TY - JOUR
T1 - Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600–mutant anaplastic thyroid cancer
AU - Subbiah, Vivek
AU - Cabanillas, Maria E.
AU - Kreitman, Robert J.
AU - Wainberg, Zev A.
AU - Cho, Jae Yong
AU - Keam, Bhumsuk
AU - Schellens, Jan H.M.
AU - Soria, Jean Charles
AU - Wen, Patrick Y.
AU - Zielinski, Christoph
AU - Urbanowitz, Gladys
AU - Mookerjee, Bijoyesh
AU - Wang, Dazhe
AU - Rangwala, Fatima
N1 - Funding Information:
A disease model of acquired mutations driving ATC tumor progression is supported by transgenic mouse models. Acquisition of the BRAF V600E mutation in thyroid tissue is sufficient to initiate papillary thyroid cancer,11,22-24with subsequent p53 deletion driving progression to high-grade carcinoma with pathologic features that are consistentwith ATC. Transgenicmice thatharbor thyroid-specific mutations in BRAF V600E and TP53 developed lethal, poorly differentiated thyroid tumors that exhibited focal necrosis, local invasion, and distant metastasis.11 Treatment of these mice with the BRAF inhibitor PLX4720 improved survival, but with no evidence of tumor regression or the suppression of MAPK pathway signaling. Because ATC resistance to BRAF inhibition likely involves the reactivation of upstream receptor tyrosine kinase signaling, concurrent downstream MEK inhibition was hypothesized to produce a more complete MAPK pathway blockade. Indeed, PLX4720 plus the MEK inhibitor PD0325901 resulted in enhanced tumor regression and improved survival in ATC-bearing mice versus PLX4720 alone, with complete responses in three of four mice. These experiments confirmed that combined BRAF and MEK inhibition resulted in more complete MAPK blockade and an enhanced antitumor effect in mouse ATC tumors.11
Funding Information:
Funded by Novartis Pharmaceuticals and the National Institutes of Health (Grant No. P30-CA016672).
Publisher Copyright:
J Clin Oncol 36:7-13. © 2017 by American Society of Clinical Oncology
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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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U2 - 10.1200/JCO.2017.73.6785
DO - 10.1200/JCO.2017.73.6785
M3 - Article
C2 - 29072975
AN - SCOPUS:85039975292
SN - 0732-183X
VL - 36
SP - 7
EP - 13
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 1
ER -