The FDA has given accelerated approval to dabrafenib (Tafinlar®, Novartis) in combination with trametinib (Mekinist®, Novartis) for treatment of adult or pediatric patients with unresectable or metastatic solid tumors with a BRAF V600E mutation and no satisfactory alternative treatment options. This approval is based on three clinical trials: the Rare Oncology Agnostic Research (ROAR) phase 2 basket study, the NCI-MATCH Subprotocol H study, and Study X2101 which was specific to the enrollment of pediatric patients with refractory or recurrent tumors; with support from results in the studies COMBI-d, COMBI-v, and BRF113928.
"BRAFV600 mutations are and early and common driver mutation in these well-differentiated thyroid tumors, with additional late-event mutations that promote progressive dedifferentiation to anaplastic thyroid cancers", wrote Vivek Subbiah, MD, Associate professor in the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center, and colleagues, in their publication of the ROAR trial (NCT02034110), on which this approval was partially based. "The dual inhibition of the MAPK signaling pathway improves treatment response and delays or prevents MAPK pathway reactivation, a known resistance mechanism. This strategy has been successful in treating BRAFV600-mutant melanoma and lung cancer, whereby combined BRAF plus MEK inhibition increased overall response frequency, duration of response, progression-free survival and overall survival compared with BRAF inhibitor monotherapy."
The safety and efficacy of dabrafenib plus trametinib were assessed in of 131 adult patients from the ROAR phase 2, open-label, nonrandomized study and the NCI-MATCH Subprotocol H phase 2, open-label, single-arm study, as well as 36 pediatric patients, ages six to 18, from parts C and D of the Study X2101 phase 1/2a, multi-center, open-label study. Each study evaluated the end point of overall response rate.
Within the three studies, a total of 24 tumor types were represented, including low-grade gliomas (LGG) and high-grade gliomas (HGG), biliary tract cancers, adenocarcinomas of the small intestine, gastrointestinal stromal tumors, anaplastic thyroid cancers, and other solid tumors. In the group of the 131 adult patients evaluated, 54 patients (41%) had an objective response. Among the tumor types with the highest representation, there was an overall response rate of 46% for biliary tract cancer, 50% for LGGs of any subtype, and 33% for HGGs of any subtypes. In the group of the 36 pediatric patients with LGGs or HGGs evaluated, the overall response rate was 25%, with a secondary end point duration of response recorded to be 78% at the six-month mark and 44% at the 24-month mark.
The most common adverse reactions in ≥20% of adult patients were pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema.
The most common adverse reactions in ≥20% of pediatric patients were pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia.
"This study showed that dabrafenib plus trametinib showed meaningful response rates and durable clinical benefit in patients with recurrent gliomas with BRAFV600E mutations, regardless of glioma subtype." concluded Patrick Wen, MD, Professor of Neurology at Dana-Farber/Harvard Cancer Center, and colleagues, in their publication of the ROAR study (NCT02034110), on which the approval was partially based. "Molecular screening strategies that include BRAFV600E mutations will be crucial for identifying patients who might benefit from this treatment combination, and we recommend that testing is adopted in clinical practice for patients with glioma."
The recommended dosage for adult patients is 150mg of dabrafenib, orally twice daily plus 2 mg of trametinib orally once daily. The recommended dosage for pediatric patients being treated with dabrafenib and trametinib is based on body weight. It is noted that a recommended dose has not been established in patients who weigh less than 26 kg. Additionally, dabrafenib plus trametinib is not indicated to be used in patients with colorectal cancer because of resistance to BRAF inhibition, as well dabrafenib is not indicated to be used in patients with wild-type BRAF solid tumors.
For More Information
Wen PY, Stein A, van den Bent M, et al (2022). Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol, 23(1):53-64. DOI:10.1016/S1470-2045(21)00578-7
Salama, A, Li S, Macrae E, et al (2020). Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: results of the NCI-MATCH trial subprotocol H. J Clin Oncol, 38(33):3895-3904. DOI:10.1200/JCO.20.00762
Subbiah V, Kreitman RJ, Wainberg ZA, et al (2018). Dabrafenib and trametinib treatment in patients with local advanced or metastatic BRAF V600-mutatnt anaplastic thyroid cancer. J Clin Oncol, 36(1):7-13. DOI:10.1200/JCO.2017.73.6785
US Food and Drug Administration (2022). FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid?utm_medium=email&utm_source=govdelivery
Novartis (2022). Novartis dabrafenib plus trametinib receives FDA approval for first tumor-agnostic indication for BRAF V600E solid tumors. Available at: https://www.novartis.com/news/media-releases/novartis-tafinlar-mekinist-receives-fda-approval-first-tumor-agnostic-indication-braf-v600e-solid-tumors
Clinicaltrials.gov (2021). Study to investigate safety, pharmacokinetic (PK), pharmacodynamic (PD) and clinical activity of trametinib in subjects with cancer or plexiform neurofibromas and trametinib in combination with dabrafenib in subjects with cancers harboring V600 mutations. NLM identifier: NCT02124772.
Clinicaltrials.gov (2022). Study of selective BRAF kinase inhibitor dabrafenib monotherapy twice daily and in combination with dabrafenib twice daily and trametinib once daily in combination therapy in subjects with BRAF V600E mutation positive metastatic (stage IV) non-small cell lung cancer. NLM identifier: NCT 01336634.
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