892; p=0.0006) reduction in risk of disease recurrence in patients with stage II and III hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC) treated with adjuvant Kisqali plus a non-steroidal aromatase inhibitor as standard endocrine therapy (ET) compared to ET alone1,2. Late-breaking data from this analysis will be presented today at the 2023 San Antonio Breast Cancer Symposium (SABCS) Annual Meeting.

Kisqali iDFS benefit across pre-specified subgroups1:

Subgroup	3-year iDFS rate, %	HR (95% Cl)
ITT population	Kisqali + ET: 90.7	0.749
	ET alone: 87.6	(0.628, 0.892)
AJCC Stage II	Kisqali + ET: 94.2	0.700
	ET alone: 92.6	(0.496, 0.986)
AJCC Stage III	Kisqali + ET: 88.1	0.755
	ET alone: 83.8	(0.616, 0.926)
Node-negative (N0)	Kisqali + AI: 93.2	0.723
	ET alone: 90.6	(0.412, 1.268)

“As clinicians, we know that patients diagnosed with HR+/HER2- early breast cancer remain at risk of recurrence for decades, despite adjuvant endocrine therapy. Moreover, the real risk observed in this analysis in patients treated with endocrine therapy alone, including those with node-negative disease, highlights the need for effective and tolerable treatment options that can help keep patients cancer-free in the short and long term,” said Gabriel N. Hortobagyi, MD, FACP, Professor of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center. “The updated NATALEE results reinforce the potential of ribociclib to help address these needs for the broader at-risk population with no added disruptions to patients’ quality of life compared to endocrine therapy alone.”

Kisqali data across all secondary efficacy endpoints was also consistent, including distant disease-free survival (DDFS) (25.1% risk reduction) and recurrence-free survival (RFS) (27.3% risk reduction). With fewer than 4% of events in both treatment arms (3.3% in the Kisqali-ET arm and 3.4% in the ET only arm), overall survival (OS) results will continue to evolve in the longer term1,2.

The safety profile of Kisqali at the 400 mg dose remained consistent with previously reported results, with generally low-grade adverse events (AEs), other than laboratory abnormalities. AEs of special interest (grade 3 or higher) were neutropenia (44.3%), liver-related AEs (e.g., elevated transaminases) (8.6%), and QT interval prolongation (1.0%)1,2. No new safety signals were identified1,2.

“The final iDFS analysis of NATALEE represents a significant milestone, building upon the robust evidence supporting Kisqali as a potential new adjuvant treatment for a broad, clinically common and identifiable population of patients with stage II and III HR+/HER2- early breast cancer,” said Jeff Legos, Executive Vice President, Global Head of Oncology Development at Novartis. “We are seeking approval for Kisqali in early breast cancer from health authorities worldwide, aspiring to more than double the number of at-risk patients who could potentially benefit from CDK4/6 inhibitor treatment in this setting.”

Novartis submitted NATALEE data to the European Medicines Agency and plans to finalize submission to the U.S. Food and Drug Administration by end of year.

About NATALEENATALEE is a global Phase III multi-center, randomized, open-label trial to evaluate the efficacy and safety of Kisqali® (ribociclib) with ET as an investigational 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) Annual Meeting 2023 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 subgroups2.

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. Compared to the 600 mg dose, the safety profile of Kisqali at 400 mg was observed to have lower rates of symptomatic AEs and less need for dose modifications when administered up to three years2. AEs of special interest (grade 3 or higher) are neutropenia (44.3%), liver-related AEs (e.g., elevated transaminases) (8.6%), and QT interval prolongation (1.0%)1,2.

About Early Breast CancerMore than 90% of patients diagnosed with breast cancer have EBC16. Despite adjuvant ET, approximately one-third of those diagnosed with stage II and more than half of those diagnosed with stage III HR+/HER2- EBC experience cancer recurrence17,18. The risk of recurrence continues over decades with more than half of breast cancer recurrences occurring five or more years after diagnosis17,19. For many of these patients, there are currently no targeted therapeutic options outside of the standard chemotherapy and ET20.

About Kisqali® (ribociclib) Kisqali has consistently demonstrated OS benefit while preserving or improving quality of life across three Phase III trials in MBC4-15. 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)21. Additionally, Kisqali has the highest rating of any CDK4/6 inhibitor on the ESMO Magnitude of Clinical Benefit Scale, achieving a score of five out of five for first-line pre-menopausal patients with HR+/HER2- advanced breast cancer22. 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 line23.

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 agonist20.

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 subtype24 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 action25.

