What is the efficacy of dabrafenib and trametinib in the targeted treatment of solid tumors?

On June 22, 2022, the U.S. Food and Drug Administration granted accelerated approval to dabrafenib (Tafinlar, Novartis) in combination with trametinib (Mekinist, Novartis) for the treatment of adults and pediatric patients ≥6 years of age with BRAF V600E-mutated unresectable or metastatic solid tumors whose disease has progressed after prior therapy and who have no satisfactory alternative treatment options. Combination therapy with dabrafenib and trametinib is not indicated for patients with colorectal cancer because colorectal cancer is known to be intrinsically resistant to BRAF inhibition. Dabrafenib is not indicated for patients with wild-type BRAF solid tumors.

Safety and efficacy were evaluated in 131 adult patients in open-label, multi-cohort trials BRF117019 (NCT02034110) and NCI-MATCH (NCT02465060), 36 pediatric patients in CTMT212X2101 (NCT02124772), and Supported by results from COMBI-d, COMBI-v, and BRF113928, a melanoma and lung cancer study described in the product label. The BRF117019 study enrolled patients with specific solid tumors that are positive for the BRAF V600E mutation, including high-grade glioma (HGG), biliary tract cancer, low-grade glioma (LGG), small bowel adenocarcinoma, gastrointestinal stromal tumor, and anaplastic thyroid cancer (ATC). NCI-MATCH Subprotocol H enrolled adult patients with BRAF V600E mutation-positive solid tumors (other than patients with melanoma, thyroid cancer, or CRC).

Parts C and D of studies CTMT212X2101 enrolled 36 pediatric patients with BRAF V600-refractory or relapsed LGG or HGG. The primary efficacy outcome measure in these studies was overall response rate (ORR) using standard response criteria. Among 131 adult patients, a total of 54 (41%, 95% CI: 33, 50) patients experienced objective response. The studies enrolled patients with 24 tumor types, including different subtypes of LGG and HGG. Among the most representative tumor types, the ORR was 46% (95% CI: 31, 61) for biliary tract cancer, 33% (95% CI: 20, 48) for high-grade glioma (pooled), and 50% (95% CI: 23, 77) for low-grade glioma (pooled). For 36 pediatric patients, the ORR was 25% (95% CI: 12, 42); 78% of patients had DOR ≥ 6 months and 44% had DOR ≥ 24 months.

The most common adverse reactions (≥20%) in adult patients are fever, fatigue, nausea, rash, chills, headache, bleeding, cough, vomiting, constipation, diarrhea, myalgia, arthralgia and edema.

The most common (≥20%) adverse reactions in pediatric patients are fever, rash, vomiting, fatigue, dry skin, cough, diarrhea, acneiform dermatitis, headache, abdominal pain, nausea, bleeding, constipation, and paronychia.

The recommended dose of dabrafenib for adult patients is 150 mg (two 75 mg capsules) taken orally twice daily in combination with 2 mg of trametinib taken orally once daily. Recommended doses of dabrafenib and trametinib in pediatric patients are based on body weight. Recommended doses have not been established for patients weighing less than 26 kg.

Dabrafenib has been successfully launched in my country and has been included in medical insurance, significantly reducing the financial pressure on patients. The drug is available in the domestic market in two original specifications: 75mg 120 capsules and 50mg 120 capsules. The price of the 75mg specification drug after medical insurance is about 12,000 yuan. At the same time, dabrafenib has also attracted attention in overseas markets, and there are two versions: original research and generic versions; Novartis Pharmaceuticals’ original research drug of 75 mg and 120 tablets is sold in Turkey for 11,000 yuan per box, while many generic versions of the same specifications of drugs on the market are generally priced around 2,700 yuan. On the other hand, trametinib has also been included in my country's medical insurance catalog. Patients can easily purchase the original drug in a box of 2mg*30 tablets in China, and the price after medical insurance reimbursement is about 10,000 yuan. There are also many trametinib generic drugs circulating in overseas markets. In particular, the drug of the same specifications produced in Laos is affordable and only costs about 1,900 yuan. It is favored by patients because of its high cost performance. For questions related to trametinib, it is recommended that patients consult overseas medical consultants for professional guidance.