As reported in the Journal of Clinical Oncology by Salama et al, the NCI-MATCH trial subprotocol H (EAY131-H) has shown durable responses with dabrafenib plus trametinib in previously treated patients with BRAF V600E–mutant tumors.

Study Details

The study enrolled 35 patients with mixed-histology BRAF V600–mutant tumors. Patients with melanoma, thyroid cancer, or colorectal cancer were excluded; patients with non–small cell lung cancer were subsequently excluded in a protocol amendment. Patients received dabrafenib at 150 mg twice per day and trametinib at 2 mg per day continuously until disease progression or intolerable toxicity.

Among 29 patients included in the efficacy analysis, tumors included those of the gastrointestinal tract (n = 11; 38%), lung adenocarcinoma (n = 5; 17%), gynecologic tumors (n = 6; 21%), central nervous system tumors (n = 5; 17%), and hematologic malignancy (n = 1; 3%). In total, 45% of patients had received three or more prior lines of therapy. The primary endpoint was centrally assessed objective response rate. Efficacy was assessed using 5% one-sided exact binomial tests of the null hypothesis that the response rate was ≤ 5%.

Responses

Objective response (all partial responses) was observed in 11 of 29 evaluable patients (37.9%), with P < .0001 against a null rate of 5%. Median duration of response was 25.1 months. An additional 11 patients (37.9%) had stable disease, yielding a disease control rate of 75.9%. Responses were observed in seven distinct tumor types.

Median progression-free survival was 11.4 months, with a 6-month rate of 68.4%. With a median follow-up of 23.0 months, median overall survival was 28.6 months.

Adverse Events

Adverse events were comparable to those previously observed with dabrafenib and trametinib. Among all 35 treated patients, the most frequent adverse events of any grade considered at least possibly related to treatment were fatigue in 26 patients (74%), nausea in 20 (57%), and fever and chills in 18 (51%) and 19 (54%), respectively.

Headache was reported in 10 patients (29%), alkaline phosphatase elevation in 11 (31%), and aspartate aminotransferase elevation in 10 (29%). The most common grade 3 adverse events considered at least possibly related to treatment were fatigue, neutropenia, hyponatremia, and hypophosphatemia. Grade 4 sepsis was observed in one patient. No grade 5 adverse events were reported.

The investigators concluded, “This study met its primary endpoint, with an objective response rate of 38% in this mixed-histology, pretreated cohort. This promising activity warrants additional investigations in BRAF V600–mutated tumors outside of currently approved indications.”

April K.S. Salama, MD, of Duke University, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.