Cabozantinib Submitted for FDA Approval After Positive Phase III Thyroid Cancer Trial

Patrick Schöffski, MD

In a pivotal phase III trial, the tyrosine kinase inhibitor (TKI) cabozantinib (XL184) met its primary endpoint of progression-free survival (PFS) in patients with advanced medullary thyroid cancer (MTC), according to data presented at ASCO 2012. Based on the results, Exelixis has submitted a New Drug Application (NDA) to the FDA for cabozantinib in patients with progressive, unresectable, locally advanced, or metastatic forms of the rare thyroid cancer, with an approval decision expected by November 29.

“Cabozantinib will be an important new treatment option for patients with MTC if approved for subjects with this orphan disease,” said Patrick Schöffski, MD, professor at the Department of General Medical Oncology at the University Hospitals of Leuven, Catholic University Leuven, Belgium, who presented the data in an oral session at ASCO.

Cabozantinib inhibits the receptor tyrosine kinases MET, VEGFR2, and RET, which are associated with the development and growth of MTC. The mechanism of the targeted oral agent works to block both angiogenesis and metastasis.

In the phase III double-blinded EXAM trial, Schöffski et al randomized 330 patients (median age, 54 years) with MTC 2:1 to either 140 mg (free base equivalent) of cabozantinib daily (n = 219) or placebo (n = 111). All patients had nonresectable, locally advanced, or metastatic disease that had progressed according to RECIST criteria within 14 months of screening. Patients were not unblinded or allowed to cross over at the time of progression.

At the preplanned interim analysis, an independent radiology committee determined that the median PFS was a statistically significant 11.2 months with cabozantinib, as compared with 4.0 months in the placebo arm (hazard ratio = 0.28; 95% CI, 0.19-0.40; P <.0001). The 1-year PFS rate was 47.3% for the cabozantinib arms versus 7.2% with placebo. The positive PFS data was maintained when analyzing subpopulations of patients, according to Schöffski.

“Results of pre-specified subgroup analysis showed that cabozantinib was superior over placebo for progress-free survival independent of the number of prior anticancer regimens, previous exposure to other tyrosine kinase inhibitors, prior radiotherapy, and presence or absence of bone metastases.” Interestingly, Schöffski added, the PFS benefit was also not affected by RET mutational status.

Secondary endpoints for the study included overall survival (OS), objective response rate (ORR), and changes in serum biomarkers.

OS rates were similar between the two arms at the interim analysis; however, the OS data were not yet mature. “The final OS analysis will likely occur in the 2013 to 2014 timeframe,” Schöffski said.

The ORR was 28% and 0% (P <.0001), respectively, for patients receiving cabozantinib and placebo. The median duration of response was 14.6 months in the cabozantinib arm.

In an attempt to identify biomarkers for cabozantinib’s efficacy, the researchers measured serum calcitonin and carcinoembryonic antigen levels at baseline and during treatment. Both proved to be potential biomarkers, showing decreased levels in the cabozantinib arm and increased levels in the placebo group.

Regarding cabozantinib’s toxicity profile, Schöffski said, “Adverse events were generally manageable, allowing treatment with the oral drug for extended periods of time.”

Grade ≥3 adverse event rates were much higher in the cabozantinib arm. Schöffski attributed the disparity to the higher median duration of exposure in patients receiving the treatment (6.7 months vs 3.4 months with placebo).

“

Cabozantinib will be an important new treatment option for patients with MTC if approved for subjects with this orphan disease.”

—Patrick Schöffski, MD

The most common grade ≥3 adverse event rates with cabozantinib included diarrhea (16%), hand-foot skin reaction (13%), fatigue (9%), hypertension (8%), decreased weight (5%), and decreased appetite (5%).

Overall mortality rates were similar between the two arms; however, “deaths within 30 days of treatment cessation for reasons other than disease progression were observed in 5.6% of subjects in the cabozantinib arm versus 2.8% in the placebo arm,” Schöffski said. He suggested that “deaths due to events commonly associated with VEGF-pathway inhibition” largely explain this gap in mortality rates.

The trial was conducted under Special Protocol Assessment with the FDA, meaning the regulatory agency considers the trial’s primary endpoint of PFS to be an acceptable standard for approval. Additionally, Exelixis submitted the NDA for cabozantinib under the FDA’s Fast Track program, which is intended to expedite the evaluation of a novel therapeutic that targets an unmet medical need.

Beyond the EXAM results, Exelixis presented eight other cabozantinib-related abstracts at ASCO. In these studies, cabozantinib was explored in additional tumor types, including breast, kidney, liver, prostate, and non—small cell lung cancer, as well as melanoma.

Schöffski P, Elisei R, Müller S, et al. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin Oncol. 2012;30(suppl; abstr 5508).