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Objective The arginase inhibitor INCB001158 was evaluated for safety (primary endpoint) in locally advanced or metastatic solid tumours; pharmacokinetics, pharmacodynamics and efficacy were also assessed.Methods and analysis In this non-randomised, open-label, three-part phase 1 study, INCB001158 was orally administered two times per day as monotherapy or in combination with intravenous pembrolizumab 200 mg every 3 weeks. Dose expansion was conducted in tumour-type cohorts (with or without prior anti−PD-1/PD-L1 (programmed death protein 1/programmed death ligand 1) therapy).Results A total of 107 patients received INCB001158 50–150 mg two times per day as monotherapy, and 153 patients, including 6 with moderate renal impairment, received INCB001158 50–100 mg two times per day combined with pembrolizumab. INCB001158 exposure was similar between groups (median, 56 days (monotherapy); 84 days (combination)). 49 patients (45.8%) on monotherapy and 76 (51.7%) on combination therapy experienced grade ≥3 treatment-emergent adverse events (AEs). The most common INCB001158-related AEs were fatigue (n=10/107 (9.3%)) and nausea (n=10/107 (9.3%)) with monotherapy and diarrhoea (n=24/147 (16.3%)) and fatigue (n=22/147 (15.0%)) with combination therapy. The highest response rate was seen in the anti–PD-1/PD-L1–naive combination therapy group with head/neck squamous cell carcinoma (overall response rate, 19.2%; 4/26 partial responses, 1/26 complete response). Consistent with arginase inhibition activity, plasma arginine dose-dependently increased. Arginase 1 expression in the tumour microenvironment did not correlate with response.Conclusions INCB001158 was generally well tolerated. Response rates did not exceed background for given tumour types despite demonstrable pharmacodynamic activity. Overall, the limited antitumour activity of arginase inhibition observed suggests that the role of arginine depletion in cancer is multifaceted.Trial registration number NCT02903914.

Background Pancreatic ductal adenocarcinoma (PDAC) is a challenging target for immunotherapy because it has an immunosuppressive tumor microenvironment. Neoadjuvant chemoradiotherapy can increase tumor-infiltrating lymphocyte (TIL) density, which may predict overall survival (OS). We hypothesized that adding programmed cell death protein 1 (PD-1) blockade to chemoradiotherapy would be well tolerated and increase TILs among patients with localized PDAC.Methods Patients were randomized 2:1 to Arm A (receiving pembrolizumab plus chemoradiotherapy (capecitabine and external beam radiation)) or Arm B (receiving chemoradiotherapy alone) before anticipated pancreatectomy. Primary endpoints were (1) incidence and severity of adverse events during neoadjuvant therapy and (2) density of TILs in resected tumor specimens. TIL density was assessed using multiplexed immunofluorescence histologic examination.Results Thirty-seven patients were randomized to Arms A (n=24) and B (n=13). Grade ≥3 adverse events related to neoadjuvant treatment were experienced by 9 (38%) and 4 (31%) patients in Arms A and B, respectively, with one patient experiencing dose-limiting toxicity in Arm A. Seventeen (71%) and 7 (54%) patients in Arms A and B, respectively, underwent pancreatectomy. Median CD8+ T-cell densities in Arms A and B were 67.4 (IQR: 39.2–141.8) and 37.9 (IQR: 22.9–173.4) cells/mm2, respectively. Arms showed no noticeable differences in density of CD8+Ki67+, CD4+, or CD4+FOXP3+ regulatory T cells; M1-like and M2-like macrophages; or granulocytes. Median OS durations were 27.8 (95% CI: 17.1 to NR) and 24.3 (95% CI: 12.6 to NR) months for Arms A and B, respectively.Conclusions Adding pembrolizumab to neoadjuvant chemoradiotherapy was safe. However, no convincing effect on CD8+ TILs was observed.

Immune checkpoint blockade immunotherapy has radically changed patient outcomes in multiple cancer types. Pancreatic cancer is one of the notable exceptions, being protected from immunotherapy by a variety of mechanisms, including the presence of a dense stroma and immunosuppressive myeloid cells. Previous studies have demonstrated that CD40 stimulation can remodel the tumor microenvironment in a manner that promotes effector immune cell responses and can cooperate with immune checkpoint inhibition for durable tumor control mediated by T cells. Here we confirm the capability of this combination therapy to dramatically, and durably, control pancreatic cancer growth in an orthotopic model and that the immune memory to this cancer is primarily a function of CD4+ T cells. We extend this understanding by demonstrating that recruitment of recently primed T cells from the draining lymph nodes is not necessary for the observed control, suggesting that the pre-existing intra-tumoral cells respond to the combination therapy. Further, we find that the efficacy of CD40 stimulation is not dependent upon CD70, which is commonly induced on dendritic cells in response to CD40 agonism. Finally, we find that directly targeting the receptor for CD70, CD27, in combination with the TLR3 agonist polyIC, provides some protection despite failing to increase the frequency of interferon gamma-secreting T cells.