Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib

Abstract

Purpose To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600-mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. Patients and Methods BRAF inhibitor-naive patients with BRAF V600-mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2). Patients who received D monotherapy could cross over to D + T 150/2 postprogression. Efficacy and safety were analyzed 4 and 5 years after initiation in patients with ≥ 5 years of follow-up. Results As of October 13, 2016, 18 patients who received D + T 150/2 remained in the study (13 [24%] of 54 enrolled at this dose plus five [11%] of 45 initially administered D who crossed over to D + T). With D + T 150/2, overall survival (OS; 4 years, 30%; 5 years, 28%) and progression-free survival (4 and 5 years, both 13%) appeared to stabilize with extended follow-up. Increased OS was observed in patients who received D + T with baseline normal lactate dehydrogenase (5 years, 45%) and normal lactate dehydrogenase with fewer than three organ sites with metastasis (5 years, 51%). With extended follow-up, one additional patient who received D + T 150/2 improved from a partial to a complete response. No new safety signals were observed. Conclusion This 5-year analysis represents the longest follow-up to date with BRAF + MEK inhibitor combination therapy in BRAF V600-mutant MM. Consistent with trends observed in landmark analyses with shorter follow-up, this therapy elicits durable plateaus of long-term OS and progression-free survival that last ≥ 5 years in some patients with MM.

Trial registration: ClinicalTrials.gov NCT01072175.

Fig 1.

(A) Progression-free survival and (B) overall survival in the intention-to-treat population. D, dabrafenib; D + T 150/1, dabrafenib 150 mg twice a day plus trametinib 1 mg once daily; D + T 150/2, dabrafenib 150 mg twice a day plus trametinib 2 mg once daily.

Fig 2.

Association of selected patient baseline characteristics on progression-free survival and overall survival in the dabrafenib plus trametinib (D + T) and D monotherapy arms in the intention-to-treat population. (A and D) Patients with normal baseline lactate dehydrogenase (LDH) levels (less than or equal to the upper limit of normal [ULN]). (B and E) Patients with normal baseline LDH levels and fewer than three organ sites with metastasis. (C and F) Patients with elevated baseline LDH (greater than ULN). Patients who progressed on D monotherapy and crossed over to the D 150 mg twice a day plus T 2 mg once daily (D + T 150/2) arm were included and not censored at crossover. D + T 150/1, dabrafenib 150 mg twice a day plus trametinib 1 mg once daily.

Fig A1.

Study schema for part C of the BRF113220 trial. *Randomized arm not included in this analysis. D, dabrafenib; D + T 150/1, dabrafenib 150 mg twice a day plus trametinib 1 mg once daily; D + T 150/2, dabrafenib 150 mg twice a day plus trametinib 2 mg once daily.