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Abstract Background Xentuzumab is a humanised monoclonal antibody that binds to IGF-1 and IGF-2, neutralising their proliferative activity and restoring inhibition of AKT by everolimus. This study evaluated the addition of xentuzumab to everolimus and exemestane in patients with advanced breast cancer with non-visceral disease. Methods This double-blind, randomised, Phase II study was undertaken in female patients with hormone-receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative advanced breast cancer with non-visceral disease who had received prior endocrine therapy with or without CDK4/6 inhibitors. Patients received a weekly intravenous infusion of xentuzumab (1000 mg) or placebo in combination with everolimus (10 mg/day orally) and exemestane (25 mg/day orally). The primary endpoint was progression-free survival (PFS) per independent review. Results A total of 103 patients were randomised and 101 were treated (n = 50 in the xentuzumab arm and n = 51 in the placebo arm). The trial was unblinded early due to high rates of discordance between independent and investigator assessment of PFS. Per independent assessment, median PFS was 12.7 (95% CI 6.8–29.3) months with xentuzumab and 11.0 (7.7–19.5) months with placebo (hazard ratio 1.19; 95% CI 0.55–2.59; p = 0.6534). Per investigator assessment, median PFS was 7.4 (6.8–9.7) months with xentuzumab and 9.2 (5.6–14.4) months with placebo (hazard ratio 1.23; 95% CI 0.69–2.20; p = 0.4800). Tolerability was similar between the arms, with diarrhoea (33.3–56.0%), fatigue (33.3–44.0%) and headache (21.6–40.0%) being the most common treatment-emergent adverse events. The incidence of grade ≥ 3 hyperglycaemia was similar between the xentuzumab (2.0%) and placebo (5.9%) arms. Conclusions While this study demonstrated that xentuzumab could be safely combined with everolimus and exemestane in patients with HR-positive/HER2-negative advanced breast cancer with non-visceral disease, there was no PFS benefit with the addition of xentuzumab. Trial registration ClinicalTrials.gov, NCT03659136. Prospectively registered, September 6, 2018.

Background: Xentuzumab is a humanised monoclonal antibody that binds to IGF-1 and IGF-2, neutralising their proliferative activity and restoring inhibition of AKT by everolimus. This study evaluated the addition of xentuzumab to everolimus and exemestane in patients with advanced breast cancer with non-visceral disease. Methods: This double-blind, randomised, Phase II study was undertaken in female patients with hormone-receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative advanced breast cancer with non-visceral disease who had received prior endocrine therapy with or without CDK4/6 inhibitors. Patients received a weekly intravenous infusion of xentuzumab (1000 mg) or placebo in combination with everolimus (10 mg/day orally) and exemestane (25 mg/day orally). The primary endpoint was progression-free survival (PFS) per independent review. Results: A total of 103 patients were randomised and 101 were treated (n = 50 in the xentuzumab arm and n = 51 in the placebo arm). The trial was unblinded early due to high rates of discordance between independent and investigator assessment of PFS. Per independent assessment, median PFS was 12.7 (95% CI 6.8–29.3) months with xentuzumab and 11.0 (7.7–19.5) months with placebo (hazard ratio 1.19; 95% CI 0.55–2.59; p = 0.6534). Per investigator assessment, median PFS was 7.4 (6.8–9.7) months with xentuzumab and 9.2 (5.6–14.4) months with placebo (hazard ratio 1.23; 95% CI 0.69–2.20; p = 0.4800). Tolerability was similar between the arms, with diarrhoea (33.3–56.0%), fatigue (33.3–44.0%) and headache (21.6–40.0%) being the most common treatment-emergent adverse events. The incidence of grade ≥ 3 hyperglycaemia was similar between the xentuzumab (2.0%) and placebo (5.9%) arms. Conclusions: While this study demonstrated that xentuzumab could be safely combined with everolimus and exemestane in patients with HR-positive/HER2-negative advanced breast cancer with non-visceral disease, there was no PFS benefit with the addition of xentuzumab. Trial registration ClinicalTrials.gov, NCT03659136. Prospectively registered, September 6, 2018. [ABSTRACT FROM AUTHOR]

Abstract Background Xentuzumab—a humanised IgG1 monoclonal antibody—binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). Methods Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). Results MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3–not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7–9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57–1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05–0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). Conclusions Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). Trial registration ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.

Xentuzumab is an insulin‐like growth factor (IGF) ligand‐neutralizing antibody. This phase 1 trial assessed xentuzumab in Japanese patients with solid tumors. Patients aged ≥20 y old with solid tumors that were refractory or not amenable to standard therapy were enrolled. Patients received xentuzumab intravenously at a starting dose of 750 mg/wk. Dose escalation used a 3 + 3 design with dose de‐escalation. The primary endpoint was to determine the maximum tolerated dose (MTD) of xentuzumab. Safety, pharmacokinetics, pharmacodynamics, and anti‐tumor activity were also assessed. Fifteen patients received xentuzumab in the dose escalation part (750 mg/wk [n = 6]; 1000 mg/wk [n = 3]; 1400 mg/wk [n = 6]). There were no dose‐limiting toxicities at any dose; the MTD of xentuzumab was not reached. Xentuzumab 1000 mg/wk was recommended as the relevant biological dose. Six further patients received xentuzumab 1000 mg/wk in an expansion cohort. Of 21 patients, 13 (61.9%) experienced a drug‐related adverse event, most commonly fatigue (23.8%), neutropenia (19.0%), diarrhea, nausea, white blood cell count decrease, and muscle spasms (14.3% each). No relevant deviations from dose linearity of xentuzumab exposure were observed during dose escalation. Total IGF‐1 and IGF‐2 levels increased and bioactive IGF levels decreased from baseline to 24 h after the first infusion in cycle 1. Partial response was observed in 2 (9.5%) patients with desmoid‐type fibromatosis. Disease control was achieved in 6 (28.6%) patients (median duration 42.4 mo). Xentuzumab monotherapy was well tolerated in Japanese patients and showed evidence of anti‐tumor activity. This study was registered with www.clinicaltrials.gov (NCT02145741). [ABSTRACT FROM AUTHOR]

