Phase II study of the dual EGFR/HER3 inhibitor duligotuzumab (MEHD7945A) vs. cetuximab in combination with FOLFIRI in RAS wild-type metastatic colorectal cancer. Duligotuzumab is a dual-action antibody directed against EGFR and HER3. Metastatic colorectal cancer (mCRC) patients with ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity . Mandatory tumor samples underwent mutation and biomarker analysis. Efficacy analysis was conducted in patients with exon 2/3 wild-type tumors. Of 134 randomly assigned patients, 98 had ex2/3 wild-type. Duligotuzumab provided no progression-free survival (PFS) or overall survival (OS) benefit compared with cetuximab, although there was a trend for a lower objective response rate (ORR
Imaging EGFR and HER3 through 89Zr-labeled MEHD7945A (Duligotuzumab) Tumor resistance to treatment paved the way toward the development of single agent drugs that target multiple molecular signatures amplified within the malignancy. The discovered crosstalk between EGFR and HER3 as well as the role of HER3 in mediating EGFR resistance made these two receptor tyrosine kinases attractive targets . MEHD7945A or duligotuzumab is a single immunotherapy agent that dually targets both molecular signatures. In this study, a positron emission tomography (PET) companion diagnostic to MEHD7945A is reported and evaluated in pancreatic cancer. Tumor accretion and whole body pharmacokinetics of Zr-MEHD7945A were established. Specificity of the probe for EGFR and/or HER3 was further examined.
A Phase Ib Doseâ€Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and Duligotuzumab in Patients with Previously Treated Locally Advanced or Metastatic Cancers with Mutant KRAS Cobimetinib and duligotuzumab were well tolerated as single agents and in combination with other agents.The cobimetinib and duligotuzumab combination was associated with increased toxicity , most notably gastrointestinal, and limited efficacy in the patient population tested. -mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual-action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal
Randomized Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in Squamous Cell Carcinoma of the Head and Neck (MEHGAN Study). Duligotuzumab, a novel dual-action humanized IgG1 antibody that blocks ligand binding to epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody -dependent cell-mediated cytotoxicity. High tumor-expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab. This multicenter, open-label, randomized phase II study (MEHGAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy and among patients with NRG1-high tumors
Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck. 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. On day 1, duligotuzumab at a dose of 1650 mg intravenously was combined with cisplatin at a dose of 100 mg/m and 5-fluorouracil at a dose of 1000 mg/m /day on days 1 to 4 in treatment arm A, or carboplatin (area
. Drug: MEHD7945AMEHD7945A will be administered as per schedule specified in the respective arms.Other Name: Duligotuzumab Experimental: B: MEHD7945A + Paclitaxel + CarboplatinParticipants with previously untreated R/M SCCHN will receive MEHD7945A 1650 mg IV infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or protocol violation. Carboplatin will be administered . Drug: MEHD7945AMEHD7945A will be administered as per schedule specified in the respective arms.Other Name: Duligotuzumab
Drug: MEHD7945AMEHD7945A will be administered as IV infusion at a dose of 1100 mg q2w until disease progression or unacceptable toxicity.Other Name: Duligotuzumab Experimental: MEHD7945A + Cobimetinib - Stage 2 (CRC)CRC patients will receive MEHD7945A in combination with cobimetinib until disease progression or unacceptable Drug: MEHD7945AMEHD7945A will be administered as IV infusion at a dose of 1100 mg q2w until disease progression or unacceptable toxicity.Other Name: Duligotuzumab Experimental: MEHD7945A + Cobimetinib - Stage 2 (NSCLC)NSCLC patients will receive MEHD7945A in combination with cobimetinib until disease progression or unacceptable
WD, Penuel EM, Pirzkall A, Tabernero J. Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line RAS Wild-Type Metastatic Colorectal Cancer. Clin Cancer Res. 2018 May 15;24(10):2276-2284. doi: 10.1158/1078-0432.CCR-17-0646. Epub 2018 Mar 5. Responsible Party: Genentech, Inc