Results of the ROAR basket study: the efficacy and safety of combined tumor-agnostic therpy in pacients with BRAFV6ooE-murated rare cancers

Mutations in the BRAF gene are identified between 7-15% of all cancers, most frequently at position V600, and occur in a variety of tumor types including hairy cell leukemia, melanoma, papillary thyroid cancer, ovarian cancer, cholangiocarcinoma, multiple myeloma, and non-small cell lung cancer. BRAFV600E alterations are also prevalent in patients with rare cancers including gliomas, sarcomas, gastric and esophageal cancers, neuroendocrine cancers, and ampullary cancers, among others.

“These cancers lead to significant mortality in refractory settings. Representing an unmet clinical need, these patients are in need of new, more effective treatment options. Tumor-agnostic therapy with dabrafenib plus trametinib could open a new therapeutic avenue for patients with BRAFV600E-mutated rare cancers,” says Elena Élez, Principal Investigator of the Vall d’Hebron Institute of Oncology’s (VHIO) Colorectal Cancer Group and a Medical Oncologist at the Vall d’Hebron University Hospital (HUVH), the Vall d’Hebron Barcelona Hospital Campus.

The combination of targeted therapies dabrafenib and trametinib blocks oncogenic MAPK pathway signaling, inhibits the growth and survival of BRAFV600-mutant cells, and potentiates antitumor activity compared to either therapy alone. This therapeutic strategy received accelerated approval from the U.S. Food and Drug Administration in 2022 for the treatment of metastatic melanoma, adjuvant melanoma, non-small cell lung cancer and anaplastic thyroid cancer.

The multi-center, single-arm phase II ROAR basket study evaluated the efficacy and safety of this combination as tumor-agnostic therapy in eight cohorts of patients with BRAFV600E-mutated rare cancers. Results of this study, published ahead of print in Nature Medicine*, report encouraging clinical activity with a consistent safety profile observed in approved indications.

Directed by Vivek Subbiah, an Associate Professor at the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, the University of Texas MD Anderson Cancer Center in Houston (USA), this study included 206 patients with previously treated BRAFV600E-mutated advanced rare cancers.

These patients were divided into groups based on tumor type: anaplastic thyroid carcinoma, biliary tract cancer, small bowel adenocarcinoma, low-grade grade glioma, high-grade glioma, hairy cell leukemia and multiple myeloma. The response rate was higher than 50% in all cohorts except in hairy cell leukemia patients, which was 33%. The gastrointestinal stromal tumor cohort of patients only included one patient who presented stable disease during the 30-month follow-up period.

Durable and clinically significant responses were observed in solid and haematological tumors, with an acceptable safety profile. The most common treatment-related adverse events were pyrexia, fatigue, chills, nausea, and rash.

“The early detection of BRAFV600E mutations in clinical practice may help to improve outcomes by providing a targeted treatment option for patients with rare cancers and limited treatment options. Our results support the genetic testing and tumor profiling of these patients to rapidly identify those who may be eligible for this treatment combination,” concludes Elena Élez, a co-author of this present study.

Future studies are warranted to evaluate dabrafenib plus trametinib in patients with BRAFV600E-mutated rare cancers in earlier lines of treatment.

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Reference:

* Subbiah V, Kreitman RJ, Wainberg ZA, Gazzah A, Lassen U, Stein A, Wen PY, Dietrich S, de Jonge MJA, Blay JY, Italiano A, Yonemori K, Cho DC, de Vos FYFL, Moreau P, Fernandez EE, Schellens JHM, Zielinski CC, Redhu S, Boran A, Passos VQ, Ilankumaran P, Bang YJ. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. Nat Med. 2023 Apr 14. doi: 10.1038/s41591-023-02321-8. Epub ahead of print. PMID: 37059834.