BAMM (BRAF Autophagy and MEK Inhibition in Melanoma): A Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine in Advanced BRAFV600-mutant Melanoma

Abstract

Purpose: Autophagy is a resistance mechanism to BRAF/MEK inhibition in BRAFV600-mutant melanoma. Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg twice daily and trametinib 2 mg every day (D+T).

Patients and methods: We conducted a phase I/II clinical trial in four centers of HCQ + D+T in patients with advanced BRAFV600-mutant melanoma. The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%.

Results: Thirty-four patients were evaluable for one-year PFS rate. Patient demographics were as follows: elevated lactate dehydrogenase: 47%; stage IV M1c/M1d: 52%; prior immunotherapy: 50%. In phase I, there was no dose-limiting toxicity. HCQ 600 mg orally twice daily with D+T was the RP2D. The one-year PFS rate was 48.2% [95% confidence interval (CI), 31.0%-65.5%], median PFS was 11.2 months (95% CI, 5.4-16.9 months), and response rate (RR) was 85% (95% CI, 64%-95%). The complete RR was 41% and median overall survival (OS) was 26.5 months. In a patient with elevated LDH (n = 16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively.

Conclusions: HCQ + D+T was well tolerated and produced a high RR but did not meet criteria for success for the one-year PFS rate. There was a high proportion of patients with pretreated and elevated LDH, an increasingly common demographic in patients receiving targeted therapy. In this difficult-to-treat population, the RR and PFS were encouraging. A randomized trial of D+T + HCQ or placebo in patients with BRAFV600-mutant melanoma with elevated LDH and previous immunotherapy is being conducted.

Figure 1.

CONSORT diagram for the BAMM trial.

Figure 2.

Waterfall and Swimmer's plots for dabrafenib (D), trametinib (T), and hydroxychloroquine (HCQ). A–D, Waterfall showing maximum change in RECIST target lesions. Dashed green line indicates threshold for partial response. A, Entire study population. B, According to LDH status. C, According to prior therapy. D, According to baseline tumor size (BTS) as determined by the sum of the RECIST target lesions on baseline scans. E, Swimmer's plot showing prior therapy, BRAFV600 mutation, LDH status, response, and PFS in each patient. Rx, treatment.

Figure 3.

PFS. A, Entire study population. B, According to LDH status. C, According to prior therapy. D, According to baseline tumor size as determined by the sum of the RECIST target lesions on baseline scans. Tick marks indicate censored patients who never progressed by RECIST criteria at the time of last follow-up. Rx, treatment.