NVS Novartis AG

• If approved, patients in Europe with stage II or III HR+/HER2- early breast cancer (EBC) at high risk of recurrence, including those with node-negative disease, will be eligible for adjuvant treatment with Kisqali^® (ribociclib) in combination with an aromatase inhibitor¹
  
  
• Recommendation is based on the Phase III NATALEE trial, where Kisqali added to endocrine therapy (ET) significantly reduced the risk of recurrence by 25% versus ET alone across a broad population of patients with HR+/HER2- early breast cancer ²
  
  
• People with stage II or III HR+/HER2- EBC face significant risk of recurrence – often as incurable metastatic disease – despite adjuvant ET and regardless of nodal involvement^3,4
  
  
• In September, Kisqali was approved by the FDA in this setting⁵; at ESMO 2024, an updated analysis from NATALEE was presented, showing a deepening invasive disease-free survival benefit⁶

EAST HANOVER, N.J., Oct. 18, 2024 /PRNewswire/ -- Novartis announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion and recommended granting marketing authorization for Kisqali^® (ribociclib) for the adjuvant treatment of adults with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC), at high risk of disease recurrence, including those with node-negative disease¹.

"One-third of people diagnosed with stage II breast cancer and more than half of those diagnosed with stage III will unfortunately experience a return of their cancer in the long term, often as metastatic disease," said Peter A. Fasching, M.D., Professor of Translational Medicine, University Hospital Erlangen and Comprehensive Cancer Center Erlangen-EMN and NATALEE trial investigator. "If approved, Kisqali could provide an effective and tolerable adjuvant treatment option to mitigate the risk of recurrence in a broader patient population, particularly for patients who currently have limited treatment options, including those with high-risk node-negative disease."

Breast cancer is the most commonly diagnosed cancer in Europe⁷. HR+/HER2- is the most common subtype, accounting for approximately 70% of all breast cancers, and more than 40% of these are diagnosed in stage II or III^8-10.

The positive CHMP decision is based on robust data from the Phase III NATALEE trial^2,11,12. In the trial, Kisqali plus endocrine therapy (ET), compared to ET alone, lowered the risk of cancer recurrence by 25.1% in patients with stage II and III HR+/HER2- EBC (HR=0.749; 95% CI: 0.628, 0.892; P=0.0006) and demonstrated a consistent, clinically meaningful invasive disease-free survival (iDFS) benefit across key pre-specified subgroups^2,11. Data from the pivotal trial also showed the safety profile of Kisqali at the 400mg dose was well-tolerated with generally low-grade symptomatic adverse events^2,11.

An updated analysis from the NATALEE trial recently presented at the European Society for Medical Oncology (ESMO) Congress 2024 adds to the growing body of evidence supporting the potential of Kisqali to consistently reduce risk of recurrence across a broad population⁶. In the updated analysis, the iDFS benefit continued to deepen beyond the three-year Kisqali treatment period in all patient subgroups, including those with node-negative disease². 

"Today, many people diagnosed with HR+/HER2- early breast cancer in Europe lack options beyond endocrine therapy to help reduce their risk of cancer coming back. If approved, Kisqali could nearly double the number of patients eligible for CDK4/6 inhibitor adjuvant therapy," said Patrick Horber M.D., President, International, Novartis. "Together with the recent FDA approval and late-breaking NATALEE data presented at ESMO, today's positive CHMP recommendation further reinforces the differentiated profile of Kisqali as a new treatment option for a broad population of patients, including those with node-negative disease."

Following the CHMP's recommendation to approve Kisqali in a broad population of patients diagnosed with HR+/HER2- EBC at high risk of recurrence, the European Commission (EC) will take a final decision within approximately two months.

About NATALEE
NATALEE 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 TRIO^2,13. The adjuvant ET in both treatment arms was a non-steroidal aromatase inhibitor (NSAI; anastrozole or letrozole) and goserelin if applicable^2,13. The primary endpoint of NATALEE is invasive disease-free survival (iDFS) as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria^2,13. A total of 5,101 adult patients with HR+/HER2- EBC across 20 countries were randomized in the trial^2,13.

About Kisqali^® (ribociclib) 
Kisqali^® (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Kisqali was approved as a treatment for early breast cancer by the U.S. Food and Drug Administration (FDA) in September 2024⁵. Regulatory reviews for Kisqali as an EBC treatment are ongoing worldwide, including in the EU and China.

Kisqali has been approved as a treatment for metastatic breast cancer (MBC) patients in 99 countries worldwide, including by the U.S. FDA and the European Commission^14,15. In the U.S., Kisqali is indicated for the treatment of adults 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 men¹⁴. 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 progression¹⁵. In pre- or peri-menopausal women, the ET should be combined with a luteinizing hormone-releasing hormone agonist^14,15.

