BackgroundOX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949.MethodsPhase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7–1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics.ResultsEighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1–9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs.ConclusionNo safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors.Trial registration numberNCT02923349.

Angiogenesis is integral to tumour growth and invasion, and is a key target for cancer therapeutics. However, for many of the licensed indications, only a modest clinical benefit has been observed for both monoclonal antibody and small-molecule tyrosine kinase inhibitor anti-angiogenic therapy. Pre-clinical and clinical studies have attempted to evaluate circulating, imaging, genomic, pharmacokinetic, and pharmacodynamic markers that may aid both the selection of patients for treatment and define dosing. Correct dosing is likely to be critical in the context of vascular normalization to allow better delivery of concomitant anti-cancer therapy and novel imaging techniques hold much promise in the early evaluation of pharmacodynamic response to improve efficacy.

Tumour lysis syndrome (TLS) is a medical emergency occurring when large numbers of cancer cells rapidly undergo cell death. The resultant metabolic abnormalities results in significant morbidity and mortality. Tumour lysis syndrome most commonly occurs in 5% of haematological malignancies and is less commonly described in solid organ cancers. In breast cancer, TLS has been reported to occur both spontaneously and as a result of cancer chemotherapy, targeted therapy, or radiotherapy. However, only 1 TLS case in a breast cancer patient has been reported as a consequence of aromatase inhibitor letrozole. With the increased recent use of CDK4/6 inhibitors, 2 cases of hyperuricaemia in patients with breast cancer treated with palbociclib/letrozole combination treatment have also been reported. We present the second case of letrozole-induced TLS in a 74-year-old woman with occult breast adenocarcinoma. Despite treatment with recombinant urate oxidase and intravenous fluids, the patient deteriorated and was discharged with hospice care. Although rare, this life-threatening condition should be considered in an acutely unwell patient commencing treatment for solid malignant tumours.