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Purpose: Oncogenic fusions involving the neuregulin 1 ( NRG1 ) gene are found in approximately 0.2% of cancers of diverse histologies. The resulting chimeric NRG1 proteins bind predominantly to HER3, leading to HER3-HER2 dimerization and activation of downstream growth and survival pathways. HER3 is, therefore, a rational target for therapy in NRG1 fusion-driven cancers., Experimental Design: We developed novel patient-derived and isogenic models of NRG1-rearranged cancers and examined the effect of the anti-HER3 antibody, seribantumab, on growth and activation of signaling networks in vitro and in vivo ., Results: Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, DOC4-NRG1 fusion) and lung (LUAD-0061AS3, SLC3A2-NRG1 fusion) cancer cells harboring NRG1 fusions or NRG1 amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a CD74-NRG1 fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of proapoptotic proteins and reduced expression of the cell-cycle regulator, cyclin D1, were observed in seribantumab-treated cells. Treatment of MDA-MB-175-VII, LUAD-0061AS3, and HBECp53-CD74-NRG1 cells with seribantumab reduced phosphorylation of EGFR, HER2, HER3, HER4, and known downstream signaling molecules, such as AKT and ERK1/2. Significantly, administration of seribantumab to mice bearing LUAD-0061AS3 patient-derived xenograft (PDX) and OV-10-0050 (ovarian cancer with CLU-NRG1 fusion) PDX tumors induced regression of tumors by 50%-100%. Afatinib was much less effective at blocking tumor growth., Conclusions: Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of NRG1 fusion-dependent tumorigenesis in vitro and in vivo in breast, lung, and ovarian patient-derived cancer models., (©2021 American Association for Cancer Research.)

Purpose: HER3 is a compelling target for cancer treatment; however, no HER3-targeted therapy is currently clinically available. Here, we produced U3-1402, an anti-HER3 antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DXd), and systematically investigated its targeted drug delivery potential and antitumor activity in preclinical models., Experimental Design: In vitro pharmacologic activities and the mechanisms of action of U3-1402 were assessed in several human cancer cell lines. Antitumor activity of U3-1402 was evaluated in xenograft mouse models, including patient-derived xenograft (PDX) models. Safety assessments were also conducted in rats and monkeys., Results: U3-1402 showed HER3-specific binding followed by highly efficient cancer cell internalization. Subsequently, U3-1402 was translocated to the lysosome and released its payload DXd. While U3-1402 was able to inhibit HER3-activated signaling similar to its naked antibody patritumab, the cytotoxic activity of U3-1402 in HER3-expressing cells was predominantly mediated by released DXd through DNA damage and apoptosis induction. In xenograft mouse models, U3-1402 exhibited dose-dependent and HER3-dependent antitumor activity. Furthermore, U3-1402 exerted potent antitumor activity against PDX tumors with HER3 expression. Acceptable toxicity was noted in both rats and monkeys., Conclusions: U3-1402 demonstrated promising antitumor activity against HER3-expressing tumors with tolerable safety profiles. The activity of U3-1402 was driven by HER3-mediated payload delivery via high internalization into tumor cells., (©2019 American Association for Cancer Research.)

Purpose: ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A "window-of-opportunity" study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC., Patients and Methods: Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-week interval prior to tumor resection. The primary study objective was to achieve ≥50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed., Results: pErbB3 was detectable in all tumors prior to treatment and decreased for 10 of 12 (83%) patients following CDX-3379 dosing, with ≥50% reduction in 7 of 12 (58%; P = 0.04; 95% confidence interval, 27.7%-84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment-related toxicity was grade 1-2 and included diarrhea, fatigue, and acneiform dermatitis. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus-negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment., Conclusions: This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC., (©2019 American Association for Cancer Research.)

