A Phase Ib Study of AMG 102 in Combination with Bevacizumab or Motesanib in Patients with Advanced Solid Tumors

Rosen, Peter J.; Sweeney, Christopher J.; Park, Dorothy J.; Beaupre, Darrin M.; Deng, Hongjie; Leitch, Ian M.; Shubhakar, Poornima; Zhu, Min; Oliner, Kelly S.; Anderson, Abraham; Yee, Lorrin

doi:10.1158/1078-0432.ccr-09-2862

Cited by 68 publications

(60 citation statements)

References 46 publications

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“…2C). Mean levels of total HGF increased with rilotumumab treatment (data not shown), consistent with other rilotumumab studies (19)(20)(21)23). No apparent associations were observed between baseline plasma levels of soluble MET and total HGF with clinical response (data not shown).…”

Section: Biomarkerssupporting

confidence: 88%

“…In preclinical models, rilotumumab inhibited HGF/MET-driven signaling (15)(16)(17)(18). In clinical studies, rilotumumab administered biweekly had manageable toxicities as a single agent or combined with chemotherapy (19)(20)(21)(22), and a maximum tolerated dose was not reached (20). The favorable safety of rilotumumab and the abundant preclinical evidence supporting MET inhibition formed the basis for testing this agent in patients with advanced CRPCs.…”

Section: Introductionmentioning

confidence: 99%

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Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone

Ryan

Rosenthal

et al. 2013

Clinical Cancer Research

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Purpose: To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC).Experimental Design: This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m 2 i.v. day 1, 5 mg twice a day orally days 1-21, respectively) plus 15 mg/kg rilotumumab, 7.5 mg/kg rilotumumab, or placebo (i.v. day 1) every 3 weeks. The primary endpoint was overall survival (OS). Results: One hundred and forty-four patients were randomized. Median OS was 12.2 versus 11.1 months [HR, 1.10; 80% confidence interval (CI), 0.82-1.48] in the combined rilotumumab versus control arms. Median progression-free survival was 3.0 versus 2.9 months (HR, 1.02; 80% CI, 0.79-1.31). Treatment appeared well tolerated with peripheral edema (24% vs. 8%) being more common with rilotumumab. A trend toward unfavorable OS was observed in patients with high tumor MET expression regardless of treatment. Soluble MET levels increased in all treatment arms. Total HGF levels increased in the rilotumumab arms. Rilotumumab showed linear pharmacokinetics when co-administered with MP.Conclusions: Rilotumumab plus MP had manageable toxicities and showed no efficacy improvements in this estimation study. High tumor MET expression may identify patients with CRPC with poorer prognosis.

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Section: Biomarkerssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone

Ryan

Rosenthal

et al. 2013

Clinical Cancer Research

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“…Another drug, ARQ197, which is a selective non ATP competitive inhibitor of c-MET, when combined with erlotinib in the second/third-line treatment of EGFR inhibition naïve NSCLC patients showed increased PSF, mainly among patients with non-squamous histology, K-Ras mutations, and EGFR wild-type status [73] . Other drugs targeting MET pathways, such as AMG102 [74] , a monoclonal antibody against HGF, and MetMab (Genentech) [77] , a human recombinant agonist of the HGF-Met signaling pathway, are still in phaseⅠstudies and show promise in the treatment of NSCLC patients [76][77][78] .…”

Section: The Role Of Met Targeted Inhibitionmentioning

confidence: 99%

Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies

Mello

Marques²,

Medeiros³

et al. 2011

WJCO

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Lung cancer is currently the leading cause of cancer death in Western nations. Non-small cell lung cancer (NSCLC) represents 80% of all lung cancers, and adenocarcinoma is the predominant histological type. Despite the intensive research carried out on this field and therapeutic advances, the overall prognosis of these patients remains unsatisfactory, with a 5-year overall survival rate of less than 15%. Nowadays, pharmacogenetics and pharmacogenomics represent the key to successful treatment. Recent studies suggest the existence of two distinct molecular pathways in the carcinogenesis of lung adenocarcinoma: one associated with smoking and activation of the K-Ras oncogene and the other not associated with smoking and activation of the epidermal growth factor receptor (EGFR). The K-ras mutation is mainly responsible for primary resistance to new molecules which inhibit tyrosine kinase EGFR (erlotinib and gefitinib) and most of the EGFR mutations are responsible for increased tumor sensitivity to these drugs. This article aims to conduct a systematic review of the literature regarding the molecular pathways involving the EGFR, K-Ras and EGFR targeted therapies in NSCLC tumor behavior.

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“…A recent phase I trial with a human anti-hepatocyte growth factor monoclonal antibody, AMG102, in combination with bevacizumab, in patients with solid tumors demonstrated inhibition of tumors in patients with lung cancer. 133 The anti-MET receptor monoclonal antibody MetMab has been evaluated in a phase II trial in combination with erlotinib and the results suggest benefit in patients with overexpression of MET. 134 ARQ197 is a selective, non-ATP competitive inhibitor of MET kinase.…”

Section: Therapies Targeting Met Inhibitionmentioning

confidence: 99%

Molecular Profiling in Non–Small Cell Lung Cancer: A Step Toward Personalized Medicine

Raparia

Villa

DeCamp

et al. 2013

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Lung carcinoma is the result of sequential accumulation of genetic and epigenetic changes. Lung adenocarcinoma is a heterogeneous disease with diverse somatic mutations, and several of them include the socalled driver mutations, which may serve as ''druggable'' therapeutic targets. Thus, development of personalized approaches for the treatment of non-small cell lung carcinoma (NSCLC) mandates that pathologists make a precise histologic classification inclusive of routine molecular analysis of such tumors.Objective.-To address the molecular mechanisms underlying NSCLC and how this knowledge reflects the multidisciplinary approach in the diagnosis and management of these patients. We will also summarize the current available and investigational personalized therapies for patients with resectable early-stage, unresectable locally advanced, and metastatic NSCLC.Data Sources.-Peer-reviewed published literature and personal experience.Conclusions.-There are multiple mechanisms involved in the pathogenesis of lung cancer, which operate in parallel and involve pathways of activation and inhibition of various cellular events. Further research is essential to characterize the histologic and mutational profiles of lung carcinomas, which will ultimately translate into improved and more personalized therapeutic management of patients with lung cancer.(Arch Pathol Lab Med. 2013;137:481-491; doi: 10.5858/ arpa.2012-0287-RA) L ung cancer is the leading cause of cancer-related mortality in both men and women in the United States. It is projected that in 2012, lung cancer will account for 26% and 29% of cancer-related deaths in the female and male population, respectively.1 Historically, lung cancer has been divided into 2 major categories based on the histologic features and response to conventional therapies, and they include non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma. NSCLC includes 3 cell types (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma), and these can be further divided into various subtypes or variants.2 NSCLC accounts for most (~80%) of the lung cancers, with lung adenocarcinoma being the most common subtype in the United States. Despite significant improvements in radiologic imaging, supportive care, availability of newer antineoplastic agents, and multimodality therapy, the 5-year relative survival rate for lung cancer in the United States remains dismal, that is, at only 16% in 2007 compared to 12% in 1975, thus indicating little improvement in survival rate over a period of 3 decades.

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A Phase Ib Study of AMG 102 in Combination with Bevacizumab or Motesanib in Patients with Advanced Solid Tumors

Cited by 68 publications

References 46 publications

Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone

Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone

Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies

Molecular Profiling in Non–Small Cell Lung Cancer: A Step Toward Personalized Medicine

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