OR27-6 Combination Vemurafenib (BRAF Inhibitor)/Cobimetinib (MEK Inhibitor)/Atezolizumab (Anti-PDL1 Inhibitor) in BRAF-V600E Mutated Anaplastic Thyroid Cancer (ATC): Initial Safety and Feasibility

Abstract

Introduction: BRAF/MEK inhibitors (dabrafenib/trametinib) are FDA approved for BRAFV600E mutated ATC; however, resistance to kinase inhibitors is universal in solid tumors, thus newer approaches are warranted. Methods: ATC patients with PS </=2 were enrolled on a prospective clinical at a single tertiary center, and assigned a treatment regimen determined by whether the tumor had an oncogenic driver mutation in BRAF (cohort 1), RAS or NF1 (cohort 2) or none of these (cohort 3). Oncogenic driver mutations were identified by tissue NGS, IHC (for BRAF only) or cfDNA. Each cohort was required to enroll at least 10 patients. Here we present data for cohort 1 only. Survival and response for all 3 cohorts will be analyzed when the cohorts complete enrollment. Patients in cohort 1 received a run-in with oral vemurafenib (V) 960mg BID/cobimetinib (C) 60mg QD for 28 days, followed by atezolizumab (A) 840mg Q2 weeks IV, at which time V dose was decreased to 720mg BID. C in solution and crushed V were permitted in patients unable to swallow pills. cfDNA and tissue biopsy were obtained at baseline, before course 2 and at progression. Patients were allowed to undergo surgery and/or radiation while on trial. Results: Between August 2017 and October 2018, 10 patients were enrolled on cohort 1: 6 women/4 men; median age 68 years; 5 stage IVC and 5 stage IVB disease. One patient was on crushed/solution V/C. 6/10 patients underwent complete resection of primary or residual tumor while on trial--5 R0 and 1 R1 resection achieved. At presentation, these patients had either surgically unresectable disease or disease that would require major laryngotracheal surgery. 4/6 patients who underwent surgery have completed post-operative chemoradiation (one refused and one is too early). At a median follow-up time of 7 months, 100% of pts who underwent neoadjuvant surgery were alive. Adverse events (AEs) related to surgery were hematoma in 1 patient and tracheostomy in two patients during or after postoperative chemoradiation. AEs related to VCA were as expected for this drug combination. Serious AEs of note included grade ≥3 transaminitis (on VCA; n=1), grade 2 pancreatitis (on VCA; n=1), and grade 3 rhabdomyolysis (on VC; n=1). Conclusions: VCA is safe in ATC and use of these drugs in the neoadjuvant setting in order to achieve an R0 or R1 surgery is feasible. Assessment of changes in tissue immune environment and cfDNA are currently being analyzed and will be updated at the meeting. A phase 2 trial to investigate neoadjuvant approaches to ATC is being planned.