Introduction: Insulin-like growth factor signaling has been implicated in acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. This phase 1 trial (NCT02191891) investigated the combination of xentuzumab (an insulin-like growth factor-ligand neutralizing monoclonal antibody) and afatinib (an EGFR TKI) in patients with previously treated EGFR mutation-positive NSCLC. Methods: The trial comprised dose escalation (part A) and expansion (part B). Patients had advanced or metastatic NSCLC that had progressed on EGFR TKI monotherapy or platinum-based chemotherapy (nonadenocarcinoma only, part A) or irreversible EGFR TKI monotherapy (part B). Absence of EGFR T790M mutation was required in part B. Part A used a 3 + 3 design, with a starting dose of xentuzumab 1000 mg/wk (intravenous) and afatinib 30 mg/d (oral). Primary endpoints were the maximum tolerated dose of the combination (part A) and objective response (part B). Results: A total of 16 patients each were treated in parts A and B. Maximum tolerated dose was xentuzumab 1000 mg/wk plus afatinib 40 mg/d. No patients in part B had an objective response, but 10 had stable disease (median [range] duration of disease control: 2.3 [0.8–10.9] mo). The most common drug-related adverse events were diarrhea (75 %), paronychia (69 %), and rash (69 %) in part A and diarrhea (31 %), rash (19 %), paronychia (19 %), and fatigue (19 %) in part B. Conclusions: There were no new safety issues; xentuzumab and afatinib could be safely coadministered. Nevertheless, the combination revealed only modest activity in patients with EGFR mutation-positive, T790M-negative NSCLC after progression on afatinib.

Background: Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC).Methods: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS).Results: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]).Conclusions: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136).Trial Registration: ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013. [ABSTRACT FROM AUTHOR]

Objectives: Patients failing radiotherapy for laryngeal squamous cell carcinoma (LSCC) often require salvage total laryngectomy which has major functional consequences, highlighting a need for biomarkers of radiotherapy resistance. In other tumour types, radioresistance has been linked to epidermal growth factor receptor (EGFR) and type 1 insulin‐like growth factor receptor (IGF‐1R). Here, we evaluated IGF‐1R and EGFR as predictors and mediators of LSCC radioresistance. Design: We compared IGF‐1R and EGFR immunohistochemical scores in patients with LSCC achieving long‐term remission post‐radiotherapy (n = 23), patients treated with primary laryngectomy (n = 22) or salvage laryngectomy following radiotherapy recurrence (n = 18). To model radioresistance in vitro, two LSCC cell lines underwent clinically relevant irradiation to 55 Gy in 2.75 Gy fractions. Results: Type 1 insulin‐like growth factor receptor expression was higher in pre‐treatment biopsies of radiotherapy failures compared with those in long‐term remission and was upregulated post‐radiotherapy. Patients undergoing primary laryngectomy had more advanced T/N stage and greater tumour IGF‐1R content than those achieving long‐term remission. Pre‐treatment EGFR did not associate with radiotherapy outcomes but showed a trend to upregulation post‐irradiation. In vitro, radiosensitivity was enhanced by inhibition of EGFR but not IGF. Repeated irradiation upregulated IGF‐1R in BICR18 and SQ20B cells and EGFR in SQ20B, and enhanced SQ20B radioresistance. Repeatedly irradiated SQ20B_55 cells were not radiosensitised by inhibition of IGF and/or EGFR, but IGF‐1R:EGFR co‐inhibition suppressed baseline cell survival more effectively than blockade of either pathway alone, and more effectively than in parental cells. Conclusions: Radiation upregulates IGF‐1R and may enhance IGF/EGFR dependence, suggesting that IGF/EGFR blockade may have activity in LSCCs that recur post‐radiotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Insulin-like growth factor signaling has been implicated in acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. This phase 1 trial (NCT02191891) investigated the combination of xentuzumab (an insulin-like growth factor-ligand neutralizing monoclonal antibody) and afatinib (an EGFR TKI) in patients with previously treated EGFR mutation-positive NSCLC., Methods: The trial comprised dose escalation (part A) and expansion (part B). Patients had advanced or metastatic NSCLC that had progressed on EGFR TKI monotherapy or platinum-based chemotherapy (nonadenocarcinoma only, part A) or irreversible EGFR TKI monotherapy (part B). Absence of EGFR T790M mutation was required in part B. Part A used a 3 + 3 design, with a starting dose of xentuzumab 1000 mg/wk (intravenous) and afatinib 30 mg/d (oral). Primary endpoints were the maximum tolerated dose of the combination (part A) and objective response (part B)., Results: A total of 16 patients each were treated in parts A and B. Maximum tolerated dose was xentuzumab 1000 mg/wk plus afatinib 40 mg/d. No patients in part B had an objective response, but 10 had stable disease (median [range] duration of disease control: 2.3 [0.8-10.9] mo). The most common drug-related adverse events were diarrhea (75 %), paronychia (69 %), and rash (69 %) in part A and diarrhea (31 %), rash (19 %), paronychia (19 %), and fatigue (19 %) in part B., Conclusions: There were no new safety issues; xentuzumab and afatinib could be safely coadministered. Nevertheless, the combination revealed only modest activity in patients with EGFR mutation-positive, T790M-negative NSCLC after progression on afatinib., (© 2021 by the International Association for the Study of Lung Cancer.)