Local Neoplasm Recurrence

TAKOMA PARK, Md.--( BUSINESS WIRE )--The Jerome Canady Research Institute for Advanced and Biological Technological Sciences (JCRI-ABTS) and US Medical Innovations, LLC (USMI) announced significant positive results from the first FDA Phase I IDE (#G190165) clinical trial for cancer using Canady Helios TM Cold Plasma (CHCP) combined with standard surgical resections at the 2023 American Society of Clinical Oncologists (ASCO) Annual Meeting in Chicago, IL (May 31-June 4, 2023). Safety was the primary endpoint; secondary endpoints were the effect on local regional recurrence (LRR), cancer cell death, preservation of surrounding healthy tissue, and patient survival. (ClinicalTrials.gov identifier: NCT04267575) Cancer remains a significant global health challenge, with over 1.9 million new cases and 608,570 cancer-related fatalities in the United States in 2021. Advances in chemotherapy, radiation, surgery, immunotherapy, and molecular targeted therapy regimes have improved survival, but solid tumor resections still have a risk of LRR and a poor five-year survival rate. Surgery is the primary treatment for most solid tumors, but complete removal of cancerous tissue (R0), microscopic tumor cells (R1) or visible tumor (R2) is challenging which can lead to LRR in 5% to 65% of cases. USMI’s Canady Helios Cold Plasma (CHCP) system, a non-thermal (26-30°C) and non-contact Cold Atmospheric Plasma (CAP) jet, offers a promising solution. The three-dimensional bioelectric Plasma Treated Electromagnetic Field (PTEF)™ created by CHCP causes a biophysical phenomenon known as Irreversible Electroporation (IRE), that increases cancer cell membrane permeability to CAP species such as Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS). This process results in cancer cell death while sparing the noncancerous tissue. The JCRI-ABTS research laboratory discovered and patented the process by which CHCP-treated cancer cells undergo histone mRNA oxidation and degradation, leading to the activation of DNA damage response genes and cell death ( link ) 1 . Standard CHCP treatment dosages for 32 cancer cell lines including breast, sarcoma, glioblastoma, melanoma, ovarian, prostate, colorectal, and lung cancers. have been developed in the JCRI-ABTS laboratory. The Clinical Trial was a multi-center, open-label, prospective, and controlled study conducted between March 2020 - April 2021 at Rush University Medical Center (RUMC) in Chicago, IL, USA, and Sheba Medical Center (SMC) in Tel HaShomer, Israel. Molecular biological studies were performed at JCRI-ABTS. Twenty patients ranging from 26-85 years of age undergoing surgery for advanced stage 4 or recurrent solid tumors were enrolled. Patients with preoperative treatments such as neoadjuvant chemotherapy, immunotherapy, radiation, and previous surgery were eligible. Characteristics of Patients Characteristic No. % No. of Patients 20 Sheba Medical Center 5 25 Rush Medical Center 15 75 Age Median 59.5 Range 26-85 Female 10 50 Male 10 50 Ethnicity White 18 90 African American 1 5 Other 1 5 ECOG 1 Performance Status <2 20 100 Cancer types (all metastatic) Adenoid Cystic Carcinoma 1 5 Anal 1 5 Angiosarcoma 1 5 Breast 1 5 Cholangiocarcinoma 1 5 Chordoma 1 5 Colon 2 10 Melanoma 1 5 Mesothelioma 1 5 Non-Small Cell Lung* 3 15 Ovarian 1 5 Renal 1 5 Sarcoma** 4 20 Squamous Cell Carcinoma 1 5 1 ECOG – Eastern Cooperative Oncology Group * Two Carcinomas and 1 Adenocarcinoma ** Desmoplastic small round cell sarcoma, myxofibrosarcoma, pleomorphic sarcoma, and pleomorphic spindle cell sarcoma Overall response rates (ORR) at 26 months for R0 and R0 with Microscopic Positive Margins (R0-MPM) patients were 69% (95% CI, 19-40%) and 100% (95% CI, 100 – 100.0%), respectively. ORR was defined as no recurrence from the time of CHCP treatment to LRR in R0 resected patients. ORR was evaluated by postoperative T2 weighted MRI, PET or CT scans. Overall Survival (OS) for R0 (n=7), R0-MPM (n=5), R1 (n=6), and R2 (n=2) patients at 28 months were 86%, 40%, 67%, and 0%, respectively. The cumulative OS rate was 24% at 31 months (n=20, 95% CI, 5.3 – 100.0). OS was defined as the duration