Exelixis has completed the submission of a supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) for Cabometyx (cabozantinib) tablets as a treatment for patients with previously untreated advanced renal cell carcinoma (RCC).

The sNDA submission is based on results from the CABOSUN randomized phase 2 trial of Cabometyx in patients with previously untreated advanced RCC with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

“All of us at Exelixis are focused on improving care and outcomes for patients with cancer. Having successfully launched Cabometyx for patients with previously treated advanced RCC, the submission of this sNDA for Cabometyx as a treatment in the first-line RCC setting represents an important milestone for us,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “If approved, Cabometyx will offer an important new alternative for the treatment of patients with previously untreated advanced RCC, having demonstrated a clinically meaningful and statistically significant progression-free survival benefit over sunitinib, a current standard of care. We would like to sincerely thank the study patients and clinicians who participated in the CABOSUN trial, the Alliance and NCI-CTEP, as well as our dedicated clinical, medical and regulatory teams for bringing us one step closer to our goal of expanding the population of patients who may benefit from Cabometyx.”

CABOSUN was conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP). On May 23, 2016, Exelixis announced that CABOSUN met its primary endpoint, demonstrating a clinically meaningful and statistically significant improvement in progression-free survival (PFS) compared with sunitinib in patients with advanced intermediate- or poor-risk RCC as determined by investigator assessment. These results were first presented by Dr. Toni Choueiri at the meeting of the European Society for Medical Oncology 2016, and published in the Journal of Clinical Oncology (Choueiri, JCO, 2016).1 In June 2017, Exelixis announced that the analysis of the review by a blinded independent radiology review committee (IRC) confirmed the primary efficacy endpoint results of investigator-assessed PFS from the CABOSUN trial.

An sNDA is an application to the FDA that, if approved, will allow a drug sponsor to make changes to a previously approved product label, including modifications to the indication. Cabometyx was previously approved by the FDA on April 25, 2016 for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy. The approval was based on results from the phase 3 METEOR trial, which demonstrated that Cabometyx provided a statistically significant and clinically meaningful improvement in overall survival, PFS and objective response rate as compared with everolimus in this patient population.

CABOSUN was a randomized, open-label, active-controlled phase 2 trial that enrolled 157 patients with advanced RCC determined to be intermediate- or poor-risk by the IMDC criteria. Patients were randomized 1:1 to receive cabozantinib (60 mg once daily) or sunitinib (50 mg once daily, 4 weeks on followed by 2 weeks off). The primary endpoint was PFS. Secondary endpoints included overall survival and objective response rate. Eligible patients were required to have locally advanced or metastatic clear-cell RCC, ECOG performance status 0-2 and had to be intermediate or poor risk per the IMDC criteria (Heng, JCO, 2009).2 Prior systemic treatment for RCC was not permitted.

Cabometyx is the tablet formulation of cabozantinib. Its 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 tumour 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, 2016, the FDA approved Cabometyx tablets for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy. In February of 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. This agreement was amended in December of 2016 to include commercialization rights for Ipsen in Canada. On September 9, 2016, the European Commission approved Cabometyx tablets for the treatment of advanced RCC in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland. Ipsen has confirmed its intent to submit the regulatory dossier for cabozantinib as a treatment for first-line advanced RCC in the European Union in the third quarter of 2017.

On January 30, 2017, Exelixis and Takeda Pharmaceutical Company Limited announced an exclusive licensing agreement for the commercialization and further clinical development of cabozantinib for all future indications in Japan, including RCC.

Cabometyx is not indicated for the treatment of previously untreated advanced RCC.