First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors.

BACKGROUND: OX40 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. METHODS: Phase 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. RESULTS: Eighty-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. CONCLUSION: No 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 NUMBER: NCT02923349.

Tumour Lysis Syndrome in Occult Breast Cancer Treated With Letrozole - A Rare Occurrence. A Case Report and Review.

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.

Testicular cancer: a 13-year retrospective review of ethnic disparities in the Waikato region, New Zealand.

BACKGROUND: The testicular cancer incidence in New Zealand is rising. We evaluated if testicular cancer outcomes differed by ethnicity in NZ. AIMS: To study if ethnic disparities existed among testicular cancer patients and their outcomes treated at Waikato Regional Cancer Centre. METHODS: Retrospective review of testicular cancer cases in the Medical Oncology database, Waikato Hospital, between 2001 and 2013 inclusive. RESULTS: Three hundred and twenty-five patients were seen, with median follow up of survivors being 101 (range 13-230) months. 95 (29.2%) were Maori, 210 (64.6%) NZ European and 20 (6.1%) of other ethnicity. One hundred and eighty-two patients were diagnosed with seminoma and 143 with non-seminoma. Maori represented 27.5% of seminoma and 31.4% of non-seminoma patients. Median age at diagnosis was 39 years for seminoma and 30 years for non-seminoma; Maori were significantly younger than non- Maori for both seminoma (median age 35 versus 42 years) and non-seminoma (median age 28 vs 34 years, respectively). While stage distribution of seminoma at diagnosis was similar for Maori and non-Maori (chi-squared P = 0.31), significantly more Maori had higher-stage non-seminoma than non-Maori (stage III in 44% and 22%, respectively, chi-squared P = 0.014). Survival for seminoma (logrank P = 0.19) and non-seminoma (logrank P = 0.89) patients did not differ significantly by ethnicity. CONCLUSIONS: Maori patients were younger at diagnosis of testicular cancer and presented with more advanced non-seminoma testicular tumours compared with non-Maori but survival was comparable.