from the intraoperative CHCP treatment to death. CHCP treatment did not affect intraoperative physiological vital signs (blood pressure, pulse, O 2 saturation, end tidal CO 2 , and temperature, p > 0.05). No systemic toxicities or device-related adverse events were observed. Overall, CHCP treatment combined with surgery is safe, selective towards microscopic tumor cells at the margin, and demonstrates exceptionally low LRR in R0 and R0-MPM patients. Time (Months) Number at Risk Deaths Survival Rate Standard Error Lower 95% CI Upper 95% CI 0 20 0 100% 0.00 1.00 1.00 5 18 2 90% 0.07 0.78 1.00 10 16 3 75% 0.10 0.58 0.97 15 15 0 75% 0.10 0.58 0.97 20 15 1 70% 0.10 0.53 0.93 25 8 0 70% 0.10 0.53 0.93 30 3 2 48% 0.15 0.26 0.88 31 2 1 24% 0.19 0.05 1.00 OS analysis for CAP-treated patients (n=20). P=0.0058. Jerome Canady, MD., FACS., Surgical Oncologist, and CEO stated, “One inherent problem of excising any solid tumor tissue is ensuring complete surgical removal of the tumor and the microscopic tumor cells at the margins, which reduces the chance of local regional recurrence. To date, there are no treatments on the market that ensure the complete eradication of microscopic tumor cells at the surgical margin without damaging the surrounding healthy tissue. CHCP treatment with surgery shows immense promise in controlling local recurrence and improving survival in patients with advanced solid tumors. The treatment selectively kills microscopic tumor cells at the surgical margin. CHCP treatment is non-invasive, administered for 5 - 7 minutes intraoperatively, and has no side effects. It seamlessly integrates into existing treatment protocols without disruption." Professor of Surgery Giacomo Basadonna MD., Ph.D., FACS Department of Surgery University of Massachusetts School of Medicine Worcester and co-author of the study stated, "The results of this clinical investigation are truly remarkable and offer renewed hope to cancer patients with advanced disease. The data from the trial combined with the amount of mechanistic information collected over many years, clearly show that Canady Helios Cold Plasma treatment causes cancer cells to die within a brief period leaving normal tissue untouched. The current trial shows that treating the surrounding tissue following tumorectomy prevents local recurrence and increases overall survival. Although this trial was conducted in patients with severe disease for regulatory reasons, the results open the door to treating the tumor bed and the adjacent tissue following removal of primary malignancies and truly guarantee cancer-free surgical margins." These groundbreaking results highlight the safety, selectivity, and significant reduction of local regional recurrence achieved through the combination of CHCP treatment and surgery. USMI's Canady Helios Cold Plasma system opens a new and promising avenue for addressing the challenges of eradicating microscopic residual cancer cells following surgical tumor resection without damaging surrounding healthy tissue. JCRI-ABTS and USMI thank the participating patients and their families, prior compassionate use patients, surgical teams performing these advanced surgical procedures, and allowance by SMC and RUMC. USMI’s FDA Phase 2 Multi-Center Clinical Trial is expected to take place in Q/4 2023. The accompanying report for this Phase 1 Clinical Trial has been submitted to a peer review journal. The Abstract can be viewed on the ASCO website at https://meetings.asco.org/abstracts-presentations/225003 Reference data 1 JCRI Discovers the Mechanism using Canady Helios™ Cold Plasma to Induce Cell Death in Breast Cancer For more information about the CHCP clinical trial and USMI's innovative medical technologies, please visit ClinicalTrials.gov identifier: NCT04267575. About US Medical Innovations US Medical Innovations, LLC (USMI), based out of Takoma Park, MD, is a privately held FDA registered life science and biomedical device company. USMI is dedicated to expanding the boundaries of plasma medicine by pioneering new technologies for the development of state-of-the-art medical devices that advance patient outcomes and improve human lives.

