Endocrine Abstracts

Introduction and objectives: Anaplastic thyroid cancer (ATC) has a very low overall survival (OS) and progression free survival (PFS) due to fast growth and resistance to non-target therapies. A recent phase II study showed a dramatic increase in OS and PFS of BRAF V600E mutated ATC patients treated with Dabrafenib and Trametinib (DT). However as commonly reported in melanoma durable responses in ATC may be compromised by resistance mechanisms. Until now only a few case reports and a small case series has been published. We present our experience with DT in BRAF-positive ATC patients and compare the outcomes with usual therapy. In addition, we studied the molecular alterations at baseline and during progression in DT group.

Materials and methods: ATC patients treated between May 2018 and October 2021 were included. BRAF positive patients underwent next generation sequencing (NGS) at baseline and at progression. Bioinformatic analyses filtered and selected relevant somatic genomic variants. Patients were classified in the following groups: BRAF WT under compassionate care (CC); BRAF wild type (WT) under multimodal therapy (MT) with surgery, radiotherapy ± chemotherapy or lenvatinib and BRAF V600E treated with DT. Response was assessed monthly in the first 6 months and then every 3 months by RECIST 1.1: OS, PFS, duration of response (DOR) was estimated with Kaplan-Meier method and compared with log-rank test.

Results: 27 ATC patients were included (CC=10, MT=8 and DT=9). Median follow-up was 24, 96 and 410 days for CC, MT and DT respectively due to differences in survival time. Median OS was 39, 156 and 475 days for CC, MT and DT respectively (P<0.001). At 12 months only patients in the DT group were alive (71%). Median PFS and DOR were 270 and 215 days, respectively (MT group<32 days) (P<0.001). In the DT group only 1 patient needed trametinib dose reduction to 225 mg/d and no G3 adverse events were reported. Molecular profiling by NGS showed that the nine patients in the DT group had a BRAF V600E and a TERTp mutation at baseline. In one of the four clinical disease progressions during DT treatment a pathogenic NRAS mutation was found.

Conclusions: Our results show a significant real-world efficacy of DT in both OS and PFS compared with contemporary standard treatment with a good safety profile. Molecular profiling allowed the patient with RAS mutations to change treatment strategy.