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

DisclaimerThis press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

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References

1. Novartis Data on File.
2. Slamon D, Stroyakovskiy D, Yardley D, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer: primary results from the Phase III NATALEE trial. Presented at the American Society of Clinical Oncology Annual Meeting, June 2, 2023. Chicago, USA.
3. Fasching P, Slamon D et al. Health-related quality of life in the phase 3 NATALEE study of adjuvant ribociclib plus a NSAI vs NSAI alone in patients with HR+/HER2− early breast cancer). Presentation at European Society for Medical Oncology (ESMO) Virtual Plenary on 14 September 2023.
4. Yardley DA, Yap YS, et al. Pooled exploratory analysis of survival in patients (pts) with HR+/HER2- advanced breast cancer (ABC) and visceral metastases (mets) treated with ribociclib (RIB) + endocrine therapy (ET) in the MONALEESA (ML) trials. Poster presented at the European Society of Medical Oncology Congress. September 9-13, 2022. Paris, France.
5. Neven P, Fasching PA, et al. Updated overall survival (OS) results from the first-line (1L) population in the Phase III MONALEESA-3 trial of postmenopausal patients with HR+/HER2- advanced breast cancer (ABC) treated with ribociclib (RIB) + fulvestrant (FUL). Mini oral presented at the European Society for Medical Oncology Breast Cancer Congress. May 4, 2022. Paris, France.
6. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. New England Journal of Medicine. 2022;386(10):942-950. doi:10.1056/NEJMoa2114663 
7. Hortobagyi GN, et al. Overall survival (OS) results from the phase III MONALEESA (ML)-2 trial of postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib. Proffered paper presented at the European Society of Medical Oncology Congress, September 16-21, 2021. Lugano, Switzerland. 
8. Im S-A, Lu Y-S, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. New England Journal of Medicine. 2019;381(4):307-316. doi:10.1056/nejmoa1903765
9. Slamon DJ, Neven P, Chia S, et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. New England Journal of Medicine. 2020;382(6):514-524. doi:10.1056/NEJMoa1911149
10. Slamon DJ, Neven P, Chia S, et al. Overall survival (OS) results of the Phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor 2–negative (HER2−) advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB). Presented at the European Society of Medical Oncology Congress, September 29, 2019, Barcelona, Spain.
11. Slamon DJ, Neven P, Chia S, et al. Updated overall survival (OS) results from the Phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2− advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB. Presented at the American Society of Clinical Oncology Annual Meeting, June 5, 2021. Chicago, USA.
12. Tripathy D, Im S-A, Colleoni M, et al. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib. Presented at the San Antonio Breast Cancer Symposium, December 9, 2020. Texas, USA.
13. Yardley D, Nusch A, Yap YS, et al. Overall survival (OS) in patients (pts) with advanced breast cancer (ABC) with visceral metastases (mets), including those with liver mets, treated with ribociclib (RIB) plus endocrine therapy (ET) in the MONALEESA (ML) -3 and -7 trials. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting. June 2020. Chicago, USA.
14. O’Shaughnessy J, Stemmer SM, Burris HA, et al. Overall survival subgroup analysis by metastatic site from the Phase III MONALEESA-2 study of first-line ribociclib + letrozole in postmenopausal patients with HR+/HER2− advanced breast cancer. Presented at the San Antonio Breast Cancer Symposium, December 7-10, 2021. Texas, USA.
15. Kisqali (ribociclib) Prescribing Information.
16. Iqbal J, Ginsburg O, Rochon PA, Sun P, Narod SA. Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States [published correction appears in JAMA. 2015 Jun 9;313(22):2287]. JAMA. 2015;313(2):165-173. doi:10.1001/jama.2014.17322
17. Pan H, Gray R, Braybrooke J, et al; EBCTCG. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846. doi:10.1056/NEJMoa1701830 
18. Pan H, Gray R, Braybrooke J, et al; EBCTCG. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846;(suppl). doi:10.1056/NEJMoa1701830 
19. Gomis R, Gawrzak S. Tumor cell dormancy. Mol Oncol. 2017;11(1):62-78.
20. American Cancer Society. Treatment of breast cancer stages I-III. Revised April 12, 2022. Available at: https://www.cancer.org/cancer/breast-cancer/treatment/treatment-of-breast-cancer-by-stage/treatment-of-breast-cancer-stages-i-iii.html/ Accessed August 2023.
21. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) - Breast Cancer. NCCN Guidelines. Published March 2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf/ Accessed August 2023.
22. European Society for Medical Oncology – Magnitude of Clinical Benefit Scale Scorecard. Published April 20, 2020. Updated August 21, 2020. Available at: https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-158-1/ Accessed August 2023.
23. European Society for Medical Oncology – Magnitude of Clinical Benefit Scale Scorecard. Published March 29, 2022. Available at: https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-9-1/ Accessed August 2023.
24. Ribociclib vs. palbociclib in patients with advanced breast cancer within the HER2-enriched intrinsic subtype (HARMONIA). Identifier NCT05207709. Revised April 4, 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT05207709/ Accessed August 2023.
25. Novartis and Vestre Viken Hospital Trust (2022, April 1 – 2024, December 1). Neoadjuvant Treatment of Locally-advanced Breast Cancer Patients With Ribociclib and Letrozole (NEOLETRIB). Identifier NCT05163106. Available at: https://clinicaltrials.gov/ct2/show/NCT05163106/ Accessed August 2023.

*Ibrance® is a registered trademark of Pfizer, Inc.

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