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

Abstract

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-inhuman 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.

Phase 1b Open-Label Trial of Afatinib Plus Xentuzumab (BI 836845) in Patients With EGFR Mutation-Positive NSCLC After Progression on EGFR Tyrosine Kinase Inhibitors

“…11 Changes in IGF-axis biomarkers (total IGF-1 and IGF-2, bioactive IGF, and free IGF-1) were consistent with the mechanism of xentuzumab and previous reports. 6 Overall, xentuzumab and afatinib could be safely coadministered, although the combination did not reveal substantial clinical activity in patients with EGFRmþ T790M-negative NSCLC after progression on afatinib. We suggest that such "reversal of resistance" trials represent a novel concept to avoid larger randomized trials for signal detection of rare resistance mechanisms, such as IGF-axis dependency.…”

“… 11 Changes in IGF-axis biomarkers (total IGF-1 and IGF-2, bioactive IGF, and free IGF-1) were consistent with the mechanism of xentuzumab and previous reports. 6 …”

“…Xentuzumab, a humanized monoclonal antibody that targets IGF ligands, IGF-1 and IGF-2, is found to have tolerability and preliminary efficacy in two phase 1 studies. 6 This trial evaluated xentuzumab plus afatinib in patients with previously treated EGFR m+ NSCLC.…”

Growth Hormone/Insulin Growth Factor Axis in Sex Steroid Associated Disorders and Related Cancers

“…Xentuzumab has a binding affinity for both IGF-1 and IGF-2. The advantage of this drug is that it does not target the isoform B of the IR which is involved in glucose metabolism and therefore does not induce the hyperglycaemia and metabolic toxicity observed with IGF-1R targeted therapies or TKIs ( de Bono et al, 2020 ). Xentuzumab has already been evaluated in combination with enzalutamide for the treatment of castration resistant prostate cancer (NCT02204072), however it failed to improve progression free survival over enzalutamide alone.…”

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

“…Similarly, in prostate cancer, xentuzumab + enzalutamide inhibited the growth of castration-resistant patient-derived xenograft (PDX)-derived cells with acquired resistance to enzalutamide and improved in vivo survival [130]. In the clinic, two preliminary studies testing xentuzumab as single agent in advanced solid tumors indicated a good tolerability and preliminary anti-tumor activity [131]. However, a phase Ib/II study indicated that the addition of xentuzumab to everolimus/exemestane did not improve progression free survival in breast cancer patients, leading to early termination of this trial [132].…”