In MBC, Kisqali has consistently demonstrated statistically significant overall survival benefit across three Phase III trials^16-26. The NCCN Guidelines^® for breast cancer recommend ribociclib (Kisqali) as the only Category 1 preferred CDK4/6 inhibitor for first-line treatment of people living with HR+/HER2- when combined with an AI, making Kisqali the preferred first-line treatment of choice for US prescribers in HR+/HER2- MBC²⁷. 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 cancer²⁸. 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 line²⁹.

Kisqali was developed by Novartis under a research collaboration with Astex Pharmaceuticals.

Please see full Prescribing Information for Kisqali, available at www.Kisqali.com

About Novartis in Breast Cancer
For more than 30 years, Novartis has been at the forefront of driving scientific advancements for people touched by breast cancer and improving clinical practice in collaboration with the global community. With one of the most comprehensive breast cancer portfolios and pipeline, Novartis leads the industry in discovery of new therapies and combinations in HR+/HER2- breast cancer, the most common form of the disease.

Indication

What is KISQALI?

KISQALI^® (ribociclib) is a prescription medicine used to treat adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer:

• in combination with an aromatase inhibitor for stage II and III early breast cancer with a high risk of coming back
• that has gotten worse or has spread to other parts of the body (advanced or metastatic breast cancer) in combination with:
  • an aromatase inhibitor as the first endocrine-based therapy; or
  • fulvestrant as the first endocrine-based therapy or following disease progression on endocrine therapy

It is not known if KISQALI is safe and effective in children.

IMPORTANT SAFETY INFORMATION

KISQALI may cause serious side effects, including:

Lung problems. KISQALI may cause severe or life-threatening inflammation of the lungs during treatment that may lead to death. Tell your health care provider right away if you have any new or worsening symptoms, including:

• trouble breathing or shortness of breath
• cough with or without mucus
• chest pain

Severe skin reactions. Tell your health care provider or get medical help right away if you get severe rash or rash that keeps getting worse; reddened skin; flu-like symptoms; skin pain or burning, blistering of the lips, eyes, or mouth, blisters on the skin or skin peeling, with or without fever.

Heart rhythm problems (QT prolongation). KISQALI can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death.

• Your health care provider should check your heart and do blood tests before and during treatment with KISQALI
• Tell your health care provider right away if you have a change in your heartbeat (a fast or irregular heartbeat), or if you feel dizzy or faint

Liver problems. KISQALI can cause serious liver problems. Your health care provider should do blood tests to check your liver before and during treatment with KISQALI. Tell your health care provider right away if you get any of the following signs and symptoms of liver problems:

• yellowing of your skin or the whites of your eyes (jaundice)
• dark or brown (tea-colored) urine
• feeling very tired
• loss of appetite
• pain on the upper right side of your stomach area (abdomen)
• bleeding or bruising more easily than normal

Low white blood cell counts (neutropenia). Low white blood cell counts are very common during treatment with KISQALI and may result in infections that may be severe. Your health care provider should check your white blood cell counts before and during treatment with KISQALI. Tell your health care provider right away if you have signs and symptoms of low white blood cell counts or infections, such as fever and chills.

Your health care provider may tell you to decrease your dose, temporarily stop, or completely stop taking KISQALI if you develop certain serious side effects during treatment with KISQALI.

What should I tell my health care provider before taking KISQALI?

Before you take KISQALI, tell your health care provider if you:

• have any heart problems, including heart failure, irregular heartbeats, and QT prolongation
• have ever had a heart attack
• have a slow heartbeat (bradycardia)
• have high blood pressure that is not controlled
• have decreased thyroid gland (hypothyroidism)
• have problems with the amount of potassium, calcium, phosphorus, or magnesium in your blood
• have fever, chills, or any other signs or symptoms of infection
• have liver problems
• have kidney problems
• are pregnant, or plan to become pregnant. KISQALI can harm your unborn baby
  • If you are able to become pregnant, your health care provider should do a pregnancy test before you start treatment with KISQALI
  • Females who are able to become pregnant and who take KISQALI should use effective birth control during treatment and for at least 3 weeks after the last dose of KISQALI
  • Talk to your health care provider about birth control methods that may be right for you during this time
  • If you become pregnant or think you are pregnant, tell your health care provider right away
• are breastfeeding or plan to breastfeed. It is not known if KISQALI passes into your breast milk. Do not breastfeed during treatment with KISQALI and for at least 3 weeks after the last dose of KISQALI

Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. KISQALI and other medicines may affect each other, causing side effects. Know the medicines you take. Keep a list of them to show your health care provider or pharmacist when you get a new medicine.

What should I avoid while taking KISQALI?

Avoid eating grapefruit and avoid drinking grapefruit juice during treatment with KISQALI since these may increase the amount of KISQALI in your blood.

