Neuregulin 1 Expression Is a Predictive Biomarker for Response to AV-203, an ERBB3 Inhibitory Antibody, in Human Tumor Models

Meetze, Kristan; Vincent, Sylvie; Tyler, Steven; Mazsa, Elizabeth K.; Delpero, Andrea R.; Bottega, Steve; McIntosh, Donna; Nicoletti, Richard; Winston, William M.; Weiler, Solly; Feng, Bin; Gyuris, Jenő; Weng, Zhigang

doi:10.1158/1078-0432.ccr-14-2407

Cited by 47 publications

(41 citation statements)

References 52 publications

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“…HER3 expression has been associated with worse clinical outcome, and agents trying to neutralize its activity are in clinical development [9]. The fact that NRGs are the main activating ligands of HER3 suggests that tumors with high levels of NRG could be those that respond better to anti-HER3 therapies [10, 11]. …”

Section: Introductionmentioning

confidence: 99%

Neuregulin expression in solid tumors: Prognostic value and predictive role to anti-HER3 therapies

et al. 2016

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BackgroundNeuregulins (NRG) are a family of epidermal growth factor ligands which act through binding to HER3 and HER4 receptors. NRGs are widely expressed in solid tumors. Their prognostic significance or their role as predictors of benefit from anti-HER3 therapy is not known.ResultsOf 29 included studies, 7 studies reported the association between NRG and outcome. NRG was most commonly expressed in breast, prostate, colon and bladder cancers. NRG expression was not associated with either OS or PFS (HR: 3.47, 95% CI 0.78–15.47, p = 0.10 and HR: 1.64, 95% CI 0.94–2.86, p = 0.08, respectively). In 4 placebo controlled trials of anti-HER3 therapy, the addition of anti-HER3 antibodies to control therapy in unselected patients was not associated with improved PFS (HR: 0.88, 95% CI 0.75–1.04. p = 0.14). However, in patients with high NRG expression, there was significantly delayed progression (HR: 0.35, 95% CI 0.23–0.52, p < 0.001). Anti-HER3 antibodies were associated with increased risk of diarrhea, nausea and rash.MethodsA search of electronically available databases identified studies exploring clinical outcomes based on NRG expression, as well as placebo-controlled trials of HER3-directed therapy reporting results based on NRG expression status. Data were combined in a meta-analysis using generic inverse variance and random effects modeling for studies reporting the hazard ratio (HR) for overall (OS) or progression-free survival (PFS). Mantel-Haenszel random-effect modeling was used for odds ratio (OR) for 3-year and 5-year OS and PFS.ConclusionsNRG expression is not associated with either OS or PFS, but is a predictor of benefit from anti-HER3 antibodies.

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Section: Introductionmentioning

confidence: 99%

Neuregulin expression in solid tumors: Prognostic value and predictive role to anti-HER3 therapies

et al. 2016

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“…AV-203 is a HER3-targeting IgG1 mAb designed to inhibit both liganddependent and ligand-independent HER3 signaling [100]. AV-203 showed preclinical activity in a number of different tumor models including breast, head and neck, lung, ovarian, and pancreatic cancers [100].…”

Section: Av-203mentioning

confidence: 99%

“…AV-203 showed preclinical activity in a number of different tumor models including breast, head and neck, lung, ovarian, and pancreatic cancers [100]. AVEO has completed a Phase 1 safety study showing no doselimiting toxicities at maximum dose of 20 mg/kg and CLIA (Clinical Laboratory Improvements Amendment) validation has been completed for a biomarker for potential patient selection [101].…”

Section: Av-203mentioning

confidence: 99%

HER3/ErbB3, an emerging cancer therapeutic target

Zhang

Chang²,

Rios

et al. 2016

ABBS

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HER3 is a member of the HER (EGFR/ErbB) receptor family consisting of four closely related type 1 transmembrane receptors (EGFR, HER2, HER3, and HER4). HER receptors are part of a complex signaling network intertwined with the Ras/Raf/MAPK, PI3K/AKT, JAK/STAT, and PKC signaling pathways. Aberrant activation of the HER receptors and downstream signaling molecules tips the balance on cellular events, leading to various types of cancers. Monoclonal antibodies (mAbs) and small molecule inhibitors targeting EGFR and HER2 tyrosine kinase activities exhibit clinical benefits in the treatment of several types of cancers, but their clinical efficacy is limited by the occurrence of drug resistance. HER3 is the preferred dimerization partner of HER2 and it is well established that HER3 plays an important role in drug resistance to EGFR-and HER2-targeting therapies. Since HER3 has limited kinase activity, mAbs are being explored to target HER3 for cancer therapy. Currently, approximately a dozen of anti-HER3 mAbs are at different stages of clinical development. However, the lack of established biomarkers has made it more challenging to stratify cancer patients to whom HER3-targeting therapies can be more effective. In this review, we focus on the validation of HER3 as a cancer drug target, the recent development in biomarker discovery for anti-HER3 therapies, and the progress made in the clinical development of HER3-targeting mAbs.

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“…125,126 AV-203 inhibits both NRG-induced and HER2-dependent activation of HER3, and it acts as a potent inhibitor of downstream signaling pathways by preventing HER2-HER3 dimerization. This mAb appears to be effective when tested in several cancer models, such as breast and pancreatic tumors; its safety has been successfully tested in a phase 1 clinical trial on patients with metastatic or advanced solid tumors.…”

Section: Monospecific Antibodies To Her3mentioning

confidence: 99%

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

Gaborit

Lindzen

Yarden

2015

Human Vaccines & Immunotherapeutics

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Cancer progression depends on stepwise accumulation of oncogenic mutations and a select group of growth factors essential for tumor growth, metastasis and angiogenesis. Agents blocking the epidermal growth factor receptor (EGFR, also called HER1 and ERBB1) and the co-receptor called HER2/ERBB2 have been approved over the last decade as anti-cancer drugs. Because the catalytically defective member of the family, HER3/ERBB3, plays critical roles in emergence of resistance of carcinomas to various drugs, current efforts focus on antibodies and other anti-HER3/ERBB3 agents, which we review herein with an emphasis on drug combinations and some unique biochemical features of HER3/ERBB3.

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Neuregulin 1 Expression Is a Predictive Biomarker for Response to AV-203, an ERBB3 Inhibitory Antibody, in Human Tumor Models

Cited by 47 publications

References 52 publications

Neuregulin expression in solid tumors: Prognostic value and predictive role to anti-HER3 therapies

Neuregulin expression in solid tumors: Prognostic value and predictive role to anti-HER3 therapies

HER3/ErbB3, an emerging cancer therapeutic target

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

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