Second-Line Cabozantinib Improves OS, PFS in mRCC

Toni Choueiri, MD

Treatment with cabozantinib (Cometriq) improved progression-free survival (PFS) and overall survival (OS) compared with everolimus (Afinitor) in pretreated patients with metastatic renal cell carcinoma (mRCC), according to top-line findings from the phase III METEOR study.

In the open-label trial, cabozantinib reduced the risk of progression or death by 42% versus everolimus (HR = 0.58; P <.0001), which was the primary endpoint of the study. OS with cabozantinib was improved by 33% versus everolimus, with data continuing to mature (HR = 0.67; P = .005). Statistical significance for this endpoint was represented by a P value of .0019.

Exelixis, the company developing the multikinase inhibitor, plans to submit the data for regulatory approval in early 2016 in the United States and European Union. Additionally, the company is preparing the results for presentation at an upcoming medical conference.

“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,” METEOR trial principal investigator Toni K. Choueiri, MD, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, said in a statement. “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.”

In the METEOR study, 658 patients were randomized in a 1:1 ratio to received 60 mg of cabozantinib daily or 10 mg of everolimus daily. All patients had progressed following treatment with at least 1 prior VEGF TKI. The primary endpoint of PFS was assessed in the first 375 patients enrolled in the study. Analysis for OS and 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, given the data released by Exelixis, the actual improvement in OS and PFS appears better than estimates.

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

“The positive top-line results from METEOR represent strong progress for the kidney cancer community and for Exelixis, bringing us one step closer to our shared goal of delivering a new and meaningfully differentiated therapeutic option for the many metastatic RCC patients in need,” Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, said in a statement. “With these data now in hand, Exelixis’ highest corporate priority becomes the submission of US and EU regulatory filings, which we intend to complete in early 2016.”

In April 2015, cabozantinib received a fast track designation from the FDA for patients with advanced RCC who had received 1 prior therapy. Under this program, 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. This designation was based on data from a phase I study in the later line RCC setting in which cabozantinib demonstrated a median PFS of 12.9 months and a median OS of 15.0 months.

“Delivering these top-line results for METEOR is one of multiple clinical development and regulatory milestones that we have planned for this year," Morrissey said. "We look forward to sharing the detailed results of METEOR with the oncology community at an upcoming medical conference, and we thank all of the patients, families, investigators, and clinical staff who made the trial possible.”

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, including the phase III CELESTIAL trial, which is comparing cabozantinib to placebo for patients with HCC following treatment with sorafenib (NCT01908426).