The publication includes safety data from all 85 patients enrolled in the phase 1 cabozantinib study, and also includes tumor response, genotyping, pharmacokinetic, and pharmacodynamic biomarker data for the 37 patients in the study with medullary thyroid cancer (MTC). Exelixis is currently conducting a phase 3 registration trial of cabozantinib in MTC and, assuming positive results from this registration trial, intends to file a New Drug Application (NDA) with the U.S. Food and Drug Administration for this indication by the end of 2011.
“We are pleased that these data have been published in the Journal of Clinical Oncology, and believe that inclusion of these results in this publication reflect the high level of interest in cabozantinib among the oncology community,” said Gisela M. Schwab, M.D., Exelixis’ executive vice president and chief medical officer. “These data provided the foundation for our ongoing phase 3 registration trial in MTC, and we are preparing to file an NDA in this indication by the end of the year. The safety data reported here are consistent with what we are observing in the broad phase 2 program that is currently ongoing in a variety of cancer indications, including metastatic castration-resistant prostate cancer (mCRPC), ovarian cancer, hepatocellular cancer, breast cancer, non-small cell lung cancer and melanoma.”
Thirty-five of 37 MTC patients had measurable disease. Partial responses were achieved in 10 of these patients (29%), and 5 of these patients had a partial response at the first radiologic assessment. Responses were observed in patients regardless of prior tyrosine kinase inhibitor therapy status. Seventeen patients (49%) experienced a 30% or greater decrease in the sum of tumor measurements compared with baseline. Stable disease for at least 6 months was observed in 25 of the 37 patients (41%) with MTC, ranging from 6.4 to 31.1 months. Stable disease of at least 3 months was reported in 38% of patients in the non-MTC subset.
The phase 1 cabozantinib study was conducted in 85 patients with metastatic or unresectable solid tumors or lymphoma who were no longer responding to standard therapy or who had disease for which no standard therapy exists. Most patients had received 2 or 3 prior therapies. The study evaluated different dose levels, schedules and formulations. Patients were assigned to one of 13 cohorts. Dose cohorts 1-11 received an oral suspension formulation of cabozantinib on intermittent (dose levels 1-9) or continuous fixed daily dosing schedules (dose levels 10-11). Dose cohorts 12-13 and the maximum-tolerated dose (MTD) cohort used continuous fixed daily dosing of a capsule formulation. Patients in the phase 1 study remained on study until disease progression or occurrence of unacceptable adverse events.
Genotyping analyses indicated that 25 of the 31 MTC patients analyzed (81%) had activating mutations in RET, a known target of cabozantinib. There was no apparent correlation between RET mutational status and either clinical response or time on study. Biomarker analyses identified changes in circulating analytes related to the mechanism of action of cabozantinib, including placental growth factor, VEGF-A, VEGFR2, erythropoietin, and soluble MET. Decreased phosphorylation of MET and RET were observed in skin biopsies obtained from one MTC patient.
As previously reported, dose-limiting toxicities (DLTs) were observed at dose levels 9, 11, and 13 (11.52 mg/kg suspension with intermittent dosing, 265 mg suspension with daily dosing, and 250 mg capsule). Grade 3 DLTs were palmar plantar erythrodysesthesia (PPE), AST/ALT elevations, lipase elevation, and mucositis; grade 2 DLT was mucositis. These results established the 175 mg daily dose as the MTD for cabozantinib capsules, and this dose is being used in the ongoing phase 3 MTC trial. A total of 77 patients (90%) reported at least one treatment-related adverse event (AE), of which 43% were grade 1 or 2. Adverse events occurring in at least 20% of patients were diarrhea, fatigue, decreased appetite, nausea, PPE, rash, increased AST, vomiting, and mucosal inflammation. One treatment-related grade 4 pulmonary embolism was reported in a patient receiving the 175 mg suspension daily. Treatment-related hypertension was reported in 16% of patients (2% grade 3, 14% grade 1-2), most of whom had a history of hypertension. There were no treatment-related grade 5 AEs, and the nature of AEs was similar between those patients with MTC and those with other solid tumors.