A Phase II Pharmacodynamic Study of Erlotinib in Patients with Advanced Non–Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy

Felip, Enriqueta; Rojo, Federico; Reck, Martin; Heller, Astrid; Klughammer, Barbara; Sala, Gemma Laguillo; Cedrés, S.; Peralta, Sergio; Maacke, Heiko; Foernzler, Dorothee; Parera, Marta; Möcks, Joachim; Saura, Cristina; Gatzemeier, U.; Baselga, José

doi:10.1158/1078-0432.ccr-07-5186

Cited by 67 publications

(33 citation statements)

References 34 publications

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“…In general, the gold-standard pharmacodynamic assay is immunohistochemistry on a tumor sample. Several clinical studies evaluated the phosphorylation status of the drug target or molecules on the downstream pathway (39,40). Although the evaluation of differential phosphorylation could be used to assess inhibitor activity in the tumor, there are limitations to phospho-related assays.…”

Section: Discussionmentioning

confidence: 99%

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

Nakanishi¹,

Mizuno²,

Sase³

et al. 2015

Molecular Cancer Therapeutics

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Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the extracellular signal-regulated kinase (ERK) gene signature was altered in several FGFR inhibitor-sensitive cell lines. Consistent with these findings, CH5183284/Debio 1347 suppressed phospho-ERK in every tested FGFR inhibitor-sensitive cell line. Because the mitogen-activated protein kinase (MAPK) pathway functions downstream of FGFR, we searched for a pharmacodynamic marker of FGFR inhibitor efficacy in a collection of cell lines with the ERK signature and identified dual-specificity phosphatase 6 (DUSP6) as a candidate marker. Although a MEK inhibitor suppressed the MAPK pathway, most FGFR inhibitor-sensitive cell lines are insensitive to MEK inhibitors and we found potent feedback activation of several pathways via FGFR. We therefore suggest that FGFR inhibitors exert their effect by suppressing ERK signaling without feedback activation. In addition, DUSP6 may be a pharmacodynamic marker of FGFR inhibitor efficacy in FGFR-addicted cancers.

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Section: Discussionmentioning

confidence: 99%

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

Nakanishi¹,

Mizuno²,

Sase³

et al. 2015

Molecular Cancer Therapeutics

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“…Using an approach previously described in NSCLC studies, [2][3][4][5] the expression data were first used to generate an immunohistochemistry score for each tumor on a continuous scale of 0-300. Subpopulation treatment effect pattern plot analysis 6 of response rate was then used to select a discriminatory immunohistochemistry score threshold of 200 allowing the outcome-based classification of patients into subgroups with low and high tumor EGFR expression.…”

Section: Also See P 1176mentioning

confidence: 99%

Reproducibility of Immunohistochemical Scoring for Epidermal Growth Factor Receptor Expression in Non–Small Cell Lung Cancer: Round Robin Test

Rüschoff

Kerr

Grote

et al. 2013

Archives of Pathology & Laboratory Medicine

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Context.-The addition of cetuximab to first-line chemotherapy substantially prolonged survival in patients with advanced non-small cell lung cancer whose tumors expressed high levels of epidermal growth factor receptor (EGFR; immunohistochemistry score of !200 on a scale of 0-300).Objective.-To evaluate the interobserver reproducibility of this EGFR immunohistochemistry scoring system, based on both the tumor cell membrane staining intensity (graded 0-3þ) and the percentage of cells staining at each intensity.Design.-In parts 1 (initial feasibility study) and 2 of this 2-part round robin test, sections of different non-small cell lung cancer tissue microarrays were stained in a central reference laboratory. Following reference evaluation, EGFR expression in 30 selected tumor cores was characterized in serial sections by lung cancer pathology specialists. The reproducibility of scoring by different raters was assessed. Analysis of between-rater agreement was based on the allocation of EGFR immunohistochemistry scores into low-(,200) and high-(!200) EGFR expression groups.Results.-After discussion with raters of the issues impacting reproducibility identified in part 1 and following adjustment of processes, part 2 of the round robin test showed a high interobserver agreement in EGFR immunohistochemistry scoring, with an overall concordance rate of 90.9% and a mean coefficient of 0.812. Specimens with a reference EGFR immunohistochemistry score of lower than 200 and of 200 or higher showed mean concordance rates of 94.7% and 85.6%, respectively.Conclusions.-After appropriate training, assessing EGFR expression by this immunohistochemistry-based method allowed a highly reproducible allocation of nonsmall cell lung cancers into clinically relevant high-or low-EGFR expression groups.

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“…In one small phase II study, unselected patients with advanced NSCLC were treated with erlotinib after failure of first-line chemotherapy (28). In 14 patients, paired tumor biopsies were obtained before treatment and after 6 weeks of therapy.…”

Section: Serial Tumor Biopsiesmentioning

confidