A Pilot Study of Durvalumab (MEDI4736) with Tremelimumab in Combination with Image Guided Stereotactic Body Radiotherapy (SBRT) in the Treatment of Metastatic Anaplastic Thyroid Cancer.

BACKGROUND Metastatic anaplastic thyroid cancer (ATC) has a dismal prognosis. This pilot study aims to evaluate tremelimumab plus durvalumab with stereotactic body radiotherapy (SBRT) to improve overall survival (OS). METHODS Eligible patients received up to 4 doses tremelimumab (75mg) given q4 weeks and up to 1 year of durvalumab (1500 mg) given q4 weeks. SBRT at 9Gy x 3 fractions was given within the first 2 weeks of treatment. Paired biopsies (pre-treatment and between 3 and 10 weeks after the first dose of the drug) were done in medically qualified patients. Major inclusion criteria: Metastatic ATC; ECOG PS 0-2; no prior immunotherapy; last anti-cancer treatment > 7 days prior to starting study. The primary endpoint was 1-year OS with the combination of durvalumab, tremelimumab and SBRT in metastatic ATC patients with target OS at 1 year of > 2 out of 12 patients. RESULTS 13 subjects signed consent but 12 subjects ultimately participated in this trial. One patient who consented to the protocol was admitted to urgent care prior to starting protocol treatment and was deemed no longer eligible for protocol due to decreased performance status, continued drop in hemoglobin, and requirement of steroids. 50% were male with a median age of 71 (range: 49 to 82); ECOG = 1. Prior radiation to neck in 75% of the subjects. 75% of the subjects had prior chemotherapy. 9 subjects underwent analysis with next-generation sequencing or had tissue available for PD-L1 staining. Microsatellite instability (MSI)-high corresponding to mismatch repair defect was noted in 2 subjects. There were 0 confirmed responses and only 1 subject with stable disease treated with >/=4 cycles. The median time that the subjects were on treatment was 11 weeks (1-28 weeks). Microsatellite instability (MSI) status did not affect treatment response. MSI-high patients were on treatment before progression for 8-14 weeks. The median OS was 14.5 weeks with only one person alive beyond 1 year. The presence of a BRAF or p53 mutation did not appear to have affect any outcome. CONCLUSION Tremelimumab and durvalumab with SBRT did not improve OS for ATC. Future studies looking at other novel immunotherapy combinations in ATC +/- radiation should be evaluated.