A B S T R A C T PurposeCabozantinib, 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 MethodsWe 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.
ResultsThe 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 Ͻ .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 cabozantinibassociated 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.
ConclusionCabozantinib (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.
5508 Background: MTC arises from parafollicular cells of the thyroid gland, accounts for 5-8% of thyroid cancers and represents an unmet medical need. Cabozantinib (cabo) is an oral inhibitor of MET, VEGFR2, and RET. We conducted a phase III study of cabo vs placebo (P) in pts with progressive, unresectable, locally advanced or metastatic MTC. Methods: Eligible pts were required to have documented RECIST progression within 14 months of screening. The primary efficacy measure was progression-free survival (PFS) as assessed by an independent review facility (IRF) using RECIST. Secondary efficacy measures included objective response rate (ORR) and overall survival (OS). The study has 90% power to detect a 75% increase in PFS and 80% power to detect a 50% increase in OS. Tumor assessments occurred every 12 weeks. Crossover between treatment arms was not allowed. Results: Between Sept 2008 and Feb 2011, 330 pts (median age 55 yrs; 67% male; 96% measureable disease; RET mutation status: pos 48%; neg 12%; unknown 39%; prior TKI exposure: yes 21%, no 78%, unknown 2%) were randomized 2:1 to cabo (140 mg free base [175 mg salt form] qd; n=219) or P (n=111). The planned primary PFS analysis included events through the date of the 138th event. As of 15June2011, 44.7% of pts on cabo and 13.5% on P were still receiving study treatment. Statistically significant PFS prolongation of 7.2 mo was observed; median PFS for cabo was 11.2 mo vs 4.0 mo for P (HR 0.28, 95% CI 0.19-0.40, p<0.0001). PFS results favored the cabo group across subset analyses including RET status and prior TKI use. ORR was 28% for cabo vs 0% for P (p<0.0001). An interim analysis of OS (44% of the 217 required events) did not show a difference between cabo and P. The most frequent grade ≥3 adverse events (cabo vs P) were diarrhea (15.9 vs 1.8%), palmar-plantar erythrodysesthesia (12.6 vs 0%), fatigue (9.3 vs 2.8%), hypocalcemia (9.3 vs 0%), and hypertension (7.9 vs 0%). Conclusions: This phase III study met its primary objective of demonstrating substantial PFS prolongation with cabo vs. P in a patient population with MTC and documented progressive disease in need of therapeutic intervention.
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