Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours

BACKGROUND: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. METHODS: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. RESULTS: Study 1280.1 involved 61 patients (part I: xentuzumab 10–1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10–3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. CONCLUSIONS: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity

Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma

Background & Aims: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. Methods: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). Results: Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 >= 1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). Conclusions: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. Lay summary: Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V

Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma

Background & Aims: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. Methods: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). Results: Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 >= 1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). Conclusions: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. Lay summary: Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours

BACKGROUND: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. METHODS: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. RESULTS: Study 1280.1 involved 61 patients (part I: xentuzumab 10–1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10–3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. CONCLUSIONS: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity

Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial

Background: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. Methods: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. Findings: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. Interpretation: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks