A Phase Ib/II Study of Xentuzumab, an IGF-Neutralising Antibody, Combined With Exemestane and Everolimus in Hormone Receptor-Positive, HER2-Negative Locally Advanced/Metastatic Breast Cancer

Peter Schmid; Marie-Paule Sablin; Jonas Bergh; Seock-Ah Im; Yen-Shen Lu; Noelia Martínez; Patrick Neven; Keun Seok Lee; Serafín Morales; J. Alejandro Pérez-Fidalgo; Douglas Adamson; Anthony Gonçalves; Aleix Prat; Guy Jerusalem; Laura Schlieker; Rosa-Maria Espadero; Thomas Bogenrieder; Dennis Chin-Lun Huang; John Crown; Javier Cortés


Breast Cancer Res. 2021;23(8) 

In This Article

Abstract and Introduction


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.


Standard treatment for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor (HER2)-negative advanced breast cancer is endocrine therapy, using an aromatase inhibitor (AI; e.g. letrozole, anastrozole [non-steroidal], or exemestane [steroidal]), tamoxifen, or fulvestrant.[1] Despite initial benefit, disease progression typically ensues due to acquired endocrine resistance. Additionally, patients may have primary resistance, rendering them unresponsive to endocrine therapy.[2]

Strategies to prevent acquired endocrine resistance include inhibition of cell-cycle progression in breast cancer cells using cyclin-dependent kinase (CDK) inhibitors.[2] The addition of a CDK 4/6 inhibitor (e.g. palbociclib, ribociclib, and abemaciclib) to an AI in endocrine therapy-naïve or endocrine-pre-treated patients, or to fulvestrant in endocrine-pre-treated patients, improved progression-free survival (PFS) and overall survival (OS)[3,4] and is recommended in current treatment guidelines.[1]

Alternatively, treatment or reversal of endocrine resistance may be achieved by targeting molecular pathways that become activated during acquired resistance.[2] While activating ESR1 mutations have emerged as a key mechanism in resistance to AIs (but not to fulvestrant),[5] adaptive signalling via the mammalian target of rapamycin (mTOR)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway also plays an important role.[2] Everolimus, an mTOR inhibitor, is approved in combination with exemestane for advanced breast cancer with endocrine resistance, having demonstrated improved PFS versus exemestane alone in the BOLERO-2 trial;[6,7] however, in contrast to some CDK4/6 inhibitors,[3,4] OS benefit was not observed. Additionally, everolimus was associated with a higher incidence of adverse events (AEs), such as stomatitis, fatigue, and hyperglycaemia. Notably, everolimus plus exemestane has shown similar efficacy irrespective of prior CDK4/6 inhibitor therapy.[8]

Insulin-like growth factor (IGF) signalling can influence cancer progression and prognosis, and drives resistance to various anti-cancer treatments.[9] In breast cancer, regulatory feedback loops between the IGF axis and the mTOR/PI3K/AKT pathway may limit the efficacy of mTOR inhibitor/endocrine therapy combinations due to compensatory IGF ligand-driven signalling.[2,10] Preclinical data also suggest that IGF signalling may have a key role in non-visceral disease, particularly bone and lymph node metastases development.[11,12]

Xentuzumab (BI 836845), a humanised IgG1 monoclonal antibody, binds IGF-1 and IGF-2 ligands with high affinity and potently neutralises their proliferative signalling.[10] Xentuzumab has shown preclinical activity across a range of cancer types.[10] Xentuzumab monotherapy was associated with mild-to-moderate AEs, most commonly gastrointestinal disorders, and preliminary anti-tumour activity in two phase I studies.[13] We hypothesised that combining xentuzumab with everolimus and exemestane would block the negative feedback between IGF and PI3K/AKT/mTOR signalling, thus enhancing sensitivity and/or overcoming endocrine resistance. This phase I/II study (NCT02123823) evaluated the efficacy and safety of xentuzumab plus everolimus and exemestane, versus exemestane and everolimus alone, in women with locally advanced or metastatic breast cancer (MBC).