Tafinlar (dabrafenib) + Mekinist (trametinib) - 6 indications

• for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations; approved in January of 2014
• for the treatment of metastatic non-small cell lung cancer with BRAF V600E mutations; approved June of 2017
• for the adjuvant treatment of melanoma with BRAF V600E or V600K mutations; approved April of 2018
• for the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutations; approved May of 2018 
• for the treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutations; approved June of 2022
• for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation; approved March of 2023

General Information

Tafinlar (dabrafenib) is an inhibitor of some mutated forms of BRAF kinases. Mekinist (trametinib) is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity.

The combination is specifically indicated for the following:

• the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test;
• the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection;
•  the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test;
• the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options;
• the treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options;
• the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy

Tafinlar and Mekinist are supplied as capsules and as an oral suspension. 

The recommended dosage of Mekinist in adult patients is 2 mg orally once daily. The recommended dosage for Mekinist in pediatric patients is based on body weight. Take Mekinist at least 1 hour before or at least 2 hours after a meal. 

Take Mekinist at the same time each day, approximately 24 hours apart. Take Mekinist at least 1 hour before or 2 hours after a meal. Do not take a missed dose of Mekinist within 12 hours of the next dose of Mekinist. If vomiting occurs after Mekinist administration, do not take an additional dose. Take the next dose at its scheduled time.

The recommended dosage of Tafinlar in adult patients is 150 mg (two 75 mg capsules) orally twice daily. The recommended dosage for Tafinlar in pediatric patients is based on body weight. Take Tafinlar at least 1 hour before or at least 2 hours after a meal.

Take Tafinlar at the same time each day, approximately 12 hours apart. Take Tafinlar at least 1 hour before or 2 hours after a meal. Do not take a missed dose of Tafinlar within 6 hours of the next dose of Tafinlar. If vomiting occurs after Tafinlar administration, do not take an additional dose. Take the next dose at its scheduled time.

The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity. The recommended duration of treatment in the adjuvant melanoma setting is until disease recurrence or unacceptable toxicity for up to 1 year. The recommended duration of treatment for pediatric patients with LGG is until disease progression or until unacceptable toxicity.

Mechanism of Action

Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.

Dabrafenib is an inhibitor of some mutated forms of BRAF kinases, including BRAF V600E, BRAF V600K, and BRAF V600D enzymes. Dabrafenib also inhibits wild-type BRAF and CRAF kinases and other kinases, such as SIK1, NEK11, and LIMK1. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Dabrafenib inhibits cell growth of various BRAF V600 mutation positive tumors in vitro and in vivo.

Trametinib and dabrafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive tumor xenografts compared with either drug alone.

Side Effects

Adverse effects associated with the use of Mekinist plus Tafinlar may include, but are not limited to, the following:

• Unresectable or metastatic melanoma: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema.
•  Adjuvant treatment of melanoma: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. 
•  NSCLC: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.
• Adult patients with solid tumors: pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema.
•  Pediatric patients with solid tumors: pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia.
• Pediatric patients with LGG: pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain and dermatitis acneiform

Indication 1: unresectable or metastatic melanoma with BRAF V600E or V600K mutations

FDA approval was based on results from the randomized Phase II part of the Phase I/II open-label study, which evaluated the combination of trametinib and dabrafenib at the recommended dose (150/2mg) (N=54) and single-agent dabrafenib (150mg) (N=54). The results were as follows:

• The investigator-assessed overall response rate (ORR) (main efficacy endpoint) was 76% for patients treated with the combination, and 54% for patients treated with single-agent dabrafenib. The median duration of response was 10.5 months for patients treated with the combination, and 5.6 months for patients treated with single-agent dabrafenib.
• Data analyses of the blinded independent radiologic review committee (IRRC) supported the investigator results. The IRRC-assessed ORR was 57% for patients treated with the combination, and 46% for patients receiving single-agent dabrafenib. The median duration of response as assessed by the IRRC was 7.6 months for patients treated with the combination, and 7.6 months for patients treated with single-agent dabrafenib.

Indication 2: metastatic non-small cell lung cancer with BRAF V600E mutations

The FDA approval was based on safety and efficacy of Tafinlar in combination with Mekinist in a Phase II, three-cohort, multicenter, non-randomized, non-comparative and open-label study in which patients with stage IV BRAF V600E mutant NSCLC were enrolled (36 treatment-naïve [previously untreated] and 57 previously treated with chemotherapy). 

Among the 36 treatment-naïve patients receiving 150 mg of Tafinlar twice daily and 2 mg of Mekinist once daily, the overall response rate (ORR) was 61%. In the previously treated population receiving the same dosage, patients demonstrated an ORR of 63%. The ORR was assessed by independent review committee. The median duration of response in the treatment naïve cohort was not estimable and in the previously treated patient cohort was 12.6 months.

Indication 3: adjuvant treatment of melanoma with BRAF V600E or V600K mutations

The FDA approval was based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with Tafinlar + Mekinist after complete surgical resection. Patients received the Tafinlar (150 mg BID) + Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met. Treatment with the combination therapy significantly reduced the risk of disease recurrence or death by 53% as compared to placebo; median not reached with combination therapy vs. 16.6 months with placebo. The RFS benefit among the combination arm was observed across all patient subgroups, including disease sub-stage. Improvements were also observed in key secondary endpoints including overall survival (OS), distant metastasis-free survival (DMFS) and freedom from relapse (FFR).

Indication 4: locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutations

approved in May of 2018

The FDA approval was based on open-label clinical trial of patients with rare cancers with the BRAF V600E mutation. Data from trials in BRAF V600E mutation-positive, metastatic melanoma or lung cancer and results in other BRAF V600E mutation-positive rare cancers provided confidence in the results seen in patients with ATC. The trial measured the percent of patients with a complete or partial reduction in tumor size (overall response rate). Of 23 evaluable patients, 57 percent experienced a partial response and 4 percent experienced a complete response; in nine (64 percent) of the 14 patients with responses, there were no significant tumor growths for six months or longer.

Indication 5: adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutations

approved in June of 2022

The FDA approval was based on clinical efficacy and safety demonstrated in three clinical trials. In the Phase II ROAR (Rare Oncology Agnostic Research) basket study and the NCI-MATCH Subprotocol H study, Tafinlar + Mekinist resulted in overall response rates of up to 80% in patients with BRAF V600E solid tumors, including high- and low-grade glioma, biliary tract cancer and certain gynecological and gastrointestinal cancers. An additional study (Study X2101) demonstrated the clinical benefit and acceptable safety profile of Tafinlar + Mekinist in pediatric patients.

Indication 6: pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation

approved in March of 2023

The FDA approval  was based on results from the Phase II/III TADPOLE trial that showed patients randomized to receive Tafinlar + Mekinist experienced a statistically significant improvement in overall response rate (ORR) of 47% compared to 11% for those randomized to receive chemotherapy. At a median follow-up of 18.9 months, median progression-free survival (PFS) was 20.1 months with Tafinlar + Mekinist compared to 7.4 months with chemotherapy.