ALAMEDA, Calif. - Exelixis, Inc. (Nasdaq: EXEL) announced detailed results from the first planned analysis of COSMIC-312, the ongoing phase 3 pivotal trial evaluating cabozantinib (CABOMETYX) in combination with atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma (HCC). The data are being presented at 7:00 p.m. SGT (6:00 a.m. EST, 3:00 a.m. PST) on Saturday, November 20 in the Virtual Plenary Session during the European Society for Medical Oncology (ESMO) Asia Virtual Oncology Week 2021.
As announced in June and presented today, at a median follow-up of 15.8 months, the primary analysis showed the primary endpoint of progression-free survival (PFS) per RECIST 1.1 by blinded independent review committee (BIRC) was met; in the PFS intent-to-treat (PITT) population, cabozantinib in combination with atezolizumab significantly reduced the risk of disease progression or death by 37% compared with sorafenib (hazard ratio [HR]: 0.63; 99% confidence interval [CI]: 0.44-0.91; P=0.0012; pre-specified critical p-value of 0.01). Median PFS was 6.8 months for cabozantinib in combination with atezolizumab (n=250) versus 4.2 months for sorafenib (n=122).
New results presented during the 2021 ESMO Virtual Plenary include detailed data for a prespecified interim analysis for the primary endpoint of overall survival (OS) in the intent-to-treat (ITT) population, which was conducted at the same time as the primary analysis for PFS in the PITT population. At a median follow-up of 13.6 months, the interim OS analysis in the ITT population showed a trend that favored cabozantinib in combination with atezolizumab but did not reach statistical significance (HR: 0.90; 96% CI: 0.69-1.18; P=0.438). Median OS was 15.4 months for cabozantinib in combination with atezolizumab (n=432) versus 15.5 months for sorafenib (n=217). The trial is continuing as planned to the final analysis of OS, anticipated in early 2022.
'We are encouraged by the significant improvement in progression-free survival observed in COSMIC-312, suggesting cabozantinib in combination with atezolizumab holds potential as a treatment to reduce the risk of disease progression or death for patients with advanced liver cancer,' said R. Kate Kelley, M.D., Professor of Clinical Medicine, Division of Hematology/Oncology, University of California, San Francisco, and lead investigator on COSMIC-312. 'Patients with this aggressive form of cancer, who may also have other comorbid conditions due to liver disease, face a poor prognosis and are in need of additional approaches to treatment.'
Subgroup analyses of PFS in the PITT population and preliminary interim OS results in the ITT population were performed by disease etiology:
Median PFS in hepatitis B virus patients (n=109): 6.7 months for patients treated with cabozantinib in combination with atezolizumab compared with 2.7 months for sorafenib (HR: 0.46; 95% CI: 0.29-0.73).
Median OS in hepatitis B virus patients (n=191): 18.2 months for patients treated with cabozantinib in combination with atezolizumab compared with 14.9 months for sorafenib (HR: 0.53; 95% CI: 0.33-0.87).
Median PFS in hepatitis C virus patients (n=105): 7.9 months for patients treated with cabozantinib in combination with atezolizumab compared with 5.6 months for sorafenib (HR: 0.64; 95% CI: 0.38-1.09).
Median OS in hepatitis C virus patients (n=203): 13.6 months for patients treated with cabozantinib in combination with atezolizumab compared with 14.0 months for sorafenib (HR: 1.10; 95% CI: 0.72-1.68).
Median PFS in non-viral patients (n=158): 5.8 months for patients treated with cabozantinib in combination with atezolizumab compared with 7.0 months for sorafenib (HR: 0.92; 95% CI: 0.60-1.41).
Median OS in non-viral patients (n=255): 15.2 months for patients treated with cabozantinib in combination with atezolizumab, and not reached for sorafenib (HR: 1.18; 95% CI: 0.78-1.79).
In an interim analysis of the secondary endpoint of PFS per RECIST 1.1 by BIRC performed to determine the contribution of cabozantinib to the combination with atezolizumab, cabozantinib monotherapy reduced the risk of disease progression or death in the ITT population by 29% versus sorafenib (HR: 0.71; 99% CI: 0.51-1.01; P=0.0107; pre-specified critical p-value of 0.00451). Median PFS was 5.8 months for cabozantinib (n=188) versus 4.3 months for sorafenib (n=217).
Objective response rates per RECIST 1.1 by BIRC in the ITT population were 11% for cabozantinib in combination with atezolizumab, 3.7% for sorafenib and 6.4% for cabozantinib monotherapy. Disease control rates (complete response + partial response + stable disease) were 78%, 65% and 84%, respectively.
'Exelixis has a longstanding commitment to patients with liver cancer, and we are pleased to present more detailed efficacy and safety data during this ESMO Virtual Plenary Session reinforcing the potential of cabozantinib in combination with atezolizumab for patients with this disease who are in need of additional first-line treatment options,' said Michael M. Morrissey, Ph.D., President and Chief Executive Officer, Exelixis. 'We look forward to the final COSMIC-312 overall survival analysis in early 2022 and to submitting an sNDA to the FDA at that time.'
The safety profile for cabozantinib in combination with atezolizumab was consistent with those previously observed for each single agent, and no new safety signals were identified. The most common grade 3 or higher adverse events (AEs) for cabozantinib in combination with atezolizumab were palmar-plantar erythrodysesthesia (7.9% versus 8.2% for sorafenib and 8.5% for cabozantinib monotherapy), hypertension (7.0%, 6.3% and 11.0%, respectively), aspartate aminotransferase increased (6.5%, 2.4% and 5.3%) and alanine aminotransferase increased (6.3%, 1.9% and 5.9%).
Rates of grade 3/4 treatment-related AEs were 51% for cabozantinib and atezolizumab, 30% for sorafenib and 52% for cabozantinib monotherapy. Rates of grade 5 treatment-related AEs were 1.9% for cabozantinib and atezolizumab, 0.5% for sorafenib and 0.5% for cabozantinib monotherapy. Treatment discontinuations due to treatment-related AEs in the combination arm were 6.1% for the combination of cabozantinib and atezolizumab and 14.0% for either cabozantinib and/or atezolizumab. The treatment-related discontinuation rate for sorafenib was 7.7% and for cabozantinib monotherapy was 8.5%.
COSMIC-312 is a global, multicenter, randomized, controlled phase 3 pivotal trial that enrolled 837 patients at 281 study centers globally. Nine enrolled patients were from Mainland China, 232 were from elsewhere in Asia, and 596 were from outside Asia. An extension phase in China is ongoing and is not included in this current analysis. Patients were randomized approximately 2:1:1 to one of three arms: cabozantinib (40 mg) in combination with atezolizumab (n=432), sorafenib (n=217) or cabozantinib (60 mg; n=188). Exelixis is sponsoring COSMIC-312, and Ipsen is co-funding the trial. Genentech, a member of the Roche Group, is providing atezolizumab for use in this trial. More information about COSMIC-312 is available at ClinicalTrials.gov.
More than 900,000 new cases of liver cancer, 90% of which are HCC, are diagnosed worldwide each year.1,2 HCC is a leading cause of cancer-related death, expected to cause 1 million global deaths annually by 2030.3 In the U.S., HCC is the fastest-rising cause of cancer-related death.4 Median survival for patients with symptomatic advanced HCC who are treated with systemic therapies is just 1 to 1.5 years.2 Research has shown that gastrointestinal varices - which are associated with a higher risk of death from bleeding - occur in about 60-75% of patients with advanced HCC, the presence of which can impact the therapies available to these patients.5,6
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 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 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 Pharmaceutical Company Limited 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 previously untreated advanced HCC.
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