Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancer

BACKGROUND: Cabozantinib significantly prolonged progression-free survival (PFS) versus a placebo in patients with progressive, metastatic medullary thyroid cancer (MTC; P <.001). An exploratory analysis of phase 3 trial data evaluated the influence of rearranged during transfection (RET) and RAS (HRAS, KRAS, and NRAS) mutations on cabozantinib clinical activity. METHODS: Patients (n = 330) were randomized to cabozantinib (140 mg/day) or a placebo. The primary endpoint was PFS. Additional outcome measures included PFS, objective response rates (ORRs), and adverse events in RET and RAS mutation subgroups. RESULTS: Among all study patients, 51.2% were RET mutation–positive (38.2% with RET M918T), 34.8% were RET mutation–unknown, and 13.9% were RET mutation–negative. Sixteen patients were RAS mutation–positive. Cabozantinib appeared to prolong PFS versus the placebo in the RET mutation–positive subgroup (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.14-0.38; P <.0001), the RET mutation–unknown subgroup (HR, 0.30; 95% CI, 0.16-0.57; P =.0001), and the RAS mutation–positive subgroup (HR, 0.15; 95% CI, 0.02-1.10; P =.0317). The RET M918T subgroup achieved the greatest observed PFS benefit from cabozantinib versus the placebo (HR, 0.15; 95% CI, 0.08-0.28; P <.0001). The ORRs for RET mutation–positive, RET mutation–negative, and RAS mutation–positive patients were 32%, 22%, and 31%, respectively. No PFS benefit was observed in patients lacking both RET and RAS mutations, although the ORR was 21%. The safety profile for all subgroups was similar to that for the overall cabozantinib arm. CONCLUSIONS: These data suggest that cabozantinib provides the greatest clinical benefit to patients with MTC who have RET M918T or RAS mutations. However, a prospective trial is needed to confirm the relation between genetic variation and the response to cabozantinib. Cancer 2016;122:3856–3864. © 2016 American Cancer Society