Xentuzumab (BI 836845)

Xentuzumab (BI 836845)

Xentuzumab: a humanized monoclonal antibody targeting IGF-1 and IGF-2

Xentuzumab* (BI 836845) is a humanized immunoglobulin G (IgG) 1 monoclonal antibody (mAb) that targets insulin-like growth factor (IGF) ligands IGF-1 and IGF-2, which are implicated in tumor proliferation, migration and invasion.1–3

Clinical trials: several Phase I and II clinical trials are underway to evaluate xentuzumab in the treatment of solid tumors, NSCLC, breast cancer, castrate resistant prostate cancer, and advanced solid tumors.4-8

Role of IGF signaling

Increased expression of IGF-1 and IGF-2 is implicated in tumor proliferation, migration and invasion; high IGFR expression has been observed in solid tumors and hematological malignancies.1,9-11 The IGF-1 and IGF-2 ligands bind to and activate insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor A (IR-A), respectively.1 These IGF receptors (IGFRs) activate pathways, including the RAS/RAF/MEK/ERK and phosphinositide-3 kinase (PI-3K) pathways, which are involved in cell proliferation, growth and survival.2,3

About xentuzumab

Mechanism of action

Xentuzumab binds to IGF-1 and IGF-2 with high affinity, preventing the activation of the receptors IGF-1R and IR-A, respectively.1 This inhibits downstream signaling that would otherwise result in cell growth, proliferation and survival. 2,3,7

Xentuzumab has shown potent anti-proliferative effects (at low nmol/L effective concentration [EC50]) against a range of cancer cell lines, including NSCLC, squamous cell lung carcinoma (SCLC) and multiple myeloma.1

IGF pathway diagram12

Xentuzumab’s mechanism of action
IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1 receptor; IGF-2, insulin-like growth factor 2; IR-A, insulin receptor A.

Watch xentuzumab’s mechanism of action

Watch xentuzumab’s mechanism of action

Potential advantage of xentuzumab over other IGF pathway inhibition strategies

Xentuzumab’s high-affinity binding to IGF-1 and -2 may offer potential benefits over other IGF pathway inhibition strategies. Small-molecule TKIs, for example, offer non-selective inhibition of all receptors in the IGF axis, while IGF-1R mAbs do not inhibit the IR-A-mediated signaling pathway.13 In contrast, xentuzumab inhibits both IGF-1R- and IR-A-mediated pathways, but spares insulin receptor B (IR-B),3 which regulates glucose metabolism and whose inhibition can cause metabolic toxicity.


Combination Therapy

Dysregulation of IGF signaling has been shown to be associated with acquired resistance to hormone therapy in breast cancer.14-17 The addition of a cyclin-dependent kinase (CDK) inhibitor (e.g. abemaciclib) to inhibit the cell cycle could be an effective strategy to circumvent resistance.17 Targeting the mammalian target of rapamycin (mTOR) pathway with everolimus may also prevent resistance; clinical trials have shown that hormone therapy improves progression-free survival (PFS) when combined with the mTOR antagonist everolimus.17

Clinical development

Preliminary antitumor activity of xentuzumab has been reported in solid tumors.18 Phase I dose-escalation studies in Asian and European patients have established a recommended Phase II dose of 1,000 mg/week (intravenous administration).19,20 Ongoing clinical trials are evaluating xentuzumab for the treatment of patients with hormone receptor-positive breast cancer, castrate resistant prostate cancer with increased PSA, and metastatic/advanced solid tumors.4-8

More information about Boehringer Ingelheim oncology clinical trials can be found on the MyStudyWindow website. Relevant trials for xentuzumab include: BI 1280-0022 and BI 1280-0018.


Xentuzumab (BI 836845) clinical trials in metastatic breast cancer

HER, human epidermal growth factor receptor; HR, hormone receptor; PSA, prostate serum antigen.
Trial number Phase Treatment Patient population Status

NCT02145741 (1280.15) 4



Advanced solid tumours

Active, not recruiting

NCT02204072 (1280.8) 5


Xentuzumab + enzalutamide

Castrate resistant prostate cancer with increased PSA

Active, not recruiting

NCT02123823 (1280.4)5



Xentuzumab + exemestane + everolimus

Postmenopausal women with non-resectable and/or metastatic HER2− and HR+ breast cancer

Active, not recruiting

XENERA™-1 NCT03659136 (1280.22)8


Xentuzumab + exemestane + everolimus

Postmenopausal women with HR+/PgR+ and HER2– locally advanced or metastatic breast cancer (non-visceral disease)

