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

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). We conducted a phase I/II clinical trial in four centers of HCQ +...

Full description

Saved in:
Bibliographic Details
Published in:Clinical cancer research Vol. 28; no. 6; p. 1098
Main Authors: Mehnert, Janice M, Mitchell, Tara C, Huang, Alexander C, Aleman, Tomas S, Kim, Benjamin J, Schuchter, Lynn M, Linette, Gerald P, Karakousis, Giorgos C, Mitnick, Sheryl, Giles, Lydia, Carberry, Mary, Frey, Noelle, Kossenkov, Andrew, Groisberg, Roman, Hernandez-Aya, Leonel F, Ansstas, George, Silk, Ann W, Chandra, Sunandana, Sosman, Jeffrey A, Gimotty, Phyllis A, Mick, Rosemarie, Amaravadi, Ravi K
Format: Journal Article
Language:English
Published: United States 15.03.2022
Subjects:
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Autophagy
Humans
Hydroxychloroquine - therapeutic use
Imidazoles
Melanoma - drug therapy
Melanoma - genetics
Melanoma - pathology
Mitogen-Activated Protein Kinase Kinases
Mutation
Oximes - therapeutic use
Proto-Oncogene Proteins B-raf - genetics
Pyridones - therapeutic use
Pyrimidinones - therapeutic use
ISSN:1557-3265, 1557-3265
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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). 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%. 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. 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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1557-3265
1557-3265
DOI:10.1158/1078-0432.CCR-21-3382