TAFINLAR is indicated, in combination with trametinib, for...the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.

Unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.

RMST and cure rate were improved with D+T across AJCC 7 substages, with the greatest benefit observed in pts with high-risk baseline stage IIIB or IIIC. RMST and cure-rate models complement conventional statistical methods for 5-year COMBI-AD analysis, demonstrating significant clinical benefit with adjuvant D+T across all stage III substages in pts with melanoma.

In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects.

COMBI-AD is a randomized, Phase III trial evaluating 12 mo of adjuvant D 150 mg twice daily + T 2 mg once daily vs 2 matched PBOs in pts with resected stage III BRAF V600E/K–mutant melanoma...The 4- and 5-year RFS rates were 55% (95% CI, 50%-60%) and 52% (95% CI, 48%-58%) with D+T vs 38% (95% CI, 34%-43%) and 36% (95% CI, 32%-41%) with PBO. These findings match those estimated by the cure rate model. The RFS benefit with D+T was evident across all AJCC 7 substages (HR [95% CI]: IIIA, 0.61 [0.35-1.07]; IIIB, 0.50 [0.37-0.67]; IIIC, 0.48 [0.36-0.64]).

Novartis announced today the US Food and Drug Administration (FDA) has accepted the Company's supplemental New Drug Application (sNDA) for filing, and granted Priority Review designation for Tafinlar (dabrafenib) in combination with Mekinist (trametinib) for the adjuvant treatment of patients with stage III melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, following complete resection.

Novartis today announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) for Tafinlar (dabrafenib) in combination with Mekinist (trametinib) for the adjuvant treatment of patients with stage III melanoma with a BRAF V600 mutation following complete resection...The designation is based on results from COMBI-AD, a Phase III study of 870 patients with stage III BRAF V600E/K mutation-positive melanoma after complete surgical resection treated with Tafinlar + Mekinist.

Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity.

Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effect.

...Stage IIIc or Stage IV BRAF V600E/K cutaneous melanoma...

...Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis more than 1 mm), IIIb or IIIc cutaneous melanoma determined to be V600E/K mutation positive by a central laboratory. Patients presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible...

We conducted a single-center, phase II clinical trial (NCT02231775) evaluating neo + adj DT in pts with surgically resectable, RECIST measurable clinical stg III or oligometastatic stg IV BRAF V600E/K mutated melanoma....Neo + adj DT is feasible and safe in pts with surgically resectable BRAF mutated melanoma. With a median follow-up of 35 mos, median RFS, DMFS, and OS have not been reached for pts with a pCR after neo DT, and are all significantly prolonged compared to non-pCR pts.

We conducted a single-center, phase II clinical trial (NCT02231775) evaluating neo + adj DT in pts with surgically resectable, RECIST measurable clinical stg III or oligometastatic stg IV BRAF V600E/K mutated melanoma….These results demonstrate durable benefit for neo + adj DT in this high-risk pt population that achieve a pCR.

Patients with resected AJCC-7 stage III BRAFV600E/K-mutant melanoma were randomized to either D (150 mg twice daily) + T (2 mg once daily)...At 5 years, DMFS rates were higher for patients with AJCC-8 stages IIIB-D disease receiving adjuvant D + T vs PBO (table). Five-year DMFS rates also favored D + T...In this retrospective analysis, adjuvant D + T provided long-term DMFS benefit vs PBO in stage IIIB-D patients with resected BRAFV600E/K-mutant melanoma.

Detection of ctDNA at baseline was associated with worse PFS (median BRAFV600 ctDNA positive = 5.8; 95% CI: 4.2-9.6 months, BRAFV600 ctDNA negative = 21.4 mos; 95% CI 10.4-NA; measured from registration to lead-in cycle 1, p = 0.001) and OS (BRAFV600 ctDNA positive = 17.8 mos; 95% CI 9.76-NA, BRAFV600 ctDNA negative = not reached; 95% CI NA-NA, p = 0.0021)....The absence of detectable BRAFV600 ctDNA at baseline is associated with improved PFS and OS in patients receiving treatment with dabrafenib and trametinib .

S1320 is a randomized phase 2 clinical trial designed to determine whether intermittent versus continuous dosing of dabrafenib and trametinib improves progression-free survival (PFS) in patients with advanced BRAFV600E/K melanoma….Continuous dosing with the BRAF and MEK inhibitors dabrafenib and trametinib yields superior PFS compared with intermittent dosing.

Furthermore, adjuvant-targeted therapy with dabrafenib and trametinib has improved survival outcomes in BRAFV600E and BRAFV600K-mutated melanomas. Three neoadjuvant trials have all shown high response rates, including complete responses, after short-term combination therapy with ipilimumab and nivolumab with no recurrences so far, although follow-up is still short.