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.

• Authors: Janice M Mehnert, Tara C Mitchell, Alexander C Huang, Tomas S Aleman, Benjamin J Kim, Lynn M Schuchter, Gerald P Linette, Giorgos C Karakousis, Sheryl Mitnick, Lydia Giles, Mary Carberry, Noelle Frey, Andrew Kossenkov, Roman Groisberg, Leonel F Hernandez-Aya, George Ansstas, Ann W Silk, Sunandana Chandra, Jeffrey A Sosman, Phyllis A Gimotty, Rosemarie Mick, Ravi K Amaravadi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 6 Pg. 1098-1106 (03 15 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35022320 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Imidazoles
• Oximes
• Pyridones
• Pyrimidinones
• trametinib
• Hydroxychloroquine
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Mitogen-Activated Protein Kinase Kinases
• dabrafenib

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Autophagy
• Humans
• Hydroxychloroquine (therapeutic use)
• Imidazoles
• Melanoma (drug therapy, genetics, pathology)
• Mitogen-Activated Protein Kinase Kinases
• Mutation
• Oximes (therapeutic use)
• Proto-Oncogene Proteins B-raf (genetics)
• Pyridones (therapeutic use)
• Pyrimidinones (therapeutic use)