Phase II trial of regorafenib in metastatic medullary thyroid carcinoma (MTC) and radioactive iodine refractory differentiated thyroid carcinoma (RAIR DTC).

Abstract

6109 Background: Multi-kinase inhibitors show activity in both MTC & RAIR DTC. However, therapeutic options are limited after disease becomes refractory to one or two lines of standard of care therapies. We report here results of an investigator-initiated phase II clinical trial evaluating regorafenib in this population (NCT02657551). Methods: Patients with MTC (disease progression within 6-12 months, mo, prior to study registration) and RAIR DTC (progression within 12 mo) were enrolled regardless of prior lines of therapy. Regorafenib (each cycle 3 weeks ON/1 week OFF) was started at 80 mg daily, with planned escalation after 1 & 2 weeks to 120 mg daily & 160 mg daily, respectively, in absence of significant treatment-related adverse events (TRAEs). The highest tolerated dose was continued from cycle 2 onwards until progression. The primary endpoints were proportion progression-free at 10 months in MTC & overall response rate (ORR) by RECIST v1.1 in RAIR DTC. Simon two-stage design was utilized; MTC: <2 in 8 progression-free in first stage stops for futility, stage 2: enroll 13, >6/21 provides 81% power for proportion >20%; DTC: <3 in 9 in response in first stage stops for futility; stage 2: enroll 11, >7/20 provides 81% power for ORR >25%. Results: 17 patients (8 MTC, 9 DTC) were enrolled between April 2016 and October 2022. Among MTC, median (range) age was 54.7y (48.1, 62.8), 25% female. Among DTC, median age (range) was 62.8y (44.3, 75.8), 55.6% female. In MTC group, the proportion progression-free at 10 months was 12.5% (95% CI 0.3%, 52.7%) & did not meet the criteria to continue into 2nd stage. ORR in MTC group was 12.5% (95% CI 0.3%, 52.7%). In DTC group, ORR was 11.1% (95% CI 0.3%, 48.2%), & did not meet the criteria to continue into 2nd stage. No patients were receiving treatment at cutoff. Patients with MTC and DTC with objective responses (1 each) had received one (vandetanib) & no prior systemic therapy, respectively. The most common reason for discontinuation was disease progression in MTC (4, 50%) & DTC (5, 55.6%). Grade 3-4 TRAEs were observed in 8/17 (47.1%), most frequent were diarrhea, hypophosphatemia, & hypertension (each grade 3: 2, 11.7%). There were no treatment-related deaths. Median progression-free survival (PFS) in MTC & DTC were 5.3 (95% CI 3.6, 20.1) & 11.0 (95% CI 1.2, 24.0) mo, respectively. Median overall survival (OS) in MTC & DTC were 16.1 (95% CI 5.2, NA) and 20.1 (95% CI 1.6, NA) mo, respectively. Conclusions: Regorafenib clinical trial did not reach its primary endpoints in MTC and DTC. Analyses are planned to investigate impact of prior VEGFR inhibitor exposure, biomarkers and resistance mechanisms. Clinical trial information: NCT02657551 . [Table: see text]