Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E Mutations: Results of the NCI-MATCH Trial Subprotocol H

Abstract

Purpose: BRAF^V600 mutations are commonly found in melanoma and thyroid cancers and to a lesser degree in other tumor types. Subprotocol H (EAY131-H) of the NCI-MATCH platform trial sought to investigate the selective BRAF inhibitor dabrafenib and the MEK1/2 inhibitor trametinib in patients with solid tumors, lymphomas, or multiple myeloma whose tumors harbored a BRAF^V600 mutation.

Patients and methods: EAY131-H is an open-label, single-arm study. Patients with melanoma, thyroid, or colorectal cancer were excluded; patients with non-small-cell lung cancer were later excluded in an amendment. Patients received dabrafenib 150 mg twice per day and trametinib 2 mg per day continuously until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival (PFS), 6-month PFS, and overall survival.

Results: Thirty-five patients were enrolled, and 29 were included in the primary efficacy analysis as prespecified in the protocol. Median age was 59 years, and 45% of the patients had received ≥ 3 lines of therapy. The confirmed ORR was 38% (90% CI, 22.9% to 54.9%) with P < .0001 against a null rate of 5%, and PFS was 11.4 months (90% CI, 8.4 to 16.3 months); responses were seen in 7 distinct tumor types. Seven patients had a duration of response of > 12 months, including 4 patients with a duration of response of > 24 months. An additional 8 patients had a PFS > 6 months. The median overall survival was 28.6 months. Reported adverse events were comparable to those noted in previously reported profiles of dabrafenib and trametinib.

Conclusion: This study met its primary end point, with an ORR of 38% (P < .0001) in this mixed histology, pretreated cohort. This promising activity warrants additional investigations in BRAF^V600-mutated tumors outside of currently approved indications.

FIG 1.

CONSORT diagram. (*) Did not receive an assignment because of ineligible histology: colorectal cancer (n = 44), melanoma (n = 14), papillary thyroid cancer (n = 9), and non–small-cell lung cancer (n = 1); (†) reasons not enrolled after receiving an assignment: central screening cohort: death (n = 2), patient refusal (n = 1), prior treatment (n = 2), disease progression (n = 1), BRAF inhibitor started before assignment (n = 2), inadequate organ/marrow function (n = 2), not able to swallow tablets (n = 1), no longer met master protocol eligibility (n = 1), and unknown (n = 2); outside assay cohort: deteriorating performance status (n = 1) and unknown (n = 1).

FIG 2.

(A) Progression-free survival. (B) Overall survival.

FIG 3.

Best percentage change from baseline in 23 patients with evaluable measurements. This plot excludes 5 unevaluable patients and 1 patient with pancreatic adenocarcinoma who was classified as having progressive disease but for whom complete data for target lesions were not available. (*) New lesions. Adeno, adenocarcinoma; ca, carcinoma; GYN, gynecologic; intra cholangia, intrahepatic cholangiocarcinoma; PD, progressive disease; PR, partial response; SD, stable disease.

FIG 4.

Duration of treatment in patients who achieved partial response (PR) or stable disease. Adeno, adenocarcinoma; ca, carcinoma; GYN, gynecologic; intra cholangio, intrahepatic cholangiocarcinoma; PD, progressive disease.

FIG 5.

Co-occurring genomic alterations with BRAF^V600E using the central NCI-MATCH assay for 29 patients. Single nucleotide variant (purple), copy number variant (dark red), insertion-deletion (light red). Response data and histology for individual patients are listed at the bottom. Adeno, adenocarcinoma; ca, carcinoma; GYN, gynecologic; intra cholangio, intrahepatic cholangiocarcinoma; PD, progressive disease; PR, partial response; SD, stable disease; UE, unevaluable.

FIG A1.

Progression-free survival by TP53 status.

FIG A2.

(A) Progression-free survival for patient cohort. (B) Overall survival for patient cohort.

FIG A3.

Best % change from baseline in 26 patients with evaluable measurements (n = 33 patient cohort). This plot excludes 5 unevaluable patients, 1 patient with multiple myeloma who had a minimal response, and 1 patient with pancreatic adenocarcinoma who was classified as having progressive disease but for whom complete data for target lesions were not available. (*) New lesions. Adeno, adenocarcinoma; ca, carcinoma; GYN, gynecologic; intra cholangio, intrahepatic cholangiocarcinoma; PD, progressive disease; PR, partial response; SD, stable disease.

FIG A4.

Duration of treatment in patients who achieved a partial response (PR) or stable disease for n = 33 patient cohort. Adeno, adenocarcinoma; ca, carcinoma; GYN, gynecologic; intra cholangio, intrahepatic cholangiocarcinoma; PD, progressive disease.