Clinical trial results show promise of targeting autophagy BRAF mutant melanoma

Abstract

Macroautophagy/autophagy is a resistance mechanism to targeted therapy in BRAF mutant cancers. Preclinical evidence and clinical trial data demonstrate that hydroxychloroquine (HCQ) is an effective autophagy inhibitor at clinically achievable concentrations. Here we highlight the results of a recently published single-arm phase I/II multi-institution trial of dabrafenib, trametinib, and the autophagy inhibitor HCQ (the BAMM trial) that established the safety and activity of this regimen in BRAF V600-mutant melanoma patients. Compared to the pivotal trials that led to FDA approval of dabrafenib and trametinib, the BAMM trial enrolled a high percentage of patients with elevated LDH and prior immunotherapy, reflecting the trend that poorer-prognosis patients are treated with targeted therapy in the modern era where multiple immunotherapy regimens are available for melanoma. Dabrafenib, trametinib, and hydroxychloroquine are safe and produce a high response rate (85%). Progression-free survival does not meet the pre-specified threshold for the entire cohort but looks especially promising in patients with elevated LDH and prior treatment. A national randomized study has been launched to study this regimen further in poor-prognosis BRAF V600-mutant melanoma patients.

Trial registration: ClinicalTrials.gov NCT02257424.

Keywords: Autophagy; clinical trial; hydroxychloroquine; melanoma; targeted therapy.

Figure 1.

Combined BRAF, MAP2K/MEK and autophagy inhibition in BRAF mutant melanoma. (A) Schematic of concurrent targeting of the MAPK pathway and autophagy. Mu: Mutant. (B) Chest CT images of a stage IV BRAF mutant melanoma patient treated on the BAMM trial with dabrafenib, trametinib and hydroxychloroquine (HCQ). Mo.: Months. Arrow: melanoma metastases to the lung.