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J Clin Oncol. 2018 Jan 1;36(1):7-13. doi: 10.1200/JCO.2017.73.6785. Epub 2017 Oct 26.

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer.

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Vivek Subbiah and Maria E. Cabanillas, The University of Texas MD Anderson Cancer Center, Houston, TX; Robert J. Kreitman, National Institutes of Health, Bethesda, MD; Zev A. Wainberg, University of California Los Angeles, Los Angeles, CA; Jae Yong Cho, Yonsei University College of Medicine Gangnam Severance Hospital; Bhumsuk Keam, Seoul National University Hospital, Seoul, Republic of Korea; Jan H.M. Schellens, Netherlands Cancer Institute, Amsterdam; Jan H.M. Schellens, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands; Jean Charles Soria, Institut Gustave Roussy, University of Paris-Sud, and University of Paris-Saclay, Villejuif, France; Patrick Y. Wen, Dana-Farber Cancer Institute, Boston, MA; Christoph Zielinski, Comprehensive Cancer Center, Medical University Vienna; Vienna, Austria; and Gladys Urbanowitz, Bijoyesh Mookerjee, Dazhe Wang, and Fatima Rangwala, Novartis Oncology, East Hanover, NJ.


Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E-mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.


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