Final results and correlative analysis of entinostat (E) plus pembrolizumab (P) in patients (Pts) with metastatic melanoma (MM) previously treated with anti–PD-(L)1 therapy (Tx).

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9522 Background: PD(L)1 inhibitors have transformed MM tx, yet several pts experience resistance. Preclinical data suggest that epigenetic modifications may overcome this. Here, we present the results of an expansion MM cohort treated with E+P following prior anti-PD(L)1 tx. Methods: Pts with unresectable stage III/IV melanoma, progression to anti-PD(L)1 and BRAF-targeted tx (if BRAF -mutant) were eligible. Pts were treated with E, 5 mg PO qwk, and P, 200 mg IV q3wks. The primary endpoint was to determine the objective response rate (ORR) per the irRECIST criteria. Secondary endpoints included assessment of the safety of E+P tx, progression-free (PFS), and overall survival (OS). Correlative analyses were performed on baseline and on-tx tissues. Results: 53 pts were treated (median [mdn] age, 61 years; 60% male; 55% with ECOG performance status of 0; 64% with visceral metastases; 23% with BRAFV600 mutation), including 43% with primary resistance to anti-PD(L)1 inhibitors, respectively. The mdn number of prior systemic tx was 3 (range 1-8), and 70% of pts had previous tx with CTLA4 inhibitors. 49% pts developed ≥ grade 3/4 toxicity, and 19% pts discontinued at least one drug due to adverse events. 10 pts had a partial (n=9) or complete (n=1) response, for an ORR of 19%. The mdn follow-up was 11.5 months (mon), and the mdn response duration was 23.7 mon (range 2.6-45.6+ mon); 9 pts had stable disease > 6 mon. The mdn PFS and OS were 4.0 and 11.5 mon, respectively. Blood analysis showed that the tx significantly decreased Ki67-PD1+ T cells and T regs and significantly increased Ki67-HLA-DR+ and ICOS+ T cells. Analysis of baseline (n=30) and on-tx (n=10) tumor biopsies using NanoString and/or bulk RNAseq showed increased immune infiltration with tx and increased expression of key genes in antigen presentation ( ß2M ), chemoattraction ( CXCL11 & 13 ), and IFNγ. Hallmark gene set enrichment analysis suggests that pts bearing inflamed, non-proliferating baseline tumors had a more durable clinical benefit to tx (i.e., no disease progression for > 6 mon). Exploratory analysis using quantitative multiplex immunohistochemistry showed that pts with more durable clinical benefit had baseline tumors with a higher lymphoid-to-myeloid (L/M) ratio, and higher numbers of tumor-infiltrating (TI) CD4+ and CD8+ cells, particularly CD8+PD1+ cells. With tx, pt tumors with clinical benefit maintained a higher L/M ratio, had lower TI CD8+PD1+ cells, and increased density of TI CD20+ cells. TI CD8+PD1+ cells increased in pt tumors without clinical benefit. Conclusions: E+P tx in anti-PD(L)1-resistant MM was associated with durable clinical benefit in a pt subset and was well tolerated. Correlative analysis revealed that tx increased inflammation across most analyzed pt tumors; the most significant benefit, however, was observed in pts with pre-existing inflamed tumors. Clinical trial information: NCT02437136 .

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