TYRO3

Detailed top-line results from Phase III CONTACT-02 trial demonstrated statistically significant progression-free survival benefit for combination of Cabometyx® and atezolizumab in metastatic castration-resistant prostate cancer Four-year extended follow-up data from landmark Phase III CheckMate -9ER trial reinforce sustained long-term efficacy benefits for the combination of Cabometyx® and nivolumab versus sunitinib in advanced renal cell carcinoma 22 January 2024 - Ipsen (Euronext: IPN; ADR: IPSEY) announced today new data to be presented for Cabometyx® (cabozantinib) in combination with immunotherapy across indications at the upcoming American Society of Clinical Oncology Genitourinary Symposium (ASCO GU) taking place on 25-27 January 2024 in San Francisco, U.S. Detailed top-line results from the Phase III CONTACT-02 trial of the combination of Cabometyx and atezolizumab versus a second novel hormone therapy (NHT) in people living with metastatic castration-resistant prostate cancer (mCRPC) and measurable extra-pelvic soft tissue disease who have progressed on one prior NHT, are to be presented as an oral presentation (Abstract #18). With a median follow-up of 14.3 months, data from the primary analysis of progression-free survival (PFS) from the CONTACT-02 trial demonstrated a statistically significant PFS benefit for the combination of Cabometyx and atezolizumab of 6.3 months versus 4.2 months for a second NHT (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.50-0.84; p=0.0007). At an interim analysis for the other primary endpoint of overall survival (OS), the data demonstrated a trend toward improvement for the combination, however, these data were immature, and the trial will continue to the next planned analysis, anticipated in 2024. Safety for the combination appeared to be consistent with the known safety profiles of the individual medicines, and no new safety signals were identified. Prostate cancer is the second most common cancer in men1 and for those living with advanced metastatic castration-resistant disease, the prognosis is poor, with an estimated survival of 1-2 years2. “At the advanced metastatic castration-resistant stage of disease, the prognosis is poor, with a median survival of two years and limited available treatment options,” said Stéphane Oudard, Professor of Oncology and Chief of the Oncology Clinical and Translational Research Unit at Georges Pompidou Hospital in Paris, France. “These results from the CONTACT-02 trial represent a positive step in the context of the current treatment landscape, contributing the first positive Phase III data of its kind for the benefit of patients, as we await further data from the overall survival analysis.” Also, four-year extended follow-up data from the landmark Phase III CheckMate -9ER trial investigating the combination of Cabometyx and nivolumab versus sunitinib in people living with previously untreated advanced renal cell carcinoma (aRCC) will be presented (Abstract #362). With a median follow-up of 55.6 months for OS, the combination of Cabometyx and nivolumab demonstrated a sustained and clinically meaningful OS benefit versus sunitinib, with an absolute median OS gain of 10.5 months (46.5 months for the combination vs 36.0 months for sunitinib, HR 0.77, 95% CI: 0.63-0.95). Additionally, median PFS remained almost double that for the combination versus sunitinib, at 16.4 vs 8.4 months respectively (HR 0.58, 95% CI: 0.49-0.70). The safety profile was consistent with the known safety profiles of the individual medicines, and no new safety signals were identified. Renal cell carcinoma is the most common form of kidney cancer3, 4 and for the 30% of people diagnosed with an advanced form of the disease, the 5-year survival rate is low at 12%, with no identified cure for this disease.5,6 “Data from our ongoing trials continue to reinforce the value of Cabometyx for patients across a number of challenging tumor types,” said Christelle Huguet, EVP and Head of Research and Development, Ipsen. “In combination with immunotherapy, Cabometyx is delivering long-term survival benefits today for people living with renal cell carcinoma worldwide, while also showcasing future potential in metastatic castration-resistant prostate cancer, an area of significant unmet need where no other trials of this modality have proven successful in recent decades.” Additionally, health-related quality of life (HRQoL) data from a modelling analysis based on the CheckMate 9ER trial explored the link between HRQoL and clinical outcomes at a median follow-up of 32.9 months (Abstract #384). These data provide further patient-focused context to the benefits of the combination of Cabometyx and nivolumab, whilst also reinforcing the association of the combination with an increased chance of tumor shrinkage, survival and progression-free survival, independent of early HRQoL deterioration. Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), including VEGFRs, MET, RET and the TAM family (TYRO3, MER, AXL).7 These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis (the growth of new blood vessels that tumors need to grow), drug resistance, modulation of immune activities and maintenance of the tumor microenvironment.7,8,9,10 Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of Cabometyx outside of the U.S. and Japan. Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited (Takeda) for the commercialization and further clinical development of Cabometyx for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize Cabometyx in the U.S. In over 60 countries outside of the United States and Japan, including in the European Union (E.U.), Cabometyx is currently indicated as:8 Monotherapy for advanced renal cell carcinoma (aRCC). as first-line treatment of adults with intermediate- or poor-risk disease. in adults following prior VEGFR-targeted therapy. in combination with nivolumab for the first-line treatment of aRCC in adults. Monotherapy for the treatment of adults living with locally advanced or metastatic differentiated thyroid carcinoma (DTC), refractory or not eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy. Monotherapy for the treatment of hepatocellular carcinoma in adults who have previously been treated with sorafenib. Prostate cancer is the second most common cancer in men and the fourth most common cancer overall globally.1 In 2020, there were more than 1.4 million new cases of prostate cancer and about 375,300 deaths worldwide.1 Prostate cancer is considered mCRPC when it has spread beyond the prostate and does not respond to androgen-suppression therapies, a common treatment for prostate cancer.11 Men diagnosed with mCRPC often have a poor prognosis, with an estimated survival of 1-2 years.2 There were over 400,000 new cases of kidney cancer diagnosed worldwide in 2020.12 Of these, RCC is the most common type of kidney cancer, accounting for approximately 90% of cases.3,4 It is almost twice as common in men, and male patients account for over two thirds of deaths.12 At diagnosis, up to 30% of patients present with advanced or metastatic RCC. If detected in the early stages, the five-year survival rate is high, but for people living with advanced or late-stage metastatic RCC, the survival rate is much lower, around 12%, with no identified cure for this disease.5,6 CONTACT-02 is a global, multicenter, randomized, Phase III, open-label study that enrolled 575 patients who were randomized 1:1 to the experimental arm of Cabometyx in combination with atezolizumab and the control arm of a second NHT (either abiraterone and prednisone or enzalutamide). The study included patients with mCRPC who have measurable visceral disease or measurable extra-pelvic adenopathy and who have progressed on one prior NHT. The two primary endpoints of the trial are PFS and OS. The PFS analysis was conducted in the first 400 randomized patients (PFS in the intent-to-treat [ITT] population) and assessed by a blinded independent radiology committee (BIRC) per RECIST 1.1. The OS analysis was conducted in the ITT population (n=507). The secondary endpoint is objective response rate (ORR) per BIRC. The trial is sponsored by Exelixis and co-funded by Ipsen, Roche and Takeda. Takeda is conducting the trial in Japan. More information about CONTACT-02 is available at ClinicalTrials.gov. CheckMate -9ER is an open-label, randomized, multi-national Phase III trial evaluating people living with previously untreated advanced or metastatic RCC. A total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1 ≥1%) were randomized to Cabometyx plus nivolumab (n= 323) versus sunitinib (n= 328). The primary endpoint is progression-free survival (PFS). The secondary endpoints include OS and ORR. The primary efficacy analysis compared the doublet combination versus sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited. More information about CheckMate -9ER is available at ClinicalTrials.gov. We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience. Our pipeline is fueled by external innovation and supported by nearly 100 years of development experience and global hubs in the U.S., France and the U.K. Our teams in more than 40 countries and our partnerships around the world enable us to bring medicines to patients in more than 100 countries. Ipsen is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com. References 1 Prostate cancer statistics. World Cancer Research Fund International. Available at: https://www.wcrf.org/cancer-trends/prostate-cancer-statistics/. Last accessed January 2024. 