Cabozantinib inhibits the activity of tyrosine kinases including MET, AXL, VEGF receptors, and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.
Cabozantinib was discovered by Exelixis, and is the focus of the company’s development and commercialization efforts in recognition of its potential to treat a wide variety of cancers. Cabozantinib’s global clinical development program includes approximately 45 ongoing or planned clinical trials, including: company-sponsored trials; studies conducted under the company’s Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP); and an Investigator-Sponsored Trial program.
Licensing Agreements for Development and Commercialization Outside the U.S.
Exelixis has strategically focused on maximizing cabozantinib’s potential in the United States, where we have retained exclusive rights, while establishing collaborative licensing agreements with partners in key ex-U.S. territories. These agreements enable Exelixis to continue to execute on U.S. commercial opportunities in progressive, metastatic medullary thyroid cancer and advanced renal cell carcinoma (RCC) while ensuring cabozantinib’s clinical and commercial progress on a global basis. In exchange for exclusive rights, Exelixis is eligible for development, commercialization and/or sales milestone payments, as well as royalties on partner sales.
Exclusive Licensing Agreement with Ipsen. Announced in February 2016 and amended in December 2016, this agreement grants Ipsen exclusive rights to commercialize and further develop cabozantinib on a worldwide basis outside of the United States and Japan. Exelixis and Ipsen have also agreed to collaborate on the development of cabozantinib for current and future potential indications. Under the terms of the agreement, Exelixis received upfront payments from Ipsen of $200 million and $10 million for signing the original agreement and its Canada amendment, respectively, and Exelixis is also eligible for regulatory and commercial milestones, as well as tiered royalties on sales.
Exclusive Japanese Licensing Agreement with Takeda. In January 2017, Exelixis announced an exclusive licensing agreement with Takeda Pharmaceutical Company for the commercialization and development of cabozantinib in Japan. In exchange, Exelixis received a $50 million upfront payment and is eligible for development, regulatory, and first-sales milestone payments of $95 million for the first three planned indications. Exelixis will also be eligible for royalties on Takeda’s sales in Japan.
For information on approved uses of cabozantinib, please visit our Medicines page.
Clinical Development Collaborations Pairing Cabozantinib with Immunotherapies
Exelixis believes that there is a strong rationale for combining cabozantinib with immunotherapies, including clinical evidence of cabozantinib’s ability to create a more immune-permissive environment, as well as preclinical data suggesting cabozantinib increases T-cell infiltration into tumors. To maximize cabozantinib’s potential to help patients, Exelixis is collaborating with other drug developers on clinical trials combining investigational and approved immunotherapies with cabozantinib.
Pursuant to the terms of their respective collaboration agreements, if they opt in and participate in the funding of these studies, Exelixis’ partners Ipsen and Takeda may participate and utilize the study results to support future regulatory submissions.
With Bristol-Myers Squibb Company (BMS). In February 2017, Exelixis entered into a clinical development collaboration with BMS for the evaluation of CABOMETYX™ (cabozantinib) with Opdivo® (nivolumab), BMS’ PD-1 immune checkpoint inhibitor, either alone or in combination with Yervoy® (ipilimumab). The clinical development program, which will be co-funded by the companies, will include a phase 3 pivotal trial in first-line RCC planned to start in 2017, as well as additional trials in bladder cancer, hepatocellular carcinoma (HCC), and potentially other tumor types. Ipsen has opted to participate in the RCC trial and will have access to the results.
With Roche. In February 2017, Exelixis entered into a clinical trial collaboration with Roche on a phase 1b dose escalation study that will evaluate the safety and tolerability of cabozantinib in combination with atezolizumab, Roche’s anti-PD-L1 immunotherapy, in patients with locally advanced or metastatic solid tumors. Following an initial dose-escalation phase, the trial protocol foresees enrollment of four expansion cohorts, including a cohort of patients with previously untreated advanced clear cell RCC and three cohorts of urothelial carcinoma (UC), namely platinum eligible first-line patients, first- or second-line platinum ineligible patients, and patients previously treated with platinum-containing chemotherapy. Enrollment is scheduled to begin mid-year 2017; Exelixis will be the sponsor of the trial, and Roche will provide atezolizumab. Ipsen has opted to participate in this study and will have access to the results.
Advanced Hepatocellular Carcinoma. Exelixis is also investigating cabozantinib in patients with advanced HCC in CELESTIAL, a global, randomized, double-blind phase 3 pivotal trial. CELESTIAL is targeting an enrollment of 760 patients with advanced HCC who have received prior treatment with sorafenib. The primary endpoint of the trial is OS. Data continue to be anticipated in 2017 following an Independent Data Monitoring Committee recommendation that the study continue as planned following its first planned interim analysis, which was announced in September 2016. There is currently no standard of care available in second- or later-line patients who have received prior sorafenib, highlighting the unmet medical need in this disease setting. For more information on CELESTIAL, visit the trial’s page on ClinicalTrials.gov.
In March 2017, Exelixis announced that the U.S. Food & Drug Administration (FDA) had granted orphan drug designation to cabozantinib for the treatment of HCC. Orphan drug status is granted to treatments for diseases that affect fewer than 200,000 people in the U.S. and provides certain incentives for medications intended for the treatment, diagnosis or prevention of rare diseases.
Research Sponsored by External Parties
Phase 1b Combination Trial with Immunotherapies. Exelixis’ collaborators at the National Cancer Institute are sponsoring a phase 1b trial of cabozantinib in combination with nivolumab alone, or in combination with nivolumab plus ipilimumab, in patients with genitourinary tumors, including bladder cancer and RCC. The primary endpoint of the trial is the determination of dose-limiting toxicities and a recommended phase 2 dose for the combinations. Data from this trial could have relevance in multiple other tumor settings.
In February 2017, investigators presented data from the trial at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) in Orlando. Among the 43 patients who were evaluable for response, the objective response rate for all tumor types was 30 percent with a 7 percent complete response rate and a 23 percent partial response rate. The ORR for patients with urothelial cancer was 38 percent, and two of 16 patients achieved a complete response, while two patients with squamous cell carcinoma of the bladder had objective responses. In the urothelial cancer cohort, 15 of 16 patients had a complete response, partial response or stable disease as their best response.
First-Line Intermediate or Poor Risk RCC (CABOSUN). The company’s collaborators at the National Cancer Institute are also sponsoring CABOSUN, a randomized phase 2 trial comparing cabozantinib to sunitinib in first-line therapy of intermediate or poor risk patients per the standard risk classification. The primary endpoint of the trial is progression-free survival. The study achieved its target enrollment of 150 patients in March 2015, and in May 2016 Exelixis announced CABOSUN met its primary endpoint. Detailed data were presented at the ESMO 2016 Congress and published in the Journal of Clinical Oncology, where investigators reported cabozantinib demonstrated a clinically meaningful and statistically significant 34 percent reduction in the rate of disease progression or death [HR=0.66, 95% CI (0.46-0.95), one-sided P=0.012] as compared to sunitinib. Median progression-free survival for cabozantinib was 8.2 months versus 5.6 months for sunitinib, corresponding to a 2.6 months (46 percent) improvement favoring cabozantinib. Objective response rate was also significantly improved. Based on these results, Exelixis plans to submit a Supplemental New Drug Application for cabozantinib as a treatment for first-line advanced renal cell carcinoma in the third quarter of 2017.
Non-Small Cell Lung Cancer. At the American Society for Clinical Oncology’s 2015 Annual Meeting, investigators presented positive results from two clinical trials of cabozantinib in molecularly-defined subsets of non-small cell lung cancer.
- An investigator-sponsored phase 2 study in NSCLC patients with RET fusion genes met its primary endpoint and exceeded the predefined number of objective responses to declare success.
- A study sponsored by the National Cancer Institute evaluated cabozantinib, cabozantinib with erlotinib, and erlotinib monotherapy in a population of EGFR wild-type NSCLC patients. Results showed that the cabozantinib arm, and the combination arm of cabozantinib with erlotinib, significantly extended both PFS (the primary endpoint) and overall survival (a secondary endpoint), as compared to erlotinib on its own.
The results from both of these studies were published recently in Lancet Oncology1. Exelixis is committed to working with its collaborators to explore further development of cabozantinib in NSCLC, including potential combination approaches with immunotherapy agents.
Additional Information on Cabozantinib’s Development
For more information on cabozantinib clinical trials, including additional trials conducted as part of our Investigator-Sponsored Trial program and collaboration with NCI-CTEP, please visit the Clinical Trials section of our site.
Cabozantinib is the subject of investigation in a variety of ongoing clinical trials; its safety and efficacy profile in these trials has not yet been established.
1Drilon A, et al. Lancet Oncol. 2016 Dec;17(12):1653-1660; Neal JW, et al.. Lancet Oncol. 2016 Dec;17(12):1661-1671.