Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancer.
Publication/Presentation Date
12-15-2016
Abstract
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.
Volume
122
Issue
24
First Page
3856
Last Page
3864
ISSN
1097-0142
Published In/Presented At
Sherman, S. I., Clary, D. O., Elisei, R., Schlumberger, M. J., Cohen, E. E., Schöffski, P., Wirth, L. J., Mangeshkar, M., Aftab, D. T., & Brose, M. S. (2016). Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancer. Cancer, 122(24), 3856–3864. https://doi.org/10.1002/cncr.30252
Disciplines
Medicine and Health Sciences
PubMedID
27525386
Department(s)
Hematology-Medical Oncology Division
Document Type
Article