SAN DIEGO, May 22, 2023 /PRNewswire/ -- Rakuten Medical, Inc. (Rakuten Medical), a global biotechnology company developing and commercializing precision, cell-targeting therapies based on its proprietary Alluminox™ platform, today announced that the Company has been granted permission from the Indian Central Drugs Standard Control Organization (CDSCO) to conduct its global, pivotal Phase 3 clinical trial (ASP-1929-301/ClinicalTrials.gov Identifier: NCT03769506) evaluating Alluminox treatment (photoimmunotherapy) using ASP-1929 in patients with locoregional, recurrent head and neck squamous cell carcinomas (HNSCC) in India, and the registration of clinical trial information with the Clinical Trial Registry of India (CTRI) has been completed (CTRI Identifier: CTRI/2023/05/052728). The study sites will include several leading medical institutions in India such as the Tata Memorial Centre and Narayana Health, and the treatment will be administered to enrolled patients once ready. This ASP-1929-301 study is currently underway in several countries such as the U.S. and Taiwan, and will enroll 275 patients globally including Indian patients. In India, more than 200,000 new cases of head and neck cancer are diagnosed each year, which accounts for approximately 25% of all new head and neck cancer cases worldwide1. One of the reasons for this is the widespread use of chewing tobacco. More than 28% of all adults (15 years and above) in India are users of tobacco, and approx. 75% of them use smokeless tobacco, including chewing tobacco2. It has been reported that more than half of oral cancer (a type of head and neck cancer) in India is attributable to smokeless tobacco, including chewing tobacco3. In addition to the high occurrence of head and neck cancer, it is known that the majority of these patients present with advanced disease, which also corresponds with poorer outcomes 4. Such high volumes of advanced stage patients can present many challenges for the surgeons and medical oncologists who treat head and neck cancer. Time and treatment options are limited. Surgery, radiation, and chemotherapy are all commonly used to manage this patient population – but more options are needed. The multi-center, randomized, open-label, global Phase 3 study of Alluminox treatment using ASP-1929 will evaluate the efficacy and safety of ASP-1929 in patients with locoregional, recurrent HNSCC who have previously failed or progressed on or after at least two lines of therapy, of which at least one line must be systemic therapy, and are not eligible for surgery or radiation. Participants will be randomized to receive experimental therapy or investigator's choice of systemic therapy (2:1). The dual-primary endpoints of the study are progression-free survival and overall survival, and a key secondary endpoint includes objective response rate. "We are very pleased to be conducting the pivotal Phase 3 study of Alluminox treatment using ASP-1929 in India, where there is a high unmet need for head and neck cancer treatment," said Mickey Mikitani, Co-CEO of Rakuten Medical. "The addition of India to this important study will help to accelerate the development of this drug. We will continue to do our utmost to bring a new treatment option to patients with head and neck cancer around the world as soon as possible, working closely with medical institutions and regulatory authorities in each country." ASP-1929 is a conjugation of an antibody cetuximab and IRDye® 700DX, a light activatable dye, and is Rakuten Medical's first pipeline drug developed on its Alluminox™ platform. It binds to epidermal growth factor receptor (EGFR), which is highly expressed in head and neck cancers. After binding to cancer cells, ASP-1929 is locally activated by non-thermal red light (690 nm) illumination, which leads to selective cell killing inpre-clinical observations. The U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the drug in January 2018. In Japan, in September 2020, ASP-1929 received marketing approval from the Ministry of Health, Labour and Welfare for unresectable locally advanced or recurrent head and neck cancer as brand name Akalux®, together with BioBlade® Laser System, the medical device used in combination with the drug under the Conditional Early Approval System. Outside of Japan, ASP-1929 and the laser device system have not yet been approved by any regulatory authority. 1 Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F (2020). Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available from: , accessed May 3, 2023 2 Global Adult Tobacco Survey (GATS) India Fact Sheet 2016-17. Centers for Disease Control and Prevention (CDC). 3 Gupta PC, Arora M, Sinha DN, Asma S, Parascandola M (eds.); Smokeless Tobacco and Public Health in India. Ministry of Health & Family Welfare, Government of India; New Delhi; 2016. 