Background: Oncogenic activation of
mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR)
thyroid cancer. Preclinical models suggest that activation of the
receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in BRAFV600E mutant
thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using
vemurafenib and the human
monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive
iodine (RAI) avidity in patients with BRAF-mutant RAIR
thyroid cancer. Methods: Patients with BRAFV600E RAIR
thyroid cancer were evaluated by
thyrogen-stimulated
iodine-124 (124I) positron emission tomography-computed tomography (PET/CT) at baseline and after 5 weeks of treatment with oral
vemurafenib 960 mg twice daily alone for 1 week, followed by
vemurafenib in combination with 1000 mg of intravenous CDX-3379 every 2 weeks. Patients with adequate 124I uptake on the second PET/CT then received therapeutic radioactive
iodine (131I) with vemurafenb+CDX-3379. All
therapy was discontinued two days later. Treatment response was monitored by serum
thyroglobulin measurements and imaging. The primary endpoints were safety and tolerability of vemurafenib+CDX-3379, as well as the proportion of patients after vemurafenb+CDX-3379
therapy with enhanced RAI incorporation warranting therapeutic 131I. Results: Seven patients were enrolled; six were evaluable for the primary endpoints. No grade 3 or 4 toxicities related to CDX-3379 were observed. Five patients had increased RAI uptake
after treatment; in 4 patients this increased uptake warranted therapeutic 131I. At 6 months, 2 patients achieved partial response after 131I and 2 progression of disease. Next-generation sequencing of 5 patients showed that all had co-occurring
telomerase reverse transcriptase promoter alterations. A deleterious mutation in the SWItch/
Sucrose Non-Fermentable (SWI/SNF) gene ARID2 was discovered in the patient without enhanced RAI avidity after
therapy and an RAI-resistant
tumor from another patient that was sampled off-study. Conclusions: The endpoints for success were met, providing preliminary evidence of vemurafenib+CDX-3379 safety and efficacy for enhancing RAI uptake. Preclinical data and genomic profiling in this small cohort suggest SWI/SNF gene mutations should be investigated as potential markers of resistance to redifferentiation strategies. Further evaluation of vemurafenib+CDX-3379 as a redifferentiation
therapy in a larger trial is warranted (ClinicalTrials.gov: NCT02456701).