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Press Release

Exelixis Announces Outcome from First Planned Interim Analysis of the Phase 3 CELESTIAL Trial of Cabozantinib in Patients with Advanced Hepatocellular Carcinoma

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Sep. 6, 2016-- Exelixis, Inc. (NASDAQ:EXEL) today announced the outcome from the first planned interim analysis of CELESTIAL, a randomized global phase 3 trial of cabozantinib compared with placebo in patients with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. Following this interim analysis, which was scheduled to take place when 50 percent of the events for the primary endpoint of overall survival (OS) had occurred, the trial’s Independent Data Monitoring Committee (IDMC) determined that the study should continue without modifications per the study protocol. The trial protocol calls for a second interim analysis to take place once 75 percent of events have been observed.

HCC is the most common form of liver cancer and the third-leading cause of cancer deaths worldwide.1 The disease originates in cells called hepatocytes, which make up the majority of the liver.2 Without treatment, patients with advanced disease usually survive less than 6 months.3 During 2003-2012, deaths in the U.S. from liver cancer increased at the highest rate of all cancer sites.4 In 2016 it is estimated that over 39,000 new cases and over 27,000 deaths occurred in the U.S. due to liver cancer.5 Across the U.S., EU5 (Italy, France, Germany, Spain, and United Kingdom), and Japan, it is estimated that approximately 117,000 new cases will be diagnosed in 2017.4,6-8 Liver cancer is a leading cause of cancer-related mortality worldwide, accounting for more than 700,000 deaths each year. 9

Cabozantinib is not approved for the treatment of HCC.

About the CELESTIAL Study

CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial is designed to enroll 760 patients with advanced HCC who received prior sorafenib. Patients are randomized 2:1 to receive 60 mg of cabozantinib daily or placebo.

The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and progression-free survival. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

Based on available clinical trial data from various published trials conducted in the second line setting of advanced HCC, the CELESTIAL trial statistics for the primary endpoint of OS assumed a median OS of 8.2 months for the placebo arm. A total of 621 events provide the study with 90 percent power to detect a 32 percent increase in OS (HR = 0.76) at the final analysis. Two interim analyses were planned to be conducted at 50 percent and 75 percent of the planned 621 events.

Please see Important Safety Information below and full U.S. prescribing information at https://cabometyx.com/downloads/cabometyxuspi.pdf.

About CABOMETYX™ (cabozantinib)

CABOMETYX is the tablet formulation of cabozantinib. CABOMETYX targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy.

On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan. On January 28, 2016, the European Medicines Agency (EMA) validated Exelixis’ Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced RCC who have received one prior therapy. The MAA has been granted accelerated assessment, making it eligible for a 150-day review, versus the standard 210 days. On July 22, 2016, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion of the MAA for cabozantinib for the treatment of adult patients with advanced RCC who have received at least one prior VEGF receptor tyrosine kinase inhibitor therapy. The CHMP's positive opinion is under review by the European Commission (EC), which has the authority to approve medicines for the European Union.

Important Safety Information

Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.

Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.

Diarrhea: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to diarrhea occurred in 26% of patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-fetal Toxicity: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation.

Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.

Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.

Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential.

Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

Please see full Prescribing Information at https://cabometyx.com/downloads/cabometyxuspi.pdf.

About Exelixis

Exelixis, Inc. (Nasdaq: EXEL) is a biopharmaceutical company committed to the discovery, development and commercialization of new medicines with the potential to improve care and outcomes for people with cancer. Since its founding in 1994, three medicines discovered at Exelixis have progressed through clinical development to receive regulatory approval. Currently, Exelixis is focused on advancing cabozantinib, an inhibitor of multiple tyrosine kinases including MET, AXL and VEGF receptors, which has shown clinical anti-tumor activity in more than 20 forms of cancer and is the subject of a broad clinical development program. Two separate formulations of cabozantinib have received regulatory approval to treat certain forms of kidney and thyroid cancer and are marketed for those purposes as CABOMETYX™ tablets (U.S.) and COMETRIQ® capsules (U.S. and EU), respectively. Another Exelixis-discovered compound, COTELLIC™ (cobimetinib), a selective inhibitor of MEK, has been approved in major territories including the United States and European Union, and is being evaluated for further potential indications by Roche and Genentech (a member of the Roche Group) under a collaboration with Exelixis. For more information on Exelixis, please visit www.exelixis.com or follow @ExelixisInc on Twitter.

Forward-Looking Statement Disclaimer

This press release contains forward-looking statements, including, without limitation, statements related to: the continuation of CELESTIAL and timing for a second interim analysis; the timing for review of the CHMP’s positive opinion of the MAA for cabozantinib for the treatment of patients with advanced RCC who have received one prior therapy; Exelixis' commitment to the discovery, development and commercialization of new medicines with the potential to improve care and outcomes for people with cancer; Exelixis’ focus on advancing cabozantinib; and the continued development of cobimetinib. Words such as “will,” “focused,” “potential,” “eligible,” “committed,” or other similar expressions identify forward-looking statements, but the absence of these words does not necessarily mean that a statement is not forward-looking. In addition, any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements. These forward-looking statements are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the availability of data at the referenced times; Exelixis’ ability to conduct clinical trials of cabozantinib sufficient to achieve a positive completion; risks related to the potential failure of cabozantinib to demonstrate safety and efficacy in clinical testing; risks and uncertainties related to regulatory review and approval processes and Exelixis’ compliance with applicable legal and regulatory requirements; Exelixis’ dependence on its relationship with Ipsen, including, the level of Ipsen’s investment in the resources necessary to successfully commercialize cabozantinib in the territories where it is approved; Exelixis’ dependence on its relationship with Genentech/Roche with respect to cobimetinib and Exelixis’ ability to maintain its rights under the collaboration; Exelixis’ dependence on third-party vendors; Exelixis’ ability to protect the company’s intellectual property rights; market competition; changes in economic and business conditions, and other factors discussed under the caption “Risk Factors” in Exelixis’ quarterly report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 3, 2016, and in Exelixis’ future filings with the SEC. The forward-looking statements made in this press release speak only as of the date of this press release. Exelixis expressly disclaims any duty, obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in Exelixis’ expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.

References

1. Hepatocellular Carcinoma – United States, 2001-2006. (7 May 2010). Morbidity and Mortality Weekly Report. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5917a3.htm. Accessed Aug 17, 2016.

2. American Cancer Society: Cancer Facts and Figures 2012. Atlanta, GA: American Cancer Society, 2012.

3. Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer. 1985. 56(4):918-28.

4. Ryerson AB, Eheman CR, Altekruse SF, et al. Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer. Cancer. 2016. 122(9):1312-37.

5. American Cancer Society: Key statistics about liver cancer. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003114-pdf.pdf. Accessed Aug 29, 2016.

6. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013. 49(6):1374-403.

7. Projected Cancer Statistics, 2016. Center for Cancer Control and Information Services, National Cancer Center (Japan). Available at: http://ganjoho.jp/en/public/statistics/short_pred.html Accessed Aug 25, 2016.

8. Exelixis internal estimates of growth rates through 2017.

9. Estimated cancer incidence, mortality and prevalence worldwide. International Agency for Research on Cancer, GLOBOCAN 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed Sep 02, 2016.

Source: Exelixis, Inc.

Exelixis, Inc.
Investors:
Susan Hubbard, 650-837-8194
Investor Relations & Public Affairs
shubbard@exelixis.com
or
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