Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma

Abstract

Background: Primary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.

Patients and methods: EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.

Results: Minimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.

Conclusion: The secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib.

Trial registration number: NCT00704730.

Keywords: RET M918T; cabozantinib; medullary thyroid cancer; overall survival; progression-free survival.

Figure 1.

Kaplan–Meier curve of overall survival (OS) and progression-free survival (PFS) in the (A) overall intent-to-treat population, (B) in patients with RET M918T–positive disease, and (C) in patients with RET M918T–negative disease. Data cut-off was 28 August 2014 for OS and 6 April 2011 for PFS. ^aAnalyses for (A) were stratified by randomization stratification factors, and analyses of subgroups (B and C) were unstratified. HR, hazard ratio; CI, confidence interval. P values were not adjusted for multiple comparisons. Methods for determining RET M918T status are described elsewhere [16].

Figure 2.

Subgroup analysis of overall survival and progression-free survival (PFS) according to RET mutation status, RET M918T status, and RAS mutations status. Data cut-off was 28 August 2014 for overall survival and 6 April 2011 for PFS. ^aAnalyses for all patients were stratified by randomization stratification factors, and analyses of subgroups were unstratified. HR, hazard ratio; CI, confidence interval. Methods for determining RET and RAS mutation status are described elsewhere [16].