Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial

Abstract

BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110.

Implementation of precision medicine in healthcare—A European perspective

“…These may still follow the traditional trial design ranging from phases 1 to 3 and phase 4 for post-marketing surveillance. However, the portfolio of trial designs has significantly widened and now includes, for example, umbrella, basket and platform trials as well as master protocols, investigating more than one drug per cancer type simultaneously in several substudies within a single protocol [39][40][41][42]. Master protocols may use umbrella or basket trial designs or combine both trial types.…”

TRKing sarcomas for precision medicine: Seek, and ye shall find!

“…18 Moreover, approval of the first oral combination targeted therapy of dabrafenib and trametinib for BRAF V600Ealtered tumors was based on the pooled analysis of Rare Oncology Agnostic Research (ROAR) basket and National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trials. 19,20 This method allows quicker access to newly effective treatments for patients with all tumor types and abrogates the need for trials of a novel agent for each tumor type for which it may prove effective.…”

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“…Retrospective analysis of these patients showed that some of them derived clinical benefit from a BRAF/MEK/ERK inhibitor. Based on the phase 2 ROAR trial (NCT02034110), combination dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) has been granted accelerated approval for the treatment of unresectable or metastatic solid tumors with a BRAF V600E mutation 27 …”