Dabrafenib and trametinib in patients with tumors with BRAF V600E/K mutations: Results from the molecular analysis for therapy choice (MATCH) Arm H.
Salama, AKS; Li, S; Macrae, ER; Park, J-I; Mitchell, EP; Zwiebel, JA; Chen, HX; Gray, RJ; McShane, L; Rubinstein, L; Patton, D; Williams, PM ...
Published in: Journal of Clinical Oncology
3002 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.
