FDA News

FDA grants breakthrough therapy designation to Tafinlar-Mekinist combination for adjuvant treatment of BRAF-positive melanoma

The FDA granted breakthrough therapy designation to the combination of dabrafenib and trametinib for adjuvant therapy of patients with stage III BRAF V600 mutation-positive melanoma, according to the agents’ manufacturer.

Dabrafenib (Tafinlar, Novartis) is a BRAF inhibitor, and trametinib (Mekinist, Novartis) is a MEK 1/2 inhibitor. The combination — which could become the first adjuvant treatment specifically for patients with BRAF V600-mutated melanoma — has been shown to slow tumor growth more than either agent alone.

The FDA based the breakthrough therapy designation on results of the randomized phase 3 COMBI-AD study, which included 870 patients with stage III BRAF V600E/K mutation-positive melanoma who underwent complete resection but no prior anticancer therapy.

Researchers assigned 438 patients to 150 mg dabrafenib twice daily plus 2 mg trametinib daily for 12 months. The other 432 patients received placebo.

RFS served as the study’s primary endpoint. Secondary endpoints included OS, distant metastasis-free survival, freedom from relapse and safety.

Median follow-up was 2.8 years.

As HemOnc Today previously reported, the results — presented at European Society for Medical Oncology Congress and published in The New England Journal of Medicine — showed treatment with the combination significantly reduced risk for disease recurrence or death (median RFS, not reached vs. 16.6 months; HR = 0.47; 95% CI, 0.39-0.58).

Researchers reported a higher 3-year RFS rate among patients assigned the combination (58% vs. 39%). The RFS benefit persisted across all patient subgroups, including those with stage IIIa, IIIb or stage IIIc disease.

Adverse events associated with the combination appeared consistent with those reported in prior studies, and researchers observed no new safety signals.

Higher percentages of patients assigned the combination than placebo experienced adverse events (97% vs. 88%), experienced grade 3 or grade 4 adverse events (41% vs. 14%), or experienced adverse events that led to treatment discontinuation (26% vs. 3%).

The most common side effects associated with combination therapy are fever, nausea, diarrhea, fatigue, chills, headache, vomiting, joint pain, high blood pressure, rash and cough.

“There is a need for more effective treatment options for stage III melanoma patients at a high risk for recurrence following surgical resection,” Samit Hirawat, executive vice president and head of global drug development at Novartis Oncology, said in a company-issued press release. “We thank the FDA for recognizing the scientific advancement Tafinlar and Mekinist may provide in this adjuvant setting.”

The combination of dabrafenib and trametinib is under evaluation for a range of tumor types. The FDA previously granted breakthrough therapy designation to the combination for treatment of metastatic melanoma, non-small cell lung cancer and anaplastic thyroid cancer.

The FDA granted breakthrough therapy designation to the combination of dabrafenib and trametinib for adjuvant therapy of patients with stage III BRAF V600 mutation-positive melanoma, according to the agents’ manufacturer.

Dabrafenib (Tafinlar, Novartis) is a BRAF inhibitor, and trametinib (Mekinist, Novartis) is a MEK 1/2 inhibitor. The combination — which could become the first adjuvant treatment specifically for patients with BRAF V600-mutated melanoma — has been shown to slow tumor growth more than either agent alone.

The FDA based the breakthrough therapy designation on results of the randomized phase 3 COMBI-AD study, which included 870 patients with stage III BRAF V600E/K mutation-positive melanoma who underwent complete resection but no prior anticancer therapy.

Researchers assigned 438 patients to 150 mg dabrafenib twice daily plus 2 mg trametinib daily for 12 months. The other 432 patients received placebo.

RFS served as the study’s primary endpoint. Secondary endpoints included OS, distant metastasis-free survival, freedom from relapse and safety.

Median follow-up was 2.8 years.

As HemOnc Today previously reported, the results — presented at European Society for Medical Oncology Congress and published in The New England Journal of Medicine — showed treatment with the combination significantly reduced risk for disease recurrence or death (median RFS, not reached vs. 16.6 months; HR = 0.47; 95% CI, 0.39-0.58).

Researchers reported a higher 3-year RFS rate among patients assigned the combination (58% vs. 39%). The RFS benefit persisted across all patient subgroups, including those with stage IIIa, IIIb or stage IIIc disease.

Adverse events associated with the combination appeared consistent with those reported in prior studies, and researchers observed no new safety signals.

Higher percentages of patients assigned the combination than placebo experienced adverse events (97% vs. 88%), experienced grade 3 or grade 4 adverse events (41% vs. 14%), or experienced adverse events that led to treatment discontinuation (26% vs. 3%).

The most common side effects associated with combination therapy are fever, nausea, diarrhea, fatigue, chills, headache, vomiting, joint pain, high blood pressure, rash and cough.

“There is a need for more effective treatment options for stage III melanoma patients at a high risk for recurrence following surgical resection,” Samit Hirawat, executive vice president and head of global drug development at Novartis Oncology, said in a company-issued press release. “We thank the FDA for recognizing the scientific advancement Tafinlar and Mekinist may provide in this adjuvant setting.”

The combination of dabrafenib and trametinib is under evaluation for a range of tumor types. The FDA previously granted breakthrough therapy designation to the combination for treatment of metastatic melanoma, non-small cell lung cancer and anaplastic thyroid cancer.

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