Home World News Pancancer Activity of Dabrafenib Plus Trametinib in Patients with BRAFV600E-Mutated Rare Cancers

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Pancancer Activity of Dabrafenib Plus Trametinib in Patients with BRAFV600E-Mutated Rare Cancers

April 24, 2023

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A phase II basket, Rare Oncology Agnostic Research (ROAR) is the first prospective study of a combination treatment approach with BRAF and MEK inhibitors in patients with advanced rare cancers harbouring the BRAFV600E mutation. The ROAR study demonstrated pancancer activity of the BRAF and MEK inhibitor combination in 21 histologies. The researchers adopted a basket design for this study where tumours expressing the same driver mutation (BRAFV600E) were grouped and treated as a single disease entity. Combination treatment with dabrafenib plus trametinib showed meaningful clinical activity in patients with BRAFV600E-mutated rare cancers.

The encouraging tumour-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers according to Dr. Vivek Subbiah of the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, TX, US, and colleagues who published the findings on 14 April 2023 in the Nature Medicine.

The authors wrote in the background that the most common BRAF mutation is the V600E mutation. BRAF mutations are detected in approximately 7–15% of all cancers, and the most common locus of the mutation is at position V600. The mutation is seen in diverse cancers, including hairy cell leukaemia (HCL, 79–100%), melanomas (40–70%), papillary thyroid cancers (PTC, 45%), ovarian cancers (35%), cholangiocarcinomas (5–7%), multiple myeloma (MM, 4%) and non-small cell lung cancers (NSCLCs, 1–3%). BRAFV600 mutations are also seen in rare and very rare cancers, such as gliomas, sarcomas, gastric and oesophageal cancer, neuroendocrine cancers and ampullary cancer, among others. In general, BRAFV600 inhibitors lack meaningful efficacy in colorectal cancer, and this appears to be a unique case.

Genome-driven treatment options/agnostic treatments are evolving in oncology. The combination of dabrafenib plus trametinib blocks oncogenic MAPK signalling pathway, inhibits growth and survival of BRAFV600-mutant cells and enhances antitumour activity versus either agent alone. This combination is approved for use in the so-called BRAFV600E anchor tumour types, namely metastatic melanoma, melanoma in adjuvant setting, NSCLC and anaplastic thyroid cancer (ATC). However, beyond these cancers, as BRAFV600 mutations are prevalent in a long list of tumour types (>40 tumour types), there is continued unmet need for treatment of rare cancers in adults and children with BRAFV600E mutations where limited or no effective treatment options existed. These tumours lead to substantial burden and mortality in the relapsed or refractory settings.

The US Food and Drug Administration (FDA) granted an accelerated approval to dabrafenib plus trametinib for the treatment of unresectable or metastatic solid tumours with a BRAFV600E mutation. The combination was approved for patients aged 6 years and older in whom the tumours progressed after prior treatment and who had no alternative treatment options. This approval was supported by the meaningful efficacy and safety for the combination in the ROAR and NCI-MATCH studies in adults and a study in paediatric patients with refractory or recurrent solid tumours. This was the first approval for a tumour-agnostic BRAF and MEK inhibitor combination approach and was a considerable advance in precision medicine.

The ROAR study was designed to assess the activity and safety of dabrafenib plus trametinib in patients with BRAFV600E-mutated rare cancers. Based on the discretion of the treating physician and according to the local available standards of care, these cancers did not have any satisfactory treatment options. Rare cancer types included in the study were ATC, biliary tract cancer (BTC), gastrointestinal stromal tumour (GIST), adenocarcinoma of the small intestine (ASI), low-grade (WHO grade 1 or grade 2) glioma (LGG), high-grade (WHO grade 3 or grade 4) glioma (HGG), non-seminomatous germ cell tumours (NSGCTs)/non-germinomatous germ cell tumours (NGGCTs), HCL and MM.

The study team previously published interim results for the ATC, BTC, LGG and HGG and HCL cohorts with data cut-off dates of 26 August 2016 to 25 July 2018. In the latest article published in the Nature Medicine, the study team reports the final efficacy and safety results of the ROAR study for 8 cohorts of patients with BRAFV600E-mutated advanced rare cancers and data cut-off date of 10 December 2021: ATC (n = 36), BTC (n = 43), GIST (n = 1), ASI (n = 3), LGG (n = 13), HGG (n = 45), HCL (n = 55) and (n = 19). The authors also discuss multiple non-melanoma cancer studies showing evidence of the actionability of BRAF beyond anchor type cancers.

The primary endpoint of investigator-assessed overall response rate (ORR) in these 8 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 authors commented that a similar multi-cohort basket design was used in the VE-BASKET study that evaluated the efficacy of vemurafenib monotherapy in 172 patients with any BRAFV600 mutation-positive cancers (26 unique cancer types) other than melanoma, PTC and HCL. After the initiation of the ROAR study, the NCI initiated the MATCH study in which dabrafenib plus trametinib was tested in various BRAFV600E-mutated solid and haematological malignancies.

Treatment with dabrafenib plus trametinib in the ROAR study showed clinically meaningful outcomes in a diverse set of rare cancers with BRAFV600E mutations and had a manageable safety profile. There was consistency in ORR by an independent radiology review and in the investigator-assessed responses in the solid tumour cohorts. Tumour profiling should be introduced early in the management plan to promptly identify those patients who may be eligible for BRAFV600E-targeted treatment. In addition to the previously treated cancers in this study, future studies could evaluate the combination treatment with dabrafenib plus trametinib in treatment-naïve BRAFV600E mutation-positive cancers.

The ROAR study was designed and data were analyzed by the sponsor (Novartis) in collaboration with the trial steering committee. Study funding was provided by Novartis. This study was originally designed and sponsored by GlaxoSmithKline. Novartis Pharmaceuticals Corporation is the current sponsor.