2 Moreira, D. M., et al. Predicting Time From Metastasis to Overall Survival in Castration-Resistant Prostate Cancer: Results From SEARCH. Clin Genitourin Cancer. 2017; 15: 60–66.e2. 3 Kidney Cancer. Mayo Clinic. Available: https://www.mayoclinic.org/diseases-conditions/kidney-cancer/symptoms-causes/syc-20352664. Accessed: January 2024. 4 Infographic: Kidney Cancer. Mayo Clinic. Available: https://www.mayoclinic.org/diseases-conditions/kidney-cancer/multimedia/kidney-cancer-infographic/ifg-20441505. Accessed: January 2024. 5 Survival rates for kidney cancer. American Cancer Society. Available: https://www.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.html Accessed: January 2024. 6 Orlin I. et al. Renal cell carcinomas epidemiology in the era of widespread imaging. Journal of Clinical Oncology. 2019; 37:15. DOI: https://ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.e13083. 7 El-Khoueiry A. et al., Cabozantinib: An evolving therapy for hepatocellular carcinoma. Cancer Treatment Reviews. 2021 Jul;98:102221. DOI: 10.1016/j.ctrv.2021.102221. 8 European Medicines Agency. Cabometyx® (cabozantinib) EU Summary of Product Characteristics. Available from: https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf. Last accessed: January 2024 9 Yakes M. et al., Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298–2308. DOI: 10.1158/1535-7163.MCT-11-0264 10 Hsu et al., AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review. Liver Cancer 2021 DOI: 10.1159/000520501 11 Prostate Cancer: Types of Treatment. Cancer.Net. Available at: https://www.cancer.net/cancer-types/prostate-cancer/types-treatment. Accessed January 2024. 12 Kidney Cancer Factsheet. GLOBOCAN 2020. Available: https://gco.iarc.fr/today/data/factsheets/cancers/29-Kidney-fact-sheet.pdf. Accessed: January 2024. 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SAN DIEGO, May 24, 2023 /PRNewswire/ -- Mirati Therapeutics, Inc.® (NASDAQ: MRTX), a commercial-stage oncology company, today announced that the SAPPHIRE study did not meet its primary endpoint of overall survival at the final analysis. SAPPHIRE is a Phase 3 study evaluating sitravatinib in combination with nivolumab (OPDIVO®)1 versus docetaxel in patients with second or third line advanced non-squamous non-small cell lung cancer (NSQ-NSCLC) who progressed on prior therapy with chemotherapy and immune checkpoint inhibitor therapy. The company plans to disclose the study data at a future date. Principal Investigators will be given the option to continue therapy for patients who are experiencing clinical benefit and would like to remain on treatment. "Mirati extends gratitude to the patients who participated in this clinical trial, their loved ones, and the trial investigators, without whom important work like this would not have been possible," said Alan Sandler, M.D., Chief Medical Officer. "As we move forward, we are optimistic about our ability to positively impact the lives of patients living with cancer through the advancement of our broad and differentiated pipeline of targeted oncology programs." About Mirati Therapeutics, Inc.® Mirati Therapeutics, Inc. is a commercial stage biotechnology company whose mission is to discover, design and deliver breakthrough therapies to transform the lives of patients with cancer and their loved ones. The company is relentlessly focused on bringing forward therapies that address areas of high unmet need, including lung cancer, and advancing a pipeline of novel therapeutics targeting the genetic and immunological drivers of cancer. Unified for patients, Mirati's vision is to unlock the science behind the promise of a life beyond cancer. For more information about Mirati, visit us at Mirati.com or follow us on Twitter, LinkedIn, and Facebook. About Sitravatinib Sitravatinib is an investigational spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. Sitravatinib is being evaluated in combination with nivolumab (OPDIVO®), an anti-PD-1 checkpoint inhibitor, in patients whose cancers have progressed despite treatment with a checkpoint inhibitor. Sitravatinib's potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation. Sitravatinib is being evaluated in multiple clinical trials to treat patients who are resistant to prior immune checkpoint inhibitor therapy and progressed on platinum doublet therapy, including the ongoing potentially registration-enabling Phase 3 trial of sitravatinib in combinations with a checkpoint inhibitor in non-small cell lung cancer (NSCLC). In addition, sitravatinib in combination with checkpoint inhibitors are being evaluated in selected checkpoint inhibitor naïve patients. For more information visit Mirati.com/science. Forward Looking Statements This press release includes forward-looking statements regarding Mirati's business, financial guidance and the therapeutic and commercial potential of KRAZATI® (adagrasib), sitravatinib (TAM receptor inhibitor), MRTX1719 (MTA-cooperative PRMT5 inhibitor), MRTX0902 (SOS1 inhibitor), and MRTX1133 (selective KRASG12D inhibitor), Mirati's technologies and Mirati's other products in development. Any statement describing Mirati's goals, expectations, intentions or beliefs, financial or other projections, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including those related to the impact COVID-19 could have on our business, and including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Mirati's forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Mirati's forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Mirati. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Mirati's programs are described in additional detail in Mirati's annual report on Form 10-K, and most recent Form 10-Q, which are on file with the Securities and Exchange Commission and available at the SEC's Internet site (). These forward-looking statements are made as of the date of this press release, and Mirati assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Mirati Contacts Investor Relations: [email protected] Media Relations: [email protected] 1OPDIVO® and the related logo are registered trademarks of Bristol-Myers Squibb Company. SOURCE Mirati Therapeutics, Inc.

Mirati Therapeutics announced that a Phase III trial evaluating sitravatinib in combination with Bristol Myers Squibb's PD-1 inhibitor Opdivo (nivolumab) in advanced non-small-cell lung cancer (NSCLC) did not meet its primary endpoint of overall survival (OS). The company said it would share the SAPPHIRE study data at a future time, but provided no other details.Company shares slid as much as 11% in after-hours trade following the disclosure Wednesday. The SAPPHIRE trial, which got under way in 2019, was comparing sitravatinib plus Opdivo versus docetaxel in up to 532 patients with second- or third-line non-squamous NSCLC who had progressed on prior chemotherapy and immune checkpoint inhibitor treatment.Previous setbackLast December, following an interim OS analysis, Mirati said the trial would continue to its final analysis. At the time, BMO Capital Markets said the update suggested sitravatinib plus Opdivo was "showing hints of efficacy and time [was perhaps] needed for OS data to mature." However, they noted that sitravatinib represented a "relatively small opportunity" with peak sales of roughly $880 million, compared to $3.1 billion projected for Mirati's KRAS-blocking therapy Krazati (adagrasib). That drug was approved by the FDA late last year for adults with KRAS G12C-mutated locally advanced or metastatic NSCLC following at least one prior systemic therapy. Mirati has also reported disappointing results from a mid-stage trial of sitravatinib plus Opdivo back in 2018.In its statement Wednesday, the company said principal investigators would be given the option to continue therapy with the combination for patients who are experiencing clinical benefit. "As we move forward, we are optimistic about our…broad and differentiated pipeline of targeted oncology programmes," stated chief medical officer Alan Sandler.Sitravatinib is a spectrum-selective kinase inhibitor that targets receptor tyrosine kinases (RTKs), including TAM family receptors TYRO3, Axl and Mer; split family receptors VEGFR2 and KIT; and RET. According to Mirati, the drug's "potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumour microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation."The drug candidate is being also evaluated in combination with checkpoint inhibitors in selected checkpoint inhibitor naïve-patients.