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

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.

Keywords: Breast cancer; HER2-negative; Hormone receptor-positive; Insulin-like growth factor; Xentuzumab.

Conflict of interest statement

PS declares an advisory council or committee role for Pfizer, AstraZeneca, Novartis, Roche/Genentech, MSD, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; has received honoraria and consulting fees from Pfizer, AstraZeneca, Novartis, Roche/Genentech, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; and has received grants or research funds for his institution from AstraZeneca, Roche, Genentech, Oncogenex, Novartis, and Astellas.

JB declares that his institute received payments from Boehringer Ingelheim for conducting this trial, and his institutes (Karolinska University Hospital and/or Karolinska Institutet) have received unrestricted research grants to perform academic clinical studies/spin-off studies from Amgen, AstraZeneca, Bayer HealthCare, Merck, Roche, Pfizer, and Sanofi Aventis.

S-AI declares an advisory council or committee role for AstraZeneca, Hanmi, Novartis, MediPacto, Roche, and Pfizer; has received consulting fees from AstraZeneca, Amgen, Hanmi, Novartis, MediPacto, Eisai, Roche, and Pfizer; and has received grants or research funds from AstraZeneca, Roche, and Pfizer.

Y-SL declares an advisory council or committee role for Boehringer Ingelheim and Novartis; has received honoraria from Novartis, Pfizer, Roche, Merck Sharp & Dohme, and Eisai; has received consulting fees from Novartis, Pfizer, Roche, and Merck Sharp; has received grants or research funds from Novartis and Roche, and grants from Merck Sharp & Dohme; and has received travel grants or lecture fees from Novartis, Pfizer, Roche, Merck Sharp & Dohme, and Eisai.

NM declares an advisory council or committee role for Eisai, AstraZeneca, Roche, Pfizer, and Novartis.

PN declares an advisory council or committee role and has received consulting fees (with payment to his institution) for Novartis, Pfizer, and Eli Lilly; he has received grants or research funds from Kom op Tegen Kanker Fund.

KSL has received consulting fees from Roche, Lilly, and Novartis and has received grants or research funds from Dong-A ST.

JAP-F is a member of a Steering Committee for two trials for AstraZeneca and Karyopharm; has received honoraria from AstraZeneca, Tesaro, Pharmamar, Roche, and Gilead; and has received consulting fees from AstraZeneca, Clovis, Roche, and Tesaro.

DA declares research funding from Boehringer Ingelheim and Roche.

AG declares receipt of travel grants from Roche, Novartis, Pfizer, and AstraZeneca.

AP declares advisory council or committee roles for Nanostring Technologies, Roche, Novartis, Pfizer, Oncoloytics Biotech, Amgen, Lilly, MSD, PUMA, and Daiichi Sankyo, Inc, and grants or research funds from Nanostring Technologies, Roche, and Novartis.

GJ declares honoraria from Novartis, Roche, Lilly, Pfizer, Amgen, and Bristol-Myers Squibb; an advisory role for Novartis, Roche, Amgen, Pfizer, Bristol-Myers Squibb, Lilly, AstraZeneca, Daiichi Sankyo, and Abbvie; research funding from Roche and Pfizer; and travel, accommodation, or expenses from Novartis, Roche, Pfizer, and Lilly.

LS is employed on behalf of Boehringer Ingelheim.

R-ME and DC-LH are employees of Boehringer Ingelheim.

TB is a former employee of Boehringer Ingelheim and holds a patent for xentuzumab.

JC declares employment and ownership of stock/shares with Oncomark Limited; is on the Board of Directors for Cancer Clinical Research Trust and Cancer Trials Ireland; has received honoraria from Eisai, Amgen, Puma Biotechnology, Seattle Genetics, Boehringer Ingelheim, Pfizer, Vertex Pharmaceuticals, Genomic Health, G1 therapeutics, AstraZeneca, Roche, MSD Oncology, and Pierre Fabre; has a consulting or advisory role with Eisai, Puma Biotechnology, Boehringer Ingelheim, Pfizer, Vertex Pharmaceuticals, Roche, Seattle Genetics, and Novartis; is part of the Speaker’s bureau for Pfizer, Eisai, and Genomic Health; has received research funding from Roche, Eisai, Boehringer Ingelheim, and Puma Biotechnology; and has received travel, accommodation, and expenses from MSD, Pfizer, Roche, AstraZeneca, Abbvie, Novartis, and Pierre Fabre.

JCo is a consultant/advisor for Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp & Dohme, GSK, and Leuko; has received honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, and Daiichi Sankyo; has received research funding to his institution from Roche, Aria Pharmaceuticals, AstraZeneca, Baxalta, GMBH/Servier Affaires, Bayer HealthCare, Eisai, F Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London, and Seagen; and holds stock, patents, or intellectual property with MedSIR.

M-PS and SM have no conflicts of interest to declare.

Figures

Fig. 1

PFS in a all patients, b patients without visceral involvement, and c patients with visceral involvement. Data are from phase II part. CI, confidence interval; HR, hazard ratio; n.c., not calculable; PFS, progression-free survival

Fig. 2

Subgroup analysis for PFS. Data are for phase II part; [1] overall results calculated as in the primary model analysis. ECOG, Eastern Cooperative Oncology Group; PFS, progression-free survival