A randomized, open-label, phase 2 study of emibetuzumab plus erlotinib (LY+E) and emibetuzumab monotherapy (LY) in patients with acquired resistance to erlotinib and MET diagnostic positive (MET Dx+) metastatic NSCLC.

Camidge, D. Ross; Morán, Teresa; Demedts, Ingel; Grosch, Heidrun; Mercurio, Jean-Pierre Di; Mileham, Kathryn F.; Molina, Julian R.; Vidal, Òscar; Bepler, Gerold; Goldman, Jonathan W.; Lewanski, Conrad; Park, Keunchil; Wallin, Johan; Wijayawardana, Sameera R.; Wang, Xuejing Aimee; Wacheck, Volker; Smit, Egbert F.

doi:10.1200/jco.2016.34.15_suppl.9070

Cited by 27 publications

(24 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In a phase II trial comparing emibetuzumab ± erlotinib, the objective response rate (ORR) was higher in both the combination and monotherapy arms, 3.8% and 4.8%, respectively, for patients with ≥ 60% of MET positive cells by IHC (n=74) than for patients with ≥ 10% positive cells (n=89) where ORR was 3.0% in the combination arm and 4.3% in the monotherapy arm. 70 In the acquired resistance setting, the same challenges associated with defining the appropriate method and positivity cut point for identifying MET gene copy-number gain as a primary driver apply to defining MET positivity as a co-driver state. Data converging with the primary driver literature recently emerged from a small phase II study in EGFR -mutant patients with acquired resistance to an EGFR TKI who were then treated with the combination of gefitinib and capmatinib.…”

Section: Met As a Co-driver In Nsclcmentioning

confidence: 99%

Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

Drilon

Cappuzzo

et al. 2017

Journal of Thoracic Oncology

Self Cite

324

277

View full text Add to dashboard Cite

The mesenchymal epithelial transition factor receptor (MET) is a potential therapeutic target in a number of cancers, including non-small cell lung cancer (NSCLC). In NSCLC, MET pathway activation is thought to occur via a diverse set of mechanisms that influence properties affecting cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggest a role for MET activation as both a primary oncogenic driver in subsets of lung cancer, and as a secondary driver of acquired resistance to targeted therapy in other genomic subsets. In this review, we explore the biology and clinical significance behind MET exon 14 (METex14) alterations and MET amplification in NSCLC, the role of MET amplification in the setting of acquired resistance to EGFR tyrosine kinase inhibitor therapy in EGFR-mutant NSCLC, and the history of MET pathway inhibitor drug development in NSCLC, highlighting current strategies that enrich for biomarkers that are likely to be predictive of response. While previous trials that focused on MET pathway-directed targeted therapy in unselected or MET overexpressing NSCLC yielded largely negative results, more recent investigations focusing on METex14 alterations and MET amplification have been notable for meaningful clinical responses to MET inhibitor therapy in a substantial proportion of patients.

show abstract

Section: Met As a Co-driver In Nsclcmentioning

confidence: 99%

Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

Drilon

Cappuzzo

et al. 2017

Journal of Thoracic Oncology

Self Cite

324

277

View full text Add to dashboard Cite

show abstract

“…In this case, Met positivity was defined as having moderate (2+) to strong (3+) staining in ≥10% of tumor cells. Unfortunately, this trial also did not meet its primary end points, which were based on objective response rates (ORRs) (62). Despite ongoing efforts, anti-Met antibody therapeutics remain unsuccessful in late-stage clinical development.…”

Section: Discussionmentioning

confidence: 98%

“…4D and SI Appendix, Fig. S7D), yet tumoral HGF levels were also not reported in the emibetuzumab trials (62,63). iii) Clinical studies typically focus on inhibition of tumor growth but rarely evaluate another major role of HGF/Met signaling, that of promoting tumor cell invasion and dissemination.…”

Section: Discussionmentioning

confidence: 99%

MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM

Casaletto

Geddie

Abu-Yousif

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challenging, however, as bivalent antibodies exhibit agonistic properties, whereas monovalent antibodies lack potency and the capacity to down-regulate Met. Through computational modeling, we found that the potency of a monovalent antibody targeting Met could be dramatically improved by introducing a second binding site that recognizes an unrelated, highly expressed antigen on the tumor cell surface. Guided by this prediction, we engineered MM-131, a bispecific antibody that is monovalent for both Met and epithelial cell adhesion molecule (EpCAM). MM-131 is a purely antagonistic antibody that blocks ligand-dependent and ligand-independent Met signaling by inhibiting HGF binding to Met and inducing receptor down-regulation. Together, these mechanisms lead to inhibition of proliferation in Met-driven cancer cells, inhibition of HGF-mediated cancer cell migration, and inhibition of tumor growth in HGF-dependent and -independent mouse xenograft models. Consistent with its design, MM-131 is more potent in EpCAM-high cells than in EpCAM-low cells, and its potency decreases when EpCAM levels are reduced by RNAi. Evaluation of Met, EpCAM, and HGF levels in human tumor samples reveals that EpCAM is expressed at high levels in a wide range of Met-positive tumor types, suggesting a broad opportunity for clinical development of MM-131.

show abstract

“…Eighteen patients were treated, and five had a partial response [43]. A similar trial (NCT01900652) with emibetuzumab and an IgG4 anti-MET monoclonal antibody (mAb) with erlotinib in MET-expressing NSCLC with acquired erlotinib resistance showed some benefit in high cMET-expressing tumors [44]. …”

Section: Targeted Agentsmentioning

confidence: 99%

Emerging therapeutic agents for lung cancer

et al. 2016

View full text Add to dashboard Cite

Lung cancer continues to be the most common cause of cancer-related mortality worldwide. Recent advances in molecular diagnostics and immunotherapeutics have propelled the rapid development of novel treatment agents across all cancer subtypes, including lung cancer. Additionally, more pharmaceutical therapies for lung cancer have been approved by the US Food and Drug Administration in the last 5 years than in previous two decades. These drugs have ushered in a new era of lung cancer managements that have promising efficacy and safety and also provide treatment opportunities to patients who otherwise would have no conventional chemotherapy available. In this review, we summarize recent advances in lung cancer therapeutics with a specific focus on first in-human or early-phase I/II clinical trials. These drugs either offer better alternatives to drugs in their class or are a completely new class of drugs with novel mechanisms of action. We have divided our discussion into targeted agents, immunotherapies, and antibody drug conjugates for small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). We briefly review the emerging agents and ongoing clinical studies. We have attempted to provide the most current review on emerging therapeutic agents on horizon for lung cancer.

show abstract

A randomized, open-label, phase 2 study of emibetuzumab plus erlotinib (LY+E) and emibetuzumab monotherapy (LY) in patients with acquired resistance to erlotinib and MET diagnostic positive (MET Dx+) metastatic NSCLC.

Cited by 27 publications

References 0 publications

Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM

Emerging therapeutic agents for lung cancer

Contact Info

Product

Resources

About