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HER2‐targeted therapy, especially the anti‐HER2 antibody trastuzumab, is standard for HER2‐positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)‐dependent HER2‐HER3 interactions play a critical role in the evasion of apoptosis and are therefore a target for oncotherapy to treat HER2‐positive breast cancer. The anti‐HER2 antibody pertuzumab and anti‐HER3 antibody patritumab both target this heregulin–HER3‐HER2 complex in different ways. This study examined the anticancer efficacy of dual HER2 and HER3 blockade in trastuzumab‐resistant HER2‐positive breast cancer. HER2‐positive SKBR3 or BT474 cells overexpressing heregulin (SKBR3‐HRG, BT474‐HRG) were used to evaluate the efficacy of trastuzumab, pertuzumab, and patritumab in vitro by performing cell viability, immunoblotting, and clonogenic assays. The effects of these agents were then evaluated in vivo using BT474‐HRG and an intrinsic heregulin‐expressing and HER2‐positive JIMT‐1 xenograft models. SKBR3‐HRG and BT474‐HRG cells lost sensitivity to trastuzumab, which was accompanied by Akt activation. Unexpectedly, trastuzumab in combination with pertuzumab or patritumab also showed limited efficacy toward these cells. In contrast, trastuzumab/pertuzumab/patritumab triple treatment demonstrated potent anticancer efficacy, concomitant with strong repression of Akt. Finally, in heregulin‐expressing BT474‐HRG and JIMT‐1 xenograft models, the addition of pertuzumab and patritumab to trastuzumab also enhanced antitumor efficacy leading to tumor regression. The current study found that triple blockade of HER2 and HER3 using trastuzumab, pertuzumab, and patritumab could overcome resistance to trastuzumab therapy in heregulin‐expressing and HER2‐positive breast cancer, which could be exploited clinically. HER2‐targeted therapy, especially the anti‐HER2 antibody trastuzumab, is standard for HER2‐positive breast cancer; however, its efficacy is limited in a subpopulation of patients. The current study found that blockade of HER2 and HER3 using pertuzumab and patritumab could overcome resistance to trastuzumab therapy in heregulin‐expressing and HER2‐positive breast cancer, which could be exploited clinically. [ABSTRACT FROM AUTHOR]

Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. Trial registration: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013. [ABSTRACT FROM AUTHOR]

Background: This open-label, multicenter, phase Ib study assessed the safety and preliminary activity of duligotuzumab, a dual-action antibody that blocks ligand binding to human epidermal growth factor receptor 3 (HER3) and epidermal growth factor receptor, in combination with chemotherapy, in the first-line treatment of patients with recurrent/metastatic squamous cell cancer of the head and neck.Methods: On day 1, duligotuzumab at a dose of 1650 mg intravenously was combined with cisplatin at a dose of 100 mg/m2 and 5-fluorouracil at a dose of 1000 mg/m2 /day on days 1 to 4 in treatment arm A, or carboplatin (area under the curve, 6 mg/mL/min) and paclitaxel (at a dose of 200 mg/m2 ) in treatment arm B. Up to 6 cycles (21 days/cycle) were followed by duligotuzumab maintenance until disease progression or intolerable toxicity occurred.Results: Nine patients in arm A and 15 patients in arm B received a median of 6 cycles of chemotherapy, and a median of 11 cycles (arm A) and 9 cycles (arm B) of duligotuzumab. Dose-limiting toxicities occurred in 3 patients in arm A and 1 patient in arm B. Grade ≥ 3 treatment-related adverse events (graded according to graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) in ≥ 3 patients were neutropenia (5 patients), hypokalemia (4 patients), dehydration (3 patients), anemia (3 patients), and diarrhea (3 patients) in arm A, and neutropenia (8 patients), anemia (5 patients), febrile neutropenia (4 patients), leukopenia (3 patients), thrombocytopenia (3 patients), and hypomagnesemia (3 patients) in arm B. The chemotherapy dose was reduced in 19 of 24 patients. Sixteen patients (67%) demonstrated objective responses regardless of human papillomavirus status or neuregulin 1 (NRG1) mRNA expression (arm A: 2 confirmed complete responses and 4 confirmed partial responses; arm B: 2 confirmed complete responses and 8 confirmed partial responses).Conclusions: Duligotuzumab in combination with cisplatin/5-fluorouracil or carboplatin/paclitaxel demonstrated encouraging activity in patients with recurrent/metastatic squamous cell cancer of the head and neck; an association with increased frequency and severity of select adverse events relative to historical data was suggestive of the potentiation of chemotherapy-related adverse events. Cancer 2016;122:3803-3811. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

HER2 (human epidermal growth factor receptor-2)-amplified tumours are characterized by constitutive signalling via the HER2-HER3 co-receptor complex. Although phosphorylation activity is driven entirely by the HER2 kinase, signal volume generated by the complex is under the control of HER3, and a large capacity to increase its signalling output accounts for the resiliency of the HER2-HER3 tumour driver and accounts for the limited efficacies of anti-cancer drugs designed to target it. In the present paper we describe deeper insights into the dynamic nature ofHER3 signalling. Signalling output by HER3 is under several modes of regulation, including transcriptional, posttranscriptional, translational, post-translational and localizational control. These redundant mechanisms can each increase HER3 signalling output and are engaged in various degrees depending on how the HER3/PI3K (phosphoinositide 3-kinase)/Akt/mTOR (mammalian target of rapamycin) signalling network is disturbed. The highly dynamic nature of HER3 expression and signalling, and the plurality of downstream elements and redundant mechanisms that function to ensure HER3 signalling throughput identify HER3 as a major signalling hub in HER2-amplified cancers and a highly resourceful guardian of tumorigenic signalling in these tumours. [ABSTRACT FROM AUTHOR]