4 Kulkarni MR. Head and Neck Cancer Burden in India. Int J Head and Neck Surg 2013;4(1):29-35 * Rakuten Medical's therapies based on Alluminox™ platform are investigational outside of Japan, and not approved in India for commercial use. About Rakuten Medical, Inc. Rakuten Medical, Inc. is a global biotechnology company developing and commercializing precision, cell targeting therapies based on its Alluminox™ platform, which, in pre-clinical studies, have been shown to induce rapid and selective cell killing and tumor necrosis. Alluminox therapies have not yet been approved outside of Japan. Rakuten Medical is committed to its mission to conquer cancer by delivering our innovative treatments as quickly as possible to as many patients all over the world as possible. The company has offices in 6 countries, including the United States, where it is headquartered, Japan, the Netherlands, Taiwan, Switzerland and India. For more information, visit . About Alluminox™ platform The Alluminox™ platform is an investigational technology platform based on a cancer therapy called photoimmunotherapy, which was developed by Dr. Hisataka Kobayashi and team from the National Cancer Institute in the United States. Rakuten Medical is developing the Alluminox platform as a technology consisting of a drug, device, and other related components. The drug component of the platform consists of a targeting moiety conjugated with one or more dyes leading to selective cell surface binding. The device component consists of a light source that locally illuminates the targeted cells with non-thermal light to transiently activate the drug. Pre-clinical data have shown that this activation elicits rapid and selective necrosis of targeted cells through a biophysical process that compromises the membrane integrity of the targeted cells. Therapies developed on the Alluminox platform may also result in local and systemic innate and adaptive immune activation due to immunogenic cell death of the targeted cancer cells and/or the removal of targeted immunosuppressive cells within the tumor microenvironment. Outside of Japan, Alluminox therapies have not yet been approved by any regulatory authority. About ASP-1929 Rakuten Medical's first pipeline drug developed on its Alluminox™ platform is ASP-1929, an antibody-dye conjugate comprised of the antibody cetuximab and IRDye® 700DX, a light activatable dye. ASP-1929 binds to epidermal growth factor receptor (EGFR), a cancer antigen expressed in multiple types of solid tumors, including head and neck, breast, lung, colorectal, prostate and pancreatic cancers. After binding to cancer cells, ASP-1929 is locally activated by non-thermal red light (690 nm) illumination emitted by a laser device system, resulting in photochemical reaction. This is believed to cause damage to the membrane of cancer cells, leading to selective necrosis of cancer cells. ASP-1929 has received Fast Track designation from the U.S. Food and Drug Administration (FDA) in January 2018, and is currently under investigation in a global Phase 3 clinical trial for recurrent head and neck cancer. In Japan, ASP-1929 received marketing approval from the Japanese Ministry of Health, Labor, and Welfare for unresectable locally advanced or recurrent head and neck cancer in September 2020, under the Sakigake Designation System and the Conditional Early Approval System. Outside of Japan, ASP-1929 has not yet been approved by any regulatory authority. Forward Looking Statements This press release contains forward looking statements that correspond to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include various risks, uncertainties, and assumptions that may cause Rakuten Medical's business plans and results to differ from the anticipated results and expectations expressed in these statements. These "forward looking statements" contain information about the status and development of our products, including the Alluminox™ platform, as well as other regulatory and marketing authorization efforts, the potential benefits, efficacy, and safety of therapies created using the Alluminox platform, and the status of regulatory filings. The approval and commercial success of the product may not be achieved. Forward looking statements relate to the potential benefits, efficacy, and safety of our therapies, and the status of regulatory filings. Such statements may include words such as "expect," "believe," "hope," "estimate," "looks as though," "anticipate," "intend," "may," "suggest," "plan," "strategy," "will," and "do", and are based on our current beliefs. In addition, this press release uses terms such as "important," "notable," and "abnormal" to express opinions about clinical trial data. Ongoing clinical trial studies include various risks and uncertainties, in particular, problems that arise during the manufacturing stage of our therapies, the occurrence of adverse safety events, situations in failure to demonstrate therapeutic benefits, and other various risks and uncertainties, both reasonable and unreasonable. For this reason, actual results, including regulatory approvals and uncertainties in the commercialization process of our therapies, may differ from published information. Except to the extent required by applicable law, we undertake no obligation to publicly update this or any other forward-looking statement, whether because of new information, future developments or events, changes in assumptions, changes in the factors affecting forward-looking statements. If one or more forward-looking statement(s) is updated, no inference should be drawn that additional updates will be made to those or other forward-looking statements. SOURCE Rakuten Medical, Inc.

Kisqali plus endocrine therapy (ET) significantly reduced the risk of disease recurrence compared to standard ET alone in the adjuvant setting1 NATALEE is the first and only positive Phase III study of a CDK4/6 inhibitor demonstrating consistent benefit in a broad population of patients with stage II and III HR+/HER2- early breast cancer (EBC) at risk of recurrence, including those with no nodal involvement Approximately 30-60% of people with HR+/HER2- stage II and III EBC treated with ET only remain at risk of breast cancer recurrence2 NATALEE results will be presented at an upcoming medical meeting and submitted to regulatory authorities worldwide EAST HANOVER, N.J., March 27, 2023 /PRNewswire/ -- Novartis today announced positive topline results from an interim analysis of NATALEE, a Phase III trial evaluating Kisqali® (ribociclib) plus endocrine therapy (ET) in a broad population of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC) at risk of recurrence1. The Independent Data Monitoring Committee recommended stopping the trial early as the primary endpoint of invasive disease-free survival (iDFS) has been met. Kisqali plus ET significantly reduced the risk of disease recurrence, compared to standard adjuvant ET alone, with consistent benefit in patients with stage II and stage III EBC regardless of nodal involvement1. "While most patients are diagnosed and treated early with the aim to cure breast cancer, the risk of cancer returning, often as metastatic disease, peaks within three years after diagnosis, but never goes away completely," said Dennis J. Slamon, MD, Director of Clinical/Translational Research, University of California, Los Angeles Jonsson Comprehensive Cancer Center and Chairman and Executive Director of Translational Research In Oncology (TRIO) and NATALEE trial lead investigator. "There is a critical need for new, well-tolerated options that keep patients cancer-free without disrupting quality of life. The NATALEE trial, where ribociclib was given for three years plus ET, was designed with these unmet needs in mind, and it is extremely encouraging that this study met its primary endpoint." Per the NATALEE study protocol, patient follow-up will continue to evaluate long-term outcomes, including overall survival1. "The positive topline results from NATALEE represent a major milestone in our ambition to expand the benefits of Kisqali to patients with earlier stages of breast cancer, building on the heritage of this effective treatment in HR+/HER2- metastatic breast cancer," said Shreeram Aradhye, M.D., President, Global Drug Development and Chief Medical Officer, Novartis. "These data have the potential to be paradigm-shifting for patients at risk of recurrence, including those with no nodal involvement, who have limited well-tolerated options to prevent recurrence. Our teams are working on submissions to health authorities around the world with the hope to bring Kisqali to many more patients diagnosed with breast cancer." These findings build on the legacy of Kisqali in metastatic breast cancer (MBC), where it has consistently demonstrated overall survival benefit while preserving or improving quality of life across three Phase III trials3-14. Updates to the NCCN Clinical Practice Guidelines in Oncology (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)15. 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 Translational Research In Oncology (TRIO)1. The primary endpoint of NATALEE is iDFS as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria; secondary endpoints include safety, quality of life, and overall survival, among others. iDFS is a composite endpoint in EBC adjuvant trials, which incorporates locoregional relapse, ipsilateral and contralateral invasive breast cancer, distant recurrence, and types of new cancer events or death from any cause. Approximately 5,100 adult patients with HR+/HER2- EBC across 20 countries were randomized in the trial, including patients with tumor stages IIA (select patients), IIB or III, regardless of nodal involvement. NATALEE explored a lower starting dose (400 mg) of Kisqali than the dose approved for treatment in MBC (600 mg) with the goal to minimize disruptions to patient quality of life without compromising efficacy1. About Early Breast Cancer More than 90% of patients diagnosed with breast cancer have EBC2,16. Approximately 30-60% of people with HR+/HER2- stage II and III EBC treated with ET only remain at risk of breast cancer recurrence2. The risk of recurrence peaks within the first three years after initial diagnosis and continues over decades2. For many of these patients, there are currently no targeted therapeutic options outside of the standard chemotherapy and ET17. About Kisqali® (ribociclib) Kisqali has consistently demonstrated overall survival benefit while preserving or improving quality of life across three Phase III trials3-14. 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 AI15. 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 premenopausal patients with HR+/HER2- advanced breast cancer18. 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 postmenopausal patients with HR+/HER2- advanced breast cancer treated in the first line19. 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 metastatic breast cancer in combination with an AI as initial ET or fulvestrant as initial ET or following disease progression on ET in postmenopausal women or in men. In the EU, Kisqali is approved for the treatment of women with HR+/HER2- advanced or metastatic breast cancer in combination with either an AI or fulvestrant as initial ET or following disease progression. In pre- or perimenopausal women, the ET should be combined with a luteinizing hormone-releasing hormone agonist14. 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 metastatic HR+/HER2-, HER2-enriched subtype20, 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 action21. Novartis also plans to build on the findings from NATALEE with ADJUVANT WIDER, an open-label Phase IIIb trial evaluating Kisqali plus ET in a population of HR+/HER2- patients with stage II and III EBC that is closer to a real-world population. 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 . Indications KISQALI® (ribociclib) is a prescription medicine used to treat adults with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer that has gotten worse or has spread to other parts of the body (metastatic), 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 in postmenopausal women or in men. It is not known if KISQALI is safe and effective in children. Important Safety Information What is the most important information I should know about KISQALI? 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/burning; blistering of the lips, eyes, or mouth; or 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 (hepatobiliary toxicity). 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 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 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 any other medical conditions 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 include: decreased white blood cell counts decreased red blood cell counts abnormal 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 if you are male and take KISQALI. This 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 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," 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 such as COVID-19; 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. 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For questions about the site or required registration, please contact [email protected]. References Novartis Data on File. Novartis Pharmaceuticals: 2022. 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. Nov 2017;377(19):1836-1846. 10.1056/NEJMoa1701830 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 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. 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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. 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. 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. 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. Kisqali (ribociclib) Prescribing Information. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) - Breast Cancer. NCCN Guidelines. . Published March 2023. Accessed March 7, 2023. American Cancer Society. Treatment of breast cancer stages I-III. Revised April 12, 2022. Accessed on September 15, 2022. European Society for Medical Oncology – Magnitude of Clinical Benefit Scale Scorecard. . Published April 20, 2020. Updated August 21, 2020. Accessed September 9, 2020. European Society for Medical Oncology – Magnitude of Clinical Benefit Scale Scorecard. . Published March 29, 2022. Accessed April 1, 2022. Ribociclib vs. palbociclib in patients with advanced breast cancer within the HER2-enriched intrinsic subtype (HARMONIA). Identifier NCT05207709. Revised April 4, 2022. Accessed on February 6, 2022. 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. *Ibrance® is a registered trademark of Pfizer, Inc. # # # SOURCE Novartis Pharmaceuticals Corporation