Evaluation of the Antitumor Effects and Mechanisms of PF00299804, a Pan-HER Inhibitor, Alone or in Combination with Chemotherapy or Targeted Agents in Gastric Cancer

Nam, Hyunwoo; Ching, Keith A.; Kan, Julie L.C.; Kim, Hwang Phill; Han, Sae Won; Im, Seock Ah; Kim, Tae You; Christensen, James G.; Oh, Do Youn; Bang, Yung Jue

doi:10.1158/1535-7163.mct-11-0494

Cited by 65 publications

(48 citation statements)

References 43 publications

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“…Therefore, targeting the EGFR alone may ultimately have modest impact, particularly for tumors with multiple oncogenic drivers within and beyond the HER system. Combinatorial strategies to target multiple HER family members have been increasingly explored in recent years (21)(22)(23)(24)(25)(26). Many aggressive tumors express both EGFR and HER3, and HER3 has been identified as a key contributor to acquired resistance to EGFR inhibitors (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Effects of MEHD7945A, a Dual-Specific Antibody against EGFR and HER3, in Combination with Radiation in Lung and Head and Neck Cancers

Huang

Armstrong

et al. 2015

Molecular Cancer Therapeutics

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Human epidermal growth factor receptor family members (EGFR, HER2, HER3, and HER4) play important roles in tumorigenesis and response to cancer therapeutics. In this study, we evaluated the capacity of the dual-target antibody MEHD7945A that simultaneously targets EGFR and HER3 to modulate radiation response in lung and head and neck cancer models. Antitumor effects of MEHD7945A in combination with radiation were evaluated in cell culture and tumor xenograft models. Mechanisms that may contribute to increased radiation killing by MEHD7945A, including DNA damage and inhibition of EGFR-HER signaling pathways, were analyzed.

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Section: Discussionmentioning

confidence: 99%

Antitumor Effects of MEHD7945A, a Dual-Specific Antibody against EGFR and HER3, in Combination with Radiation in Lung and Head and Neck Cancers

Huang

Armstrong

et al. 2015

Molecular Cancer Therapeutics

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“…Dacomitinib (PF00299804) is a 'pan-HER' small molecule inhibitor, with antitumour activity reported in HER-2-positive gastric cancer cell lines and xenografts, and synergy observed with several commonly used cytotoxics (5-FU, cisplatin, docetaxel and paclitaxel), targeted agents (trastuzumab and investigational inhibitors of IGF1R, ERK1/2 and PI3K/mTOR) [Nam et al 2011a]. A phase II study will determine its monotherapy activity in patients with previously treated HER-2-positive advanced gastric or OGJ cancers.…”

Section: Other Small Molecule Inhibitors Of Her-2mentioning

confidence: 99%

Trastuzumab: a novel standard option for patients with HER-2-positive advanced gastric or gastro-oesophageal junction cancer

Okines

Cunningham

2012

Therap Adv Gastroenterol

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Abstract:The human epidermal receptor-2 (HER-2) is amplified in up to 25% of patients with gastroesophageal adenocarcinomas. Although the presence of this amplification does not appear to confer a poor prognosis, it provides a valuable novel therapeutic target for this group of patients. Trastuzumab is a fully humanized monoclonal antibody directed at HER-2 which binds the external domain of the receptor and exerts its action via a combination of antibodydependent cytotoxicity, reduced shedding of the extracellular domain, inhibition of dimerization and possibly receptor downregulation. The ToGA trial was an international multicentre randomized phase III study which evaluated the addition of trastuzumab to a cisplatin plus fluoropyrimidine chemotherapy doublet in 594 patients with HER-2-positive advanced gastric or oesophagogastric junction adenocarcinoma. The combination of the antibody with chemotherapy significantly improved response rate, median progression-free survival and median overall survival without additional toxicity or adversely affecting quality of life. Accordingly, trastuzumab plus chemotherapy is now a standard first-line treatment option for patients with advanced HER-2-positive gastroesophageal cancer. Unfortunately, many patients with HER-2-positive cancer exhibit primary resistance to trastuzumab and the remainder will acquire resistance to the antibody; therefore, urgent investigation into novel agents which may circumvent resistance mechanisms is warranted. Small molecule inhibitors of HER-2, which commonly also target other members of the HER family of receptors, such as EGFR and HER-3, are currently undergoing evaluation in gastroesophageal cancer as first-line alternatives to trastuzumab and second-line salvage treatments for trastuzumab-resistant disease. Extrapolating the successful use of trastuzumab in the advanced disease setting, clinical trials are underway to assess the role of this antibody in the perioperative and adjuvant settings, where it is hoped that it will have a meaningful impact upon the currently poor survival rates.

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“…It was also found to offer improved progression-free survival compared to erlotinib in advanced non-small cell lung cancer (NSCLC) [66]. There appears to be a synergistic effect with dacomitinib when combined with trastuzumab or other inhibitors of downstream signaling pathways [67]. A similar finding was noted from poziotinib, also a pan-HER inhibitor [68].…”

Section: Other Her Inhibitorsmentioning

confidence: 79%

Targeted Therapy in Advanced Gastric Cancer: An Updated Review

2014

J Cancer Sci

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Despite great efforts over the years, adenocarcinoma of the stomach remains a difficult disease to manage. It is the second leading cause of cancer death and is the fifth most common cancer worldwide. If diagnosed early, surgical resection can offer definitive therapy. However, disease is often advanced or metastatic at the time of diagnosis and chemotherapy becomes the only option. With increased understanding of the molecular pathways that are responsible for tumor development and proliferation, targeted therapies have become an important part of cancer treatment in the setting of advanced or metastatic disease. Trastuzumab is widely used in HER2-positive breast cancer. Similarly, the ToGA trial established its role in gastric cancer that overexpresses HER2 by demonstrating an overall survival benefit in that cohort. Based on these results, HER2 testing should be performed routinely in patients with metastatic gastric cancer in order to identify patients who can benefit from this biologic agent. Ramucirumab also improves survival either as a single agent or when combined with chemotherapy after disease progression using standard first-line therapy. Unfortunately, these favorable responses are not seen with many other targeted agents in gastric cancer. This review aims to outline and summarize currently available knowledge and clinical data for some of the most common signaling targets and their respective therapeutic trials.

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Evaluation of the Antitumor Effects and Mechanisms of PF00299804, a Pan-HER Inhibitor, Alone or in Combination with Chemotherapy or Targeted Agents in Gastric Cancer

Cited by 65 publications

References 43 publications

Antitumor Effects of MEHD7945A, a Dual-Specific Antibody against EGFR and HER3, in Combination with Radiation in Lung and Head and Neck Cancers

Antitumor Effects of MEHD7945A, a Dual-Specific Antibody against EGFR and HER3, in Combination with Radiation in Lung and Head and Neck Cancers

Trastuzumab: a novel standard option for patients with HER-2-positive advanced gastric or gastro-oesophageal junction cancer

Targeted Therapy in Advanced Gastric Cancer: An Updated Review

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