The most common side effects of KISQALI in people with early breast cancer include:

• decreased white blood cell counts
• decreased red blood cell counts
• increased liver function tests
• infections
• increased kidney function test
• decreased platelet counts
• nausea
• headache
• tiredness

The most common side effects of KISQALI in people with advanced or metastatic breast cancer include:

• decreased white blood cell counts
• decreased red blood cell counts
• increased liver function tests
• infections
• nausea
• increased kidney function test
• tiredness
• decreased platelet counts
• diarrhea
• vomiting
• headache
• constipation
• hair loss
• cough
• rash
• back pain
• low blood sugar level

KISQALI may cause fertility problems in males, which may affect your ability to father a child. Talk to your health care provider if this is a concern for you.

Tell your health care provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of KISQALI. For more information, ask your health care provider or pharmacist. Call your doctor for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

Please see accompanying full Prescribing Information including Patient Information.

Disclaimer
This 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," "to reduce," "remains," "continue," "transform," "evaluate," "likelihood," "ensuring," "updates," "should," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for Kisqali in combination with an aromatase inhibitor (AI), or regarding potential future revenues from such product. 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 Kisqali in combination with an AI 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 Kisqali in combination with an AI will be commercially successful in the future. In particular, our expectations regarding Kisqali in combination with an AI 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.

About Novartis 
Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people's lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide.

Reimagine medicine with us: Visit us at https://www.novartis.com and https://www.novartis.us, and connect with us on LinkedIn, LinkedIn US, Facebook, X/Twitter, X/Twitter US and Instagram.

References

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2. Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med. 2024;390(12):1080-1091. doi:10.1056/NEJMoa2305488
3. Pan H, Gray R, Braybrooke J, et al. 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
4. Gomis RR, Gawrzak S. Tumor cell dormancy. Mol Oncol. 2017;11(1):62-78. doi:10.1016/j.molonc.2016.09.009
5. Novartis. Press release. FDA approves Novartis Kisqali® to reduce risk of recurrence in people with HR+/HER2- early breast cancer. September 17, 2024. Accessed October 15, 2024. https://www.novartis.com/news/media-releases/fda-approves-novartis-kisqali-reduce-risk-recurrence-people-hrher2-early-breast-cancer 
6. Fasching PA. Adjuvant Ribociclib (RIB) Plus Nonsteroidal Aromatase Inhibitor (NSAI) in Patients (Pts) With HR+/HER2− Early Breast Cancer (EBC): 4-Year Outcomes From the NATALEE Trial. LBA13. Proffered Paper presented at the European Society for Medical Oncology Congress (ESMO); September 16, 2024; Barcelona, Spain
7. The Global Cancer Observatory. Cancer Today: GLOBOCAN 2022 Europe. 2024. Accessed October 15, 2024. https://gco.iarc.who.int/media/globocan/factsheets/populations/908-europe-fact-sheet.pdf  
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10. Criscitiello C, Spurden D, Piercy J, et al. Health-Related Quality of Life Among Patients With HR+/HER2- Early Breast Cancer. Clin Ther. 2021;43(7):1228-1244.e4. doi:10.1016/j.clinthera.2021.04.020
11. Hortobagyi G, Stroyakovskiy D, Yardley DA, et al. Ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) as adjuvant treatment in patients with HR+/HER2- early breast cancer: final invasive disease-free survival (iDFS) analysis from the NATALEE trial. Presented at San Antonio Breast Cancer Symposium (SABCS); December 8, 2023; San Antonio, USA
12. 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 (ASCO); June 2, 2023; Chicago, USA.
13. Clinicaltrials.gov. NCT03701334. A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/ HER2- Early Breast Cancer (NATALEE). Updated October 10, 2024. Accessed October 14, 2024. https://clinicaltrials.gov/study/NCT03701334.
14. Kisqali. US FDA. Prescribing Information. Novartis Pharmaceuticals Corporation; 2024. Updated September 2024. Accessed October 15, 2024. https://www.novartis.com/us-en/sites/novartis_us/files/kisqali.pdf 
15. Kisqali. EMA. Summary of product characteristics (SmPC). Novartis Europharm Limited; 2024. Updated August 21, 2024. Accessed October 15, 2024. https://www.ema.europa.eu/en/documents/product-information/kisqali-epar-product-information_en.pdf 
16. Yardley DA, 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 (ESMO); September 9-13, 2022; Paris, France
17. Neven P, 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
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19. 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. LBA 17. Proffered paper presented at the European Society of Medical Oncology Congress (ESMO); September 16-21, 2021; Lugano, Switzerland
20. Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi:10.1056/NEJMoa1903765
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22. Slamon D, 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). LBA7_PR. Presented at the European Society of Medical Oncology Congress (ESMO); September 29, 2019; Barcelona, Spain
23. Slamon D, 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 (ASCO); June 5, 2021; Chicago, USA
24. Tripathy D, 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 (SABCS); December 9, 2020; Texas, USA
25. Yardley DA, 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 Annual Meeting (ASCO); May 29-31, 2020; Chicago, USA 
26. O'Shaughnessy J, 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 (SABCS); December 7-10, 2021; Texas, USA
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28. European Society for Medical Oncology. Magnitude of Clinical Benefit Scale Scorecard. Updated August 14, 2023. Accessed October 15, 2024. https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-158-1 
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