Active, not recruiting

NCT03099174 (1280.18)7


Xentuzumab + abemaciclib ± hormonal therapy (letrozole, anastrozole, fulvestrant)

Locally advanced or metastatic solid tumors (dose finding part); locally advanced or metastatic HR+, HER2− breast cancer (expansion cohorts)


Xentuzumab (BI 836845) Key Results

Xentuzumab was associated with antitumor activity and a manageable safety profile in combination with exemestane and everolimus in initial results from a Phase Ib part of a trial in breast cancer (NCT02123823).17 However, the Phase II part of this trial was stopped early due to lack of efficacy in a planned interim analysis.21 In the primary analysis the trial did not meet its primary endpoint: median PFS was not significantly different in the xentuzumab arm compared with the control arm in the overall patient population (7.3 months [95% confidence interval (CI): 3.3‒not calculable; n=70] vs 5.6 months [95% CI: 3.7‒9.1; n=70]; hazard ratio [HR]=0.97 [95% CI: 0.57‒1.65]; p=0.906).21 Interestingly, a prespecified subgroup analysis showed that xentuzumab + exemestane + everolimus arm (n=17) demonstrated favorable PFS versus the control arm (exemestane + everolimus; n=16) in breast cancer patients with non-visceral metastases subgroup (HR=0.21 [95% CI: 0.05‒0.98]; p=0.029).21

The xentuzumab and control arms had similar safety profiles. Treatment-related adverse events occurred in 96% of patients in each arm.22 The most common adverse events were diarrhea and mucosal inflammation in the xentuzumab arm, and stomatitis and asthenia in the control arm.22 Grade ≥3 AEs occurred in 60% of patients in the xentuzumab arm and 58% of patients in the control arm, with SAEs occurring in 26% and 42% of patients in each arm, respectively.22 Two deaths (attributable to pneumonitis and liver injury were reported for the xentuzumab arm, and three deaths (attributable to Burkitt’s lymphoma, acute kidney injury, and peritoneal metastases) for the control arm.22

A separate, ongoing Phase II study (NCT03659136)8 is investigating the efficacy and safety of xentuzumab combined with exemestane and everolimus in women with hormone receptor-positive, human epidermal growth factor receptor (HER) 2-negative, locally advanced/metastatic breast cancer with non-visceral disease.


Pre-specified subgroup analysis of PFS with xentuzumab + exemestane + everolimus in patients with breast cancer and non-visceral metastases

PFS in patients with HER2– breast cancer and non-visceral metastases treated with xentuzumab combined with exemestane and everolimus
The study’s primary outcome was PFS by independent review of the entire study population. This pre-specified subgroup analysis was not a primary or secondary outcome measure. CI, confidence interval; Ev, everolimus; Ex, exemestane; HR, hazard ratio; LCL, lower confidence limit; NC, not calculable; PFS, progression-free survival; UCL, upper confidence limit; Xen, xentuzumab.

Explore our latest xentuzumab data

Our latest data on xentuzumab (BI 836845) were presented at the American Society of Clinical Oncology Annual Meeting 2021.

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Friedbichler K, et al. Mol Cancer Ther 2014;13(2):399–409.


Sachdev D, Yee D. Mol Cancer Ther 2007;6(1):1–12.


Gao J, et al. Cancer Res 2012;72(1):3–12.


ClinicalTrials.gov. NCT02145741. https://clinicaltrials.gov/ct2/show/study/NCT02145741 (Accessed: September 2021).


ClinicalTrials.gov NCT02204072. https://clinicaltrials.gov/ct2/show/study/NCT02204072 (Accessed: September 2021).


ClinicalTrials.gov. NCT02123823. https://clinicaltrials.gov/ct2/show/study/NCT02123823 (Accessed: September 2021).


ClinicalTrials.gov. NCT03099174. https://clinicaltrials.gov/ct2/show/study/NCT03099174 (Accessed: September 2021).


ClinicalTrials.gov. NCT03659136. https://clinicaltrials.gov/ct2/show/study/NCT03659136 (Accessed: September 2021).


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Sachdev D, Yee D. Mol Cancer Ther 2007;6:1–12.


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Denduluri SK, et al. Genes Dis 2015;2(1):13–25.


Schmid P, et al. Breast Cancer Res 2021;23(1):8.


Lin C-C, et al. J Clin Oncol 2014;32(Suppl. 15):2617.


Doi T, et al. Ann Oncol 2016;27(Suppl. 6):374P.


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Crown J, et al. Poster presentation at the San Antonio Breast Cancer Symposium 2018 (Poster P6-21-01).


Cortes J, et al. J Clin Oncol 2016;34(Suppl. 15): Abstract 530.

*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.


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Page last updated: September 2021