On June 22, 2022, dabrafenib in combination with trametinib was granted accelerated approval for treatment of adult and pediatric patients (aged 6 and older) with unresectable or metastatic solid tumors with BRAF V600E mutation whose disease progressed following prior treatment and who have no satisfactory alternative treatment options.^1,2Dabrafenib/trametinib is not indicated in colorectal cancer, due to known intrinsic resistance to BRAF inhibition.

Supporting Efficacy Data

Approval was based on findings from 131 adults in the BRF117019 (ClinicalTrials.gov NCT02034110) and NCI-MATCH (NCT02465060) studies and 36 pediatric patients in the CTMT212X2101 study (NCT02124772) and supported by results in trials in melanoma and lung cancer already included in product labeling. The BRF117019 study enrolled patients with tumors including high-grade glioma, biliary tract cancer, low-grade glioma, small intestine adenocarcinoma, gastrointestinal stromal tumor, and anaplastic thyroid cancer. The NCI-MATCH study enrolled patients with tumors excluding melanoma, thyroid cancer, and colorectal cancer. The CTMT212X2101 trial enrolled pediatric patients with low- or high-grade glioma.

Among the 131 adults, an objective response was observed in 54 (41%, 95% confidence interval [CI] = 33%–50%); the duration of response varied by tumors. Among the 36 pediatric patients, an objective response was observed in 9 (25%, 95% CI = 12%–42%); the duration of response was at least 6 months for 78% of responders and at least 24 months for 44%.

How It Is Used

The recommended dose of the combination in adults is dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily. The recommended doses for dabrafenib and trametinib in pediatric patients are based on body weight, as specified in the product labeling.

Safety Profile

Among a total of 206 adults receiving dabrafenib/trametinib in the BRF117019 study, the most common adverse events of any grade were pyrexia (55%), fatigue (50%), nausea (40%), and rash (40%); hemorrhage occurred in 29%. Serious adverse events occurred in 45%, most commonly pyrexia (11%) and pneumonia (6%). Adverse events led to treatment discontinuation in 13%. Fatal adverse events occurred in 3.9%, most commonly sepsis (1.9%).

Among 48 pediatric patients in the CTMT212X2101 study, the most common adverse events of any grade were pyrexia (75%), rash (73%), vomiting (52%), and fatigue (48%); hemorrhage occurred in 33%. Serious adverse events occurred in 46%, most commonly pyrexia (25%) and decreased ejection fraction (6%). Adverse events led to treatment discontinuation in 21%, most commonly due to increased alanine aminotransferase levels (6%) and decreased ejection fraction (4.2%).

Dabrafenib has warnings/precautions for new primary malignancies, tumor promotion in BRAF wild-type tumors, hemorrhage, cardiomyopathy, uveitis, serious febrile reactions, serious skin toxicities, hyperglycemia, glucose-6-phosphate dehydrogenase deficiency, and embryofetal toxicity.

Trametinib has warnings/precautions for new primary malignancies, hemorrhage, colitis and gastrointestinal perforation, venous thromboembolism, cardiomyopathy, ocular toxicities, interstitial lung disease, serious febrile reactions, serious skin toxicities, hyperglycemia, and embryofetal toxicity.

REFERENCES

1. Tafinlar (dabrafenib) capsules prescribing information, Novartis, June 2022. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/202806s022lbl.pdf. Accessed November 16, 2022.

2. Mekinist (trametinib) tablets prescribing information, Novartis, June 2022. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/204114s024lbl.pdf. Accessed November 16, 2022.