Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancer
- 15 August 2016
- Vol. 122 (24), 3856-3864
- https://doi.org/10.1002/cncr.30252
Abstract
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. 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. 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. 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. © 2016 American Cancer Society.Keywords
Funding Information
- ClinicalTrials.gov (NCT00704730)
This publication has 30 references indexed in Scilit:
- SomaticRASMutations Occur in a Large Proportion of SporadicRET-Negative Medullary Thyroid Carcinomas and Extend to a Previously Unidentified ExonJournal of Clinical Endocrinology & Metabolism, 2012
- Suppression of Tumor Invasion and Metastasis by Concurrent Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine TumorsCancer Discovery, 2012
- Cabozantinib (XL184), a Novel MET and VEGFR2 Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor GrowthMolecular Cancer Therapeutics, 2011
- Increased Expression of Vascular Endothelial Growth Factor and Its Receptors, VEGFR-1 and VEGFR-2, in Medullary Thyroid CarcinomaThyroid®, 2010
- Medullary Thyroid Carcinoma: Targeted Therapies and Future DirectionsJournal of Oncology, 2009
- Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomasBritish Journal of Cancer, 2009
- Prognosis of medullary thyroid carcinomaCancer, 2006
- Familial medullary thyroid cancer: clinical aspects and prognosisEuropean Journal of Surgical Oncology, 2005
- Prognostic value of codon 918 (ATG?ACG)RET proto-oncogene mutations in sporadic medullary thyroid carcinomaInternational Journal of Cancer, 2001
- New Guidelines to Evaluate the Response to Treatment in Solid TumorsJNCI Journal of the National Cancer Institute, 2000