FDA Grants Breakthrough Designation to Cabozantinib in Renal Cell Carcinoma

Michael M. Morrissey, PhD

Michael M. Morrissey, PhD

Cabozantinib (Cometriq) was given a breakthrough therapy designation by the FDA for the treatment of patients who have advanced renal cell carcinoma (RCC), following one prior therapy, according to the multikinase inhibitor’s manufacturer, Exelixis.

This designation is based on findings from the open-label, phase III METEOR study, in which cabozantinib reduced the risk of progression or death by 42% versus everolimus (HR, 0.58;P<.0001). Overall survival (OS) for cabozantinib improved by 33% versus everolimus; the data continues to mature (HR, 0.67; P = .005). Statistical significance for the OS endpoint was represented by a&nbsp;Pvalue of .0019.

&ldquo;Receiving breakthrough therapy designation is an important regulatory achievement for cabozantinib in renal cell carcinoma,&rdquo; said Michael M. Morrissey, PhD, president and chief executive officer of Exelixis. &ldquo;Following the positive top-line results announced in July and a productive dialogue with the FDA, Exelixis believes we can expedite our regulatory timelines and complete the cabozantinib NDA submission in advanced RCC prior to the end of 2015.&rdquo;

Six hundred and fifty-eight patients with advanced RCC were randomized, in the METEOR study, in a 1:1 ratio, receiving 60 mg of cabozantinib daily or 10 mg of everolimus daily. All patients progressed following treatment with at least one prior VEGF TKI. The primary endpoint of progression-free survival (PFS) was assessed in the first 375 patients enrolled in the study. Analysis for OS, as well as other secondary endpoints, were from the full study population.

The trial was designed to show an HR for PFS of 0.67 and an HR for OS of 0.75. These statistical goals translate to an improvement in PFS of 2.5 months and an OS increase of 5 months with cabozantinib versus everolimus. However, due to the data released by Exelixis, the actual improvement in OS and PFS appears better than estimates.

&ldquo;We are eager to offer new treatment options for patients with metastatic RCC, particularly in the second-line setting where the most commonly utilized therapies have demonstrated a uniformly modest progression-free survival benefit,&rdquo; said METEOR trial principal investigator Toni K. Choueiri, MD, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, in a statement following an announcement of the findings in July. &ldquo;The magnitude of the improvement in PFS observed with cabozantinib compared to everolimus in the METEOR trial is an exciting and important development—it suggests an opportunity to improve care and outcomes for patients with metastatic RCC.&rdquo;

In addition to efficacy data, the company stated that serious adverse events (AEs) were balanced between the cabozantinib and everolimus arms in the phase III study. In both arms, there was a treatment discontinuation of approximately 10%, due to an AE.

According to a report from Exelixis, complete results from METEOR are scheduled for presentation as a late-breaking abstract on September 26 at the 2015 European Cancer Congress.

In April 2015, cabozantinib was given a fast track designation by the FDA for patients with advanced RCC who received one prior therapy. Under this program, as well as the breakthrough designation, Exelixis is able to interact with the FDA more frequently. Additionally, the company can complete a rolling submission of data for a supplemental new drug application.

&ldquo;We look forward to working closely with the FDA during the submission and review process, keeping in mind our ultimate goal of bringing a new therapeutic option to the renal cell carcinoma community as soon as possible,&rdquo; said Morrissey.

The MET, VEGFR2, and RET inhibitor cabozantinib was approved by the FDA as a treatment for patients with metastatic medullary thyroid cancer in November 2012. The agent continues to be explored in a number of solid tumors.