1). In the dose-escalation part of this phase 1b study, Mouse monoclonal to CHD3 vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who experienced progressive disease or stable disease on prior antiCPD-1 therapy. The combination of vidutolimod and pembrolizumab experienced a manageable security profile and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab experienced noninflamed tumors at baseline and induction of an interferon- gene signature following treatment, as well as increased systemic expression of the interferon-inducible chemokine CXCL10. = 31) and B (= 13) (Supplementary Fig. 1) with respect to demographics, baseline characteristics, adverse events (AEs), or treatment response; therefore, these schedules were pooled for analysis. At the time of data cutoff (May 8, 2020), one patient remained on study treatment. The other patients discontinued the study due to PD (52% [23/44]), consent withdrawal per investigator reporting (23% [10/44]), investigator decision (18% [8/44]), or treatment-related adverse events (TRAEs; 5% [2/44]) (Supplementary Fig. 1). Among the patients withdrawing consent, one patient halted after their initial total response (CR) assessment and managed a CR for at least Taranabant ((1R,2R)stereoisomer) another 22 months, and four patients experienced PD prior to study discontinuation. Table 1. Patient Demographics and Baseline Characteristicsa V600E positive, n (%) 05 (31)3 (33)2 (33)6 (60)16 (36)?Received prior BRAF/MEK inhibitor03 (19)1 (11)02 (20)6 (14)LDH levels,b n (%)?Normal/low011 (69)9 (100)3 (50)6 (60)29 (66)?High05 (31)03 (50)4 (40)12 (27)?Unknown3 (100)00003 Taranabant ((1R,2R)stereoisomer) (7)Prior therapies,c n, median (range)2 = 11) and patients with an iRECIST response (= 2). RECIST v1.1 disease status shown was based on investigator assessment. Representative photographs (D) or radiologic imaging (E, F) demonstrating tumor regression of two injected scalp metastases (D), noninjected visceral lung metastases (E), and noninjected liver (F, top) and groin (F, bottom) metastases from three different patients. aFive patients with missing or incomplete postbaseline disease assessments were not included. bPatients experienced initial PD per RECIST v1.1 and were later shown to have a PR per iRECIST as determined by blinded central review (= 2). cPatients with CR experienced less than 100% target lesion regression (target lymph nodes were less than 1.0 cm in diameter and met the RECIST v1.1 definition of CR). EOT, end of treatment; SLD, sum of longest diameters. Table 2. Clinical response with vidutolimod in combination with pembrolizumab = 44)= 3)= 16)= 9)= 6)= 10)(%) (95% CI)0 (12C74)11 (25) = 11) and iRECIST responders (= 2) are included in the CR/PR/iPR group. Horizontal lines show median values (D) Heatmap of gene expression across genes associated with the interferon- pathway and immune cell infiltration for 25 baseline samples taken from 22 patients. Three patients experienced two available biopsy samples each (archival and baseline) and both were analyzed (indicated by brackets underneath the heatmap). Samples (x-axis) were sorted by decreasing frequency of Taranabant ((1R,2R)stereoisomer) CD8+ T cells in the full tissue (measured by immunohistochemistry; bar chart) and by RECIST v1.1 best overall response (colored bars across the top of the determine). PD-L1Cpositive full tissue H-score is also shown (measured by immunohistochemistry). (E) Heatmap of gene expression across paired baseline and on-study tumor biopsies as indicated by pretreatment and posttreatment bars (grey/white) across the top of the physique for 12 biopsies taken from five patients. The responding individual on the left experienced two posttreatment biopsies; the left biopsy was taken from an injected lesion, and the right biopsy was taken from a noninjected lesion. All other posttreatment biopsies were taken from injected lesions. Grey shading is used to indicate the patient identity between (D) and (E). a Below quantitation limit Taranabant ((1R,2R)stereoisomer) values were set to the lower limit of quantitation and Taranabant ((1R,2R)stereoisomer) above quantitation limit values were set to the upper limit of quantitation. bValues capped at 50 for plotting purposes. cInadequate samples for this metric. FPKM, fragments per kilobase of transcript per million.

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