Neoadjuvant Dabrafenib/Trametinib Potential Preparation for Surgical Resection in BRAF V600E+ Anaplastic Thyroid Carcinoma

August 20, 2019
Darcy Lewis

A neoadjuvant regimen of dabrafenib plus trametinib in patients with&nbsp;<em>BRAF&nbsp;</em>V600E&ndash;mutated anaplastic thyroid carcinoma offered a feasible way to prepare patients for life-extending and quality-of-life-enhancing surgical resection, according to the results of a case series report of patients with locoregionally advanced ATC at The University of Texas MD Anderson Cancer Center.

Jennifer R. Wang, MD, ScM

A neoadjuvant regimen of dabrafenib (Taflinar) plus trametinib (Mekinist) in patients withBRAFV600E—mutated anaplastic thyroid carcinoma (ATC) offered a feasible way to prepare patients for life-extending and quality-of-life-enhancing surgical resection, according to the results of a case series report of patients with locoregionally advanced ATC at The University of Texas MD Anderson Cancer Center.

According to the report, which was published recently inThyroid, all 6 patients were able to undergo complete surgical resection following treatment with the neoadjuvant doublet.

The rate of overall survival (OS) at 6 months was 100%. At 1 year, the OS rate was 83%, and the locoregional control rate was 100%. Two patients died of distant metastases without evidence of locoregional disease at 8 and 14 months post-diagnosis. The authors, led by Jennifer R. Wang, MD, ScM, noted that the remaining 4 patients showed no evidence of disease at last follow‐up.

“Neoadjuvant utilization of dabrafenib and trametinib provides an approach to achieve locoregional control and symptom management without radical surgery. In this series, complete resection was achieved in all patients without tracheostomy or radical resection including in the re‐operative setting,” Wang et al wrote. “In our experience, this approach is feasible in ATC patients without distant metastasis at presentation and in selected patients whose distant disease responds favorably to neoadjuvant treatment.”

Patients included in the case series were those withBRAFV600E—mutated ATC who presented between January 2017 to February 2018 with unresectable disease and were treated at MD Anderson Cancer Center outside of a clinical trial.

At initial presentation, all 6 patients had a rapidly growing thyroid cancer with significant invasion of neck structures. Pre‐treatment staging included CTs of the neck and chest, MRI of the brain, and whole‐body FDG‐PET/CT. Pathologic confirmation was made via core biopsies, andBRAFV600E status was established by immunohistochemistry or sequencing of circulating tumor DNA. Five of 6 patients also received pretreatment somatic mutation testing with next-generation sequencing.

The dosing regimen called for dabrafenib to be given orally at doses of 150 mg twice daily and trametinib at 2 mg daily. If the targeted agents were not immediately accessible, patients received bridging cytotoxic chemotherapy of paclitaxel with or without carboplatin. Half of the patients also received pembrolizumab (Keytruda) prior to or after surgical resection.

Due to its antiangiogenic properties, trametinib was discontinued 5 to 7 days before surgery but dabrafenib was continued until the day prior or day of surgery. Both drugs were restarted as soon as the patients’ surgical wounds healed.

Adjuvant chemoradiation followed surgical resection as soon as possible, about 2 to 3 weeks postoperatively. A total of 60 Gy in 30 fractions was administered concurrent with chemotherapy (paclitaxel and carboplatin, or cisplatin alone), except in 1 patient who declined. The investigators discontinued the dabrafenib and trametinib regimen during radiation due to the risk of exaggerated acute toxicity. The drugs were resumed as soon as possible following radiation.

Wang et al noted that they observed high pathologic response rates in this study. All surgically resected specimens showed significant reduction in ATC viability. “Intriguingly, well-differentiated components remained in differentiated thyroid carcinomas, with papillary thyroid carcinoma being the most common,” they wrote. “Findings from this series highlight the significant intratumor heterogeneity and clonal evolution of ATC.”

The investigators noted that rapid diagnosis and treatment initiation are essential to avoid tracheostomy and local complications, and thatBRAFV600E status can be ascertained within days from biopsy by immunohistochemistry or circulating tumor DNA sequencing. “It is our preference to initiate dabrafenib and trametinib as soon as possible after confirmation of ATC diagnosis andBRAFV600E status. Similar to prior reports utilizing dabrafenib and trametinib, responses to BRAF inhibitors have been

observed within days,” they wrote. “In our series, eligibility for surgical resection occurred within weeks of dabrafenib and trametinib initiation.”

Wang et al cautioned colleagues that, due to the aggressive nature of ATC and known patterns of treatment failure, patients treated with this approach may remain at high risk for disease progression due to distant metastases after complete surgical resection and adjuvant chemoradiation.

“We hypothesize that a delay in reinitiating dabrafenib and trametinib after adjuvant chemoradiation led to distant metastases in patients 2 and 3,” they wrote. “As such, it is our current approach to minimize time without systemic therapy in these patients. Dabrafenib and trametinib [are] resumed as soon as possible after completion of adjuvant chemoradiation.”

The authors also consider pembrolizumab to be an important addition to the regimen.

They note that all patients who received pembrolizumab in addition to the combined regimen remained alive and disease‐free at the most recent follow-up. These 4 patients are continuing with maintenance dabrafenib, trametinib, and pembrolizumab.

Wang et al closed by urging colleagues to pursue timelyBRAFV600E testing in all patients with ATC, including those presenting with locoregionally advanced disease.

Reference:

Wang JR, Zafereo ME, Dadu R, et al. Complete surgical resection following neoadjuvant dabrafenib plus trametinib in&nbsp;BRAFV600E‐mutated anaplastic thyroid carcinoma [published online July 18, 2019].Thyroid. doi: 10.1089/thy.2019.0133.