Purpose: This phase Ib study was designed to determine the MTD, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) mAb SAR256212 in combination with the oral PI3K inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors. Experimental Design: Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3 + 3 dose-escalation design until occurrence of disease progression or dose-limiting toxicity. Objective response rate, pharmacokinetics, pharmacodynamics, and PIK3CA mutational status were also evaluated. Results: Twenty-seven patients were enrolled. Thirteen of 20 patients tested (65%) had a hotspot-activating mutation in PIK3CA in their tumor. The MTD was determined to be SAR256212 at 40 mg/kg loading dose followed by 20 mg/kg weekly, plus SAR245408 200 mg daily. Dose-limiting toxicities included rash and hypotension; the most frequent treatment-related side effect was diarrhea (66.7%). Twenty-three patients were evaluable for efficacy, of which 12 patients (52.2%) had stable disease and 11 patients (47.8%) had progression of disease as best response. In this study with a limited sample size, there was no difference in best response between patients with PI3KCA -mutant versus PIK3CA wild-type tumors ( P = 0.07). The concurrent administration of SAR245408 and SAR256212 did not appear to have an effect on the pharmacokinetics of either drug. Conclusions: The combination of SAR256212 and SAR245408 resulted in stable disease as the best response. Side effects seen in combination were similar to the profiles of each individual drug. Patient outcome was the same regardless of tumor PI3KCA mutation status. Clin Cancer Res; 23(14); 3520-8. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Purpose: Our previous work suggested that HER3 inhibition sensitizes head and neck squamous cell carcinoma (HNSCC) to EGFR inhibition with cetuximab. This study aimed to define the role of HER3 in cetuximab resistance and the antitumor mechanisms of EGFR/HER3 dual targeting in HNSCC., Experimental Design: We treated cetuximab-resistant HNSCC UMSCC1-C and parental UMSCC1-P cell lines with anti-EGFR antibody cetuximab, anti-HER3 antibody MM-121, and their combination. We assessed activities of HER2, HER3, and downstream signaling pathways by Western blotting and cell growth by sulforhodamine B (SRB) and colony formation assays. HER3-specific shRNA was used to confirm the role of HER3 in cetuximab response. The combined efficacy and alterations in biomarkers were evaluated in UMSCC1-C xenograft and patient-derived xenograft (PDX) models., Results: Cetuximab treatment induced HER3 activation and HER2/HER3 dimerization in HNSCC cell lines. Combined treatment with cetuximab and MM-121 blocked EGFR and HER3 activities and inhibited the PI3K/AKT and ERK signaling pathways and HNSCC cell growth more effectively than each antibody alone. HER3 knockdown reduced HER2 activation and resensitized cells to cetuximab. Cetuximab-resistant xenografts and PDX models revealed greater efficacy of dual EGFR and HER3 inhibition compared with single antibodies. In PDX tissue samples, cetuximab induced HER3 expression and MM-121 reduced AKT activity., Conclusions: Clinically relevant PDX models demonstrate that dual targeting of EGFR and HER3 is superior to EGFR targeting alone in HNSCC. Our study illustrates the upregulation of HER3 by cetuximab as one mechanism underlying resistance to EGFR inhibition in HNSCC, supporting further clinical investigations using multiple targeting strategies in patients who have failed cetuximab-based therapy. Clin Cancer Res; 23(3); 677-86. ©2016 AACR., Competing Interests: of Potential Conflicts of Interest No potential conflicts of interest to disclose., (©2016 American Association for Cancer Research.)

Purpose: Accumulating evidence indicates a high degree of plasticity and compensatory signaling within the human epidermal growth factor receptor (HER) family, leading to resistance upon therapeutic intervention with HER family members., Experimental Design/results: We have generated Pan-HER, a mixture of six antibodies targeting each of the HER family members EGFR, HER2, and HER3 with synergistic pairs of antibodies, which simultaneously remove all three targets, thereby preventing compensatory tumor promoting mechanisms within the HER family. Pan-HER induces potent growth inhibition in a range of cancer cell lines and xenograft models, including cell lines with acquired resistance to therapeutic antibodies. Pan-HER is also highly efficacious in the presence of HER family ligands, indicating that it is capable of overcoming acquired resistance due to increased ligand production. All three target specificities contribute to the enhanced efficacy, demonstrating a distinct benefit of combined HER family targeting when compared with single-receptor targeting., Conclusions: Our data show that simultaneous targeting of three receptors provides broader efficacy than targeting a single receptor or any combination of two receptors in the HER family, especially in the presence of HER family ligands. Pan-HER represents a novel strategy to deal with primary and acquired resistance due to tumor heterogeneity and plasticity in terms of HER family dependency and as such may be a viable alternative in the clinic., (©2015 American Association for Cancer Research.)

Purpose: The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A., Experimental Design: Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1-30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3., Results: No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease ≥8 weeks, including SCCHN (n = 3), colorectal cancer (n = 6), and non-small cell lung cancer (n = 3)., Conclusions: MEHD7945A was well-tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer., (©2015 American Association for Cancer Research.)