Exelixis has announced a new collaboration with Roche on a phase 1b dose escalation study that will evaluate the safety and tolerability of cabozantinib, Exelixis’ tyrosine kinase inhibitor (TKI), in combination with atezolizumab, Roche’s anti-PD-L1 immunotherapy, in patients with locally advanced or metastatic solid tumors. Enrollment is scheduled to begin mid-year 2017; Exelixis will be the sponsor of the trial, and Roche will provide atezolizumab.

Based on the dose-escalation results, the trial has the potential to enroll up to four expansion cohorts, including a cohort of patients with previously untreated advanced clear cell renal cell carcinoma (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. Ipsen, Exelixis’ global partner for cabozantinib, except in the United States and Japan, will participate in this study and have access to the results for potential future development in its territories. Takeda may also participate in these and future studies and have access to the results to support potential future regulatory submissions in their territories, if they opt into their funding obligations under the respective collaboration agreement.

“People with advanced genitorurinary malignancies are in need of additional treatment options that can improve clinical outcomes,” said Sumanta Kumar Pal, M.D., co-director, Kidney Cancer Program at City of Hope, and principal investigator in the study. “The combined approach of tyrosine kinase inhibition with cabozantinib alongside immune-checkpoint inhibition has already shown promise in an early phase 1 clinical trial. We look forward to further examining this potential with cabozantinib plus atezolizumab to treat a range of genitourinary and other tumors.”

“We are pleased to collaborate with Roche to study the potential of atezolizumab in combination with cabozantinib, our lead medicine that is the subject of a broad development program across a variety of cancers,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “Although several therapies have recently received regulatory approval to treat advanced kidney and bladder cancers, survival continues largely to be measured in months, not years. Evaluating how cabozantinib may positively impact treatment when paired with immunotherapy is central to our goal of improving therapeutic outcomes for patients with these and other cancers.”

The rationale for the collaboration is based on clinical and preclinical observations consistent with the ability of cabozantinib to promote an immunopermissive environment, which might present an opportunity for synergistic effects from combination treatment with immune checkpoint inhibitors and other immunotherapies. In an ongoing phase 1 clinical trial in subjects with refractory metastatic UC and other genitourinary tumors, cabozantinib has been evaluated in combination with nivolumab, a monoclonal antibody to PD-1. The combination was well-tolerated among all enrolled subjects, no dose-limiting toxicities were reported, and the recommended phase 2 dose was determined to be 40 mg qd for cabozantinib with 3 mg/kg of nivolumab (intravenous [IV], once every two weeks). Updated results from this part of the study as well as results from a second part evaluating the combination of cabozantinib, nivolumab and ipilimumab were presented during the poster session (Abstract #293) on February 17 at the American Society of Clinical Oncology 2017 Genitourinary Cancers Symposium, which was held in Orlando, Florida, February 16 – 18, 2017.

Exelixis’ cabozantinib is a potent inhibitor of multiple receptor tyrosine kinases known to play important roles in tumor cell proliferation and/or tumor neovascularization including MET, VEGFR, AXL and RET. Some of these receptors have also been implicated in promoting an immunosuppressive tumor microenvironment. Cabozantinib has demonstrated broad preclinical and clinical activity across several tumor types. Cabozantinib tablets (60 mg) are approved as CABOMETYX in the United States and Europe for patients with advanced RCC who have received prior anti-angiogenic/VEGF-targeted therapy, and cabozantinib capsules (140 mg) are approved as COMETRIQ for the treatment of progressive, metastatic medullary thyroid cancer (MTC) in the United States and Europe.