Phase 1 Study of Cabozantinib in Japanese Patients With Expansion Cohorts in Non-Small-Cell Lung Cancer.

BACKGROUND: Cabozantinib inhibits tyrosine kinases including MET, AXL, VEGFR2, RET, KIT, and ROS1 and has demonstrated antitumor activity in multiple tumor types. The primary objective of this phase 1 study (NCT01553656) was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of cabozantinib in Japanese patients. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled at 2 sites in Japan. After determining the MTD and RP2D, an expansion in non-small-cell lung cancer (NSCLC) consisting of 3 molecularly defined cohorts (EGFR mutation; KRAS mutation; ALK, RET, or ROS1 fusion) was initiated. The study was registered with ClinicalTrials.gov (NCT01553656). RESULTS: Forty-three Japanese patients were enrolled (dose escalation, n = 23; NSCLC expansion, n = 20). The MTD of cabozantinib capsules was 60 mg daily, and the RP2D of cabozantinib tablets was 60 mg daily. Dose-limiting toxicities were hypertension, proteinuria, and venous embolism. Safety and pharmacokinetics in Japanese patients were consistent with those in non-Japanese patients. Common adverse events included palmar-plantar erythrodysesthesia, hypertension, and diarrhea. Reduction in tumor lesion size was observed in multiple tumor types in the dose-escalation cohorts, with partial responses observed in 4 of 9 patients with NSCLC (EGFR mutation, n = 1; ALK fusion, n = 2; and RET fusion, n = 1). In the NSCLC expansion, 4 patients with EGFR-mutant NSCLC had partial responses; the remaining 16 (EGFR mutation, n = 11; KRAS mutation, n = 2; ALK fusion, n = 1; and RET fusion, n = 2) had stable disease as best response. CONCLUSION: Cabozantinib had a manageable safety profile in Japanese patients with solid tumors. Responses were observed in diverse molecular subtypes of NSCLC.

Assessment of cabozantinib treatment on QT interval in a phase 3 study in medullary thyroid cancer: evaluation of indirect QT effects mediated through treatment-induced changes in serum electrolytes.

PURPOSE: This study evaluated factors impacting QTc interval in a phase 3 trial of cabozantinib in progressive, metastatic, medullary thyroid cancer (MTC). METHODS: Electrocardiogram (12-lead ECG) measurements were obtained at screening, and at pre-dose, and 2, 4, and 6 h post-dose on Days 1 and 29 in a phase 3 study in patients with MTC treated with cabozantinib (140 mg/day). Central tendency analyses were conducted on baseline-corrected QTc values. Linear and nonlinear mixed-effects models were used to evaluate potential factors affecting the QTc interval, including serum electrolytes, patient demographics, and cabozantinib concentration. RESULTS: Central tendency analysis showed that oral cabozantinib (140 mg/day) produced a 10-15 ms increase in delta-delta Fridericia corrected QT (∆∆QTcF) and delta-delta study-specific corrected QT (∆∆QTcS) on Day 29, but not on Day 1. Further analysis showed that QTcS provided a slightly more accurate QT correction than QTcF. Mixed-effects models evaluating serum electrolytes, age, sex, and cabozantinib concentration showed that decreased serum calcium and potassium could explain the majority of cabozantinib treatment-associated QTcS prolongation observed in this study. CONCLUSIONS: Cabozantinib treatment prolongs the ∆∆QTcF interval by 10-15 ms. There was the absence of a strong relationship between cabozantinib concentration and QTcS prolongation. Cabozantinib treatment effects on serum calcium and potassium best explain the QTcS prolongation observed in this study.

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.

PURPOSE: Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib. METHODS: This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR). RESULTS: Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa. CONCLUSIONS: Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib.

Cabozantinib in progressive medullary thyroid cancer.

PURPOSE: Cabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I. PATIENTS AND METHODS: We conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety. RESULTS: The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients. CONCLUSION: Cabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.