– CABINET trial will be unblinded and stopped early due to a dramatic improvement in efficacy per a unanimous recommendation by The Alliance for Clinical Trials in Oncology independent Data and Safety Monitoring Board –
– Based on positive results, findings will be discussed with the U.S. Food and Drug Administration –
ALAMEDA, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (Nasdaq: EXEL) today announced that the Alliance for Clinical Trials in Oncology independent Data and Safety Monitoring Board (DSMB) unanimously recommended to unblind and stop the phase 3 CABINET pivotal trial early due to a dramatic improvement in efficacy that was observed at an interim analysis. CABINET is evaluating cabozantinib (CABOMETYX®) compared with placebo in patients with either advanced pancreatic neuroendocrine tumors (pNET) or advanced extra-pancreatic neuroendocrine tumors (also referred to as carcinoid tumors) who experienced progression after prior systemic therapy. Cabozantinib substantially prolonged the time without disease progression or death in both of the trial’s cohorts. CABINET is sponsored by the National Cancer Institute (NCI) and is led by The Alliance for Clinical Trials in Oncology. Detailed findings will be presented at an upcoming medical meeting and discussed with the U.S. Food and Drug Administration (FDA).
“As there is no standard of care for patients with advanced pancreatic or extra-pancreatic neuroendocrine tumors whose disease has progressed after prior therapy, we are pleased to see that cabozantinib improved outcomes for two additional patient populations living with advanced, difficult-to-treat cancers,” said Will Berg, M.D., Senior Vice President, Medical Affairs, Exelixis. “We are grateful for the recommendation of the Data and Safety Monitoring Board to unblind the CABINET study early due to a dramatic improvement in efficacy and look forward to discussing these findings with the U.S. Food and Drug Administration.”
The safety profile of cabozantinib observed in the trial was consistent with its known safety profile, and no new safety signals were identified.
“Patients with progressive neuroendocrine tumors have limited treatment options. At present, after progression on previous therapies, the treatment path is unclear, underscoring the need for additional options for this disease that is rising in incidence,” said Jennifer Chan, M.D., M.P.H., study chair for the CABINET trial and Clinical Director of the Gastrointestinal Cancer Center and Director of the Program in Carcinoid and Neuroendocrine Tumors at Dana-Farber Cancer Institute. “These promising findings from the CABINET trial, in which cabozantinib showed an efficacy benefit for patients with pancreatic and extra-pancreatic neuroendocrine tumors, are welcome news and show the potential for cabozantinib to address important unmet needs for this community.”
About CABINET (A021602)
CABINET (Randomized, Double-Blinded Phase III Study of CABozantinib versus Placebo IN Patients with Advanced NEuroendocrine Tumors After Progression on Prior Therapy) is sponsored by the NCI, part of the National Institutes of Health, and is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology with participation from the NCI-funded National Clinical Trials Network as part of Exelixis’ collaboration with the NCI’s Cancer Therapy Evaluation Program. CABINET is a multicenter, randomized, double-blinded, placebo-controlled phase 3 pivotal trial that enrolled a total of 290 patients in two separate cohorts (pNET, n=93; extra-pancreatic NET, n=197) in the U.S. Patients were randomized 2:1 into the cabozantinib or placebo arms of the study in each of the two cohorts. Patients must have had measurable disease per RECIST 1.1 criteria and must have experienced disease progression after at least one FDA-approved line of prior therapy other than somatostatin analogs. The primary endpoint was progression-free survival in each cohort. Upon confirmation of disease progression, patients were unblinded, and those receiving placebo were permitted to cross over to open-label therapy with cabozantinib. Secondary endpoints included overall survival, radiographic response rate and safety. More information about this trial is available at ClinicalTrials.gov.
About NET
NET refer to cancers that begin in the specialized cells of the body’s neuroendocrine system.1 These cells have traits of both hormone-producing endocrine cells and nerve cells.1 In the U.S., more than 12,000 people are diagnosed with NET each year and approximately 171,000 people are living with the disease.2 The number of people diagnosed with NET each year has been increasing.2 NET are classified as functional or non-functional.1 Functional NET release peptide hormones that can cause debilitating symptoms and necessitate treatment, while symptoms of non-functional NET are related primarily to tumor growth.1,3,4 Most NET take years to develop and grow slowly, but some grow quickly.5 NET can develop in any part of the body, but most commonly start in the gastrointestinal (GI) tract or in the lungs – these historically have been referred to as carcinoid tumors.5 The five-year survival rates for advanced GI-NET and lung carcinoid tumors are 68% and 55%, respectively.6,7 NET can also start in the pancreas.8 While less common, these NET can be more aggressive and the five-year survival rate for advanced pNET is only 23%.8,9 Surgery to remove the tumor and prevent it from spreading is the typical first approach to treatment for both carcinoid tumors and pNET.10 For more advanced disease, options include somatostatin analogs, targeted therapy, peptide-receptor radionuclide therapy and chemotherapy.10
About CABOMETYX® (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced renal cell carcinoma (RCC); for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen Pharma SAS exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.
CABOMETYX is not indicated as a treatment for NET.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and 3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.
Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.
Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in