Results of randomized phase II trial of dabrafenib versus dabrafenib plus trametinib in BRAF-mutated papillary thyroid carcinoma.

Abstract

6022 Background: BRAF mutations are present in ~44% of papillary thyroid carcinoma (PTC) and its role in development of PTC is well established. We hypothesized that dabrafenib (BRAF inhibitor) would have efficacy in BRAF mutated PTC and that combining it with trametinib (MEK inhibitor) would result in greater clinical efficacy than dabrafenib alone, through vertical inhibition of the RAF/MAP/ERK pathway and mitigation of potential mechanisms of resistance. Methods: Patients (pts) with BRAF mutated radioiodine refractory PTC who had evidence of disease progression within 13 months prior were randomized to Arm A (dabrafenib 150 mg PO BID) or Arm B (dabrafenib 150 mg PO BID + trametinib 2 mg PO qd). Cross-over to Arm B was allowed at time of progression. Responses were assessed by modified RECISTv1.1 every 2 months. Primary endpoint was objective response rate (ORR) (complete-, partial- and minor-response). With assumed true ORR of 15% vs 35%; and 90% power to identify the correct regimen as most promising, 26 pts were to be accrued in each Arm. Results: In this randomized phase 2 trial, 53 pts (median age 63 years, 38 females) were enrolled; 25% of pts had 1-3 prior therapy with multi-kinase inhibitors. Median follow up was 13 months. Preliminary efficacy results are outlined in Table. The treatment-related adverse events were similar to previously reported phase III clinical trial of these drugs in melanoma. Conclusions: Single agent dabrafenib, as well as combination of dabrafenib/trametinib are well tolerated therapies that result in similar high objective response rates with durable responses in pts with progressive BRAF-mutated PTC. BRAF-pathway targeted therapies provide novel treatment options. Clinical trial information: NCT01723202. [Table: see text]

Update 2020: Systemische Therapie des differenzierten und medullären Schilddrüsenkarzinoms

“…In einer Phase-1 Studie mit dem BRAF-Inhibitor Dabrafenib zeigte sich bei 14 Patienten mit BRAF-V600E-positivem RAIR-PTC bei 29 % ein partielles Ansprechen und bei 43 % eine Krankheitsstabilisierung; das PFS lag bei 11,3 Monaten [23]. In einer nachfolgenden Phase-2-Studie wurden 53 Patienten mit fortschreitendem BRAF-V600E-positivem RAIR-PTC in zwei Therapiearme randomisiert [24]. Ein Arm (n = 26) erhielt Dabrafenib als Monotherapie, ein zweiter Arm (Arm B; n = 27) eine Kombination von Dabrafenib und dem MEK-Inhibitor Trametinib.…”

BRAF-Targeted Therapy in the Treatment of BRAF -Mutant High-Grade Gliomas in Adults

“…Second, leptomeningeal disease and poor performance status secondary to intracranial disease do not need to be considered exclusionary criteria. Finally, although the addition of MEKi to BRAFi may not provide any additional benefit in objective response rate compared with BRAFi monotherapy, as seen in a recent phase II study of papillary thyroid cancer, 6 the lack of increased severe adverse events, reduction in secondary skin cancers, possibility of reduced resistance, and longer duration of response 26 would favor the use of dual BRAFi/MEKi over single-agent regimens regardless of response rate.…”

“…2,3 Furthermore, the observation that combining BRAF inhibition (BRAFi) with MEK inhibition (MEKi) leads to improved efficacy and reduced resistance without increased toxicity has set the bar for any future multidrug combination. 4,5 These observations, along with encouraging early-phase data in other histologies, such as papillary thyroid cancer 6 and hairy cell leukemia, 7 which both have high frequencies of BRAF V600E mutations, have led to increasing interest in exploring the role of BRAFi and MEKi in all BRAF-mutated cancers, regardless of histology. 8 However, the lack of efficacy in BRAF-mutated colorectal cancer cautions against the agnostic generalization of results with these agents.…”

Utility of the BRAF p.V600E immunoperoxidase stain in FNA direct smears and cell block preparations from patients with thyroid carcinoma

“…These patients also tend to have radioactive iodine‐refractory disease . Targeted therapies using selective BRAF inhibitors (vemurafenib and dabrafenib), which are approved for the treatment of melanoma, have been studied in phase 2 clinical trials in patients with PTC and small basket trials for patients with ATC with tumors harboring BRAF p.V600E mutations …”