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|Authors||April K.S. Salama, Shuli Li, Erin Renee Macrae, Jong-In Park, Edith P. Mitchell, James A. Zwiebel, Helen X. Chen, Robert James Gray, Lisa McShane, Lawrence Rubinstein, David Patton, Paul M. Williams, Stanley R. Hamilton, Deborah Kay Armstrong, Barbara A. Conley, Carlos L. Arteaga, Lyndsay Harris, Peter J. O'Dwyer, Alice P. Chen, Keith Flaherty|
|Title||Dabrafenib and trametinib in patients with tumors with BRAF V600E/K mutations: Results from the molecular analysis for therapy choice (MATCH) Arm H.|
|Journal||Journal of Clinical Oncology|
|Date||May 20, 2019|
|Abstract Text||Background: The NCI-MATCH precision medicine trial assigns patients (pts) with solid tumors, lymphomas, or multiple myeloma with progression on prior treatment to a targeted therapy based on genetic alterations identified in pre-treatment biopsies. Arm H (EAY131-H) evaluated the combination of the BRAF inhibitor (inh) dabrafenib (DAB), and the MEK inh, trametinib (TRM), in pts with BRAF V600E/K mutations. Methods: Pts with melanoma, thyroid, or colorectal cancer were excluded. Pts with NSCLC were excluded after the U.S. Food and Drug Administration (FDA) approved DAB/TRM for this indication. Pts received DAB 150 mg po BID and TRM 2 mg PO daily on 28 day cycles until disease progression or intolerable toxicity; restaging was performed every 2 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Results: A total of 35 pts were enrolled from 1/2016-2/2018; 2 were ineligible (CrCl below criteria; labs out of window). Over 17 distinct tumor histologies were represented. 58% of pts were female, median age was 63 (range 21-85), 94% were Caucasian, and 48% of pts had received at least 3 prior therapies (range 1- 8). The confirmed ORR was 33.3% (90% CI 19.9%, 49.1%), with a median duration of response (DoR) of 12 months (mon). Varied histologies had a DoR of > 12 mon: histiocytic sarcoma, cholangiocarcinoma and mixed adenoneuroendocrine carcinoma of unknown primary, among others. Median PFS was 9.4 mon; the 6 mon PFS rate was 70.6% (90% CI 58.2%-85.5%), and an additional 10 pts had a PFS > 5.5 mon. Median OS has not been reached. At the time of data cutoff (12/2018) 11 pts continue on treatment. Adverse events (AE) were comparable to previously reported profiles of DAB/TRM; no new AEs were identified. The most frequent grade 3 AEs were fatigue, neutropenia, hyponatremia, hypophosphatemia, and urinary tract infection; there was 1 grade 4 sepsis; no grade 5 AEs. Conclusions: In this pre-treated, mixed histology cohort, DAB and TRM showed promising activity outside of currently approved FDA indications warranting further investigations. Correlative analyses are planned. Clinical trial information: NCT02465060.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|BRAF V600E||Advanced Solid Tumor||sensitive||Dabrafenib + Trametinib||Phase II||Actionable||In a Phase II trial (NCI-MATCH), Tafinlar (dabrafenib) and Mekinist (trametinib) combination therapy resulted in an objective response rate of 33.3% (11/33) in patients with advanced solid tumors other than melanoma, thyroid, colorectal, and lung cancer harboring BRAF V600E, with a median duration of response of 12 months, median progression-free survival of 9.4 months, and median overall survival not reached (J Clin Oncol 37, no. 15_suppl (May 20, 2019) 3002; NCT02465060).||detail...|
|BRAF V600E||Advanced Solid Tumor||sensitive||Dabrafenib + Trametinib||FDA approved||Actionable||In 3 Phase II trials (ROAR, NCI-MATCH, X2101) that supported FDA approval, Tafinlar (dabrafenib) and Mekinist (trametinib) combination therapy demonstrated safety and efficacy in adult and pediatric (6 years or older) patients with advanced solid tumors harboring BRAF V600E (PMID: 34838156, PMID: 32818466, J Clin Oncol 37, no. 15_suppl (May 20, 2019) 3002, J Clin Oncol 38, no. 15_suppl (May 20, 2020) 10506; NCT02034110, NCT02465060, NCT02124772).||32818466 detail... detail... 34838156 detail... detail...|