Abstract CT087: Early tumor immune microenvironment (TME) modulation by the BRAF inhibitor (BRAFi) dabrafenib (D) and/or the MEK inhibitor (MEKi) trametinib (T) in patients (pts) with BRAF V600E/K-mutant melanoma in the COMBAT trial
Authors: Robert Caroline , Shen Shensi , Allard Delphine , Fernández Ana Arance , Dutriaux Caroline , Jong Egbert de , Squires Matthew , Grob Jean-Jacques 
Published: August 2018

Abstract
Several trials are evaluating combinations of BRAFi/MEKi and immunotherapy (IO) treatment (Tx) in melanoma. This descriptive biomarker study explored tumor cell and TME modification during BRAFi, MEKi or combination Tx in pts with BRAF V600E/K–mutant unresectable or metastatic melanoma and their potential impact on biomarkers implicated in response to IO. 48 pts enrolled and were randomized 1:1:1 to receive D+T, D, or T (n = 16 each). In the D and T arms, pts received D+T after 8 wk of D or T alone. Tumor biopsies were collected at baseline (BL), wk 2, 8, and 10, and at disease progression. Phosphorylated ERK (pERK), PD-L1, CD8, and CD68 protein expression was analyzed by IHC. RNA expression was assessed by NanoString immune profiling of 770 genes covering adaptive, innate, and humoral immune responses. The primary objectives were to evaluate pERK reduction from BL and characterize safety and efficacy in each Tx arm with changes in pERK H-score. At the final data cutoff, 21 pts (44%) completed the study, including 3 deaths and disease progression. Across Tx arms serious adverse events were reported in 19 pts (40%); no new safety signals were observed. In the biomarker population (pts with BL and ≥ 1 on-Tx biopsy; n = 42), the number of evaluable samples decreased with time due to insufficient tumor material (often due to good tumor response). Due to this limitation, the correlation between biomarker changes and clinical response could not be analyzed, but early biomarker changes are reported. pERK H-score, a MAPK pathway activity marker, decreased from BL to wk 2 in 13 of 17 pts (D, 4/5 pts; T, 6/7 pts; D+T, 3/5 pts) and from BL to wk 8 in 5 of 8 pts (D, 2/3 pts; T, 2/3 pts; D+T, 1/2 pts). IHC showed an early increase in CD8+ and CD68+ cells in the center of tumors compared with the periphery in all 3 arms. Innate immune response, chemotaxis, MHC class II antigen presentation, and complement pathway genes were upregulated. RNA expression of PD-L1, IFNγ pathway genes, and immunosuppressive cytokines IL-6 and CCL2 were slightly increased. Intriguingly, both M1 (IRF5) and M2 (CD163) macrophage genes were upregulated, with an increase of protumoral cytokines (eg, VEGF, TNF) and the MDSC-related cytokine CSF-1. These results indicate that D and T, alone or combined, induced early modification of the melanoma TME, with a tendency to recruit cytotoxic CD8+ cells and increase antigen presentation, which may, however, be offset by induction of immunosuppressive events. Early induction of complement pathways is a novel finding that needs further investigation as it can be both cytotoxic and cytoprotective for tumor cells. These findings provide additional rationale for evaluation of IO and/or agents targeting MDSC following or combined with BRAFi/MEKi in BRAF-mutant melanoma. Additional efficacy and safety analyses will be presented.
Citation Format: Caroline Robert, Shensi Shen, Delphine Allard, Ana Arance Fernández, Caroline Dutriaux, Egbert de Jong, Matthew Squires, Jean-Jacques Grob. Early tumor immune microenvironment (TME) modulation by the BRAF inhibitor (BRAFi) dabrafenib (D) and/or the MEK inhibitor (MEKi) trametinib (T) in patients (pts) with BRAF V600E/K-mutant melanoma in the COMBAT trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT087.