Final overall survival analysis of EXAM, an international, double-blind, randomized, placebo-controlled phase III trial of cabozantinib (Cabo) in medullary thyroid carcinoma (MTC) patients with documented RECIST progression at baseline.

6012 Background: Cabo inhibits tyrosine kinases including MET, VEGFR2, and RET. EXAM, a randomized double-blind placebo (P)-controlled study in patients (pts) with progressive, locally advanced, or metastatic MTC (NCT00704730), met its primary end point with a statistically significant improvement in progression-free survival (PFS) (hazard ratio [HR] = 0.28, p < 0.001) (Elisei et al, JCO, 2013). This report contains the final analysis of the secondary endpoint, Overall Survival (OS). Methods: Eligible pts were required to have documented RECIST progression within 14 months (mo) of screening, and were randomized 2:1 to receive Cabo (140 mg qd) or P. Crossover between treatment arms was not allowed. The primary endpoint was PFS assessed by RECIST via independent review. The study was designed with 80% power to detect a HR of 0.667 for the secondary endpoint of OS. Results: At the final analysis, median follow up time was 52.4 mo. 218 events were recorded in the intent-to-treat (ITT) population (N = 330). The estimated median OS was 26.6 mo for Cabo vs 21.1 mo for P (stratified HR = 0.85; 95% CI 0.64-1.12; p = 0.241). For 126 pts with known RET M918T mutations, median OS was 44.3 mo for Cabo vs 18.9 mo for P (HR = 0.60, p = 0.026). 32% of Cabo-treated pts received subsequent systemic anticancer therapy vs 50% for P-treated pts. The median duration of treatment was 10.8 mo for Cabo and 3.5 mo for P. 46% and 26% of Cabo-treated pts remained on study treatment for over 1 year and 2 years, and 10% and 1.8% for P, respectively. The most common serious adverse events ( ≥ 2%) on the Cabo arm were pneumonia (4.2%), pulmonary embolism (3.3%), mucosal inflammation (2.8%), hypocalcemia (2.8%), hypertension, dysphagia, dehydration and lung abscess (2.3% each). Conclusions: The secondary endpoint of improved OS was not met, with a median OS 5.5 mo longer with Cabo compared to P that did not reach significance in the ITT population. OS improvement with Cabo was greatest in patients with RET M918T mutations, with a 25.4-month increase in median OS compared to P. The safety profile of Cabo remained consistent with longer term exposure. Clinical trial information: NCT00704730.