Efficacy and safety of crizotinib in patients with advanced <i>c-MET</i>-amplified non-small cell lung cancer (NSCLC).

Camidge, D. Ross; Ou, Sai‐Hong Ignatius; Shapiro, Geoffrey I.; Otterson, Gregory A.; Villaruz, Liza C.; Villalona‐Calero, Miguel A.; Iafrate, A. John; Varella‐Garcia, Marileila; Đačić, Sanja; Cardarella, Stephanie; Zhao, Weiqiang; Tye, L.; Stephenson, Patricia; Wilner, Keith D.; James, Leonard P.; Socinski, Mark A.

doi:10.1200/jco.2014.32.15_suppl.8001

Cited by 231 publications

(202 citation statements)

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“…De novo MET amplification has been associated with primary resistance to EGFR TKIs (43). Therapeutic targeting of MET may be an effective strategy in MET amplified tumors (44,45). Results from a phase 2 study of cabozantinib (an oral MET/VEGFR2/RET inhibitor) in patients with EGFR mutant lung cancer and progression on EGFR TKI resulted in 3 partial responses out of 35 patients treated (46).…”

Section: Therapeutic Strategies Targeting Alternate Pathwaysmentioning

confidence: 99%

Therapeutic Strategies Utilized in the Setting of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors

Riely

Lovly

2014

Clinical Cancer Research

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Patients with EGFR mutant lung cancer derive significant therapeutic benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, acquired resistance is an inevitable consequence of this treatment strategy, with a broad variety of resistance mechanisms including acquired EGFR mutations (e.g., T790M) and activation of bypass signaling pathways, such as MET and HER2. Several therapeutic strategies hypothesized to delay or overcome resistance have been tested in clinical trials, including ‘next-generation’ EGFR TKIs and rational combinations of targeted agents. However, to date, there are no FDA approved therapies for patients with acquired resistance to first-line EGFR TKI therapy. There remains a critical need for more effective and better tailored treatments in this setting in order to match treatments to the individual patient and specific resistance mechanism at hand. In this review, we will discuss known mechanisms of resistance to first-line EGFR TKI therapy and describe previous and ongoing strategies to overcome resistance.

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Section: Therapeutic Strategies Targeting Alternate Pathwaysmentioning

confidence: 99%

Therapeutic Strategies Utilized in the Setting of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors

Riely

Lovly

2014

Clinical Cancer Research

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“…Furthermore, there are examples of Met driven tumors with nice responses to anti-Met therapies. Met amplification seems to be up to date, the best predictor of response to Met inhibitors [29-31]. However, evaluation of copy number changes by FISH is challenging in SCLC due to the typical crushing phenomenon of these tumors and was not feasible in our hands[32].…”

Section: Discussionmentioning

confidence: 99%

High circulating hepatocyte growth factor levels associate with epithelial to mesenchymal transition and poor outcome in small cell lung cancer patients

et al. 2014

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We have previously shown that Met activation through the hepatocyte growth factor (HGF) increases tumorogenesis, induces epithelial-to-mesenchymal transition (EMT) and chemoresistance in SCLC. We sought to evaluate circulating HGF levels in SCLC patients and assess correlation with outcome and EMT features in the tumor. Serum samples from patients with SCLC were prospectively obtained at diagnosis, response evaluation and progression. HGF serum (sHGF) was quantified by ELISA. EMT markers and p-Met/Met were assayed by immunohistochemistry in tumor samples. Clinical data were prospectively recorder. One-hundred twelve patients were included. High baseline levels of sHGF were associated with shorter overall survival (p=0.007) and remained independently associated with survival in the multivariate analysis (p=0.016). For stage IV patients, an increase of sHGF levels at response evaluation (p=0.042) and at progression (p=0.003) were associated with poor outcome. sHGF levels were associated (p<0.05) with a mesenchymal phenotype in the tumor. In conclusion, high sHGF at diagnosis and increases during the course of the disease predict for poor outcome in SCLC patients and associate with EMT in the tumor. These data provide novel evidence on a role of sHGF in the adverse clinical behavior of SCLC and support testing Met inhibitors in patients with high sHGF.

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“…All patients who responded had a MET/CEP7 ratio >2.2. [41] Final data from this study is not yet available; however, crizotinib is a promising therapeutic option for some patients with MET amplified NSCLC and there may be a role for utilizing the MET/CEP7 ratio as a biomarker to predict response. Another study also demonstrated efficacy of MET inhibitors crizotinib and cabozantinib in four patients with MET exon 14 splice site mutations.…”

Section: Metmentioning

confidence: 95%

The use of biomarkers in the treatment of non-small cell lung cancer

Baumgart

Pandya

2016

Expert Review of Precision Medicine and Drug Development

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Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC).

Cited by 231 publications

References 0 publications

Therapeutic Strategies Utilized in the Setting of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors

Therapeutic Strategies Utilized in the Setting of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors

High circulating hepatocyte growth factor levels associate with epithelial to mesenchymal transition and poor outcome in small cell lung cancer patients

The use of biomarkers in the treatment of non-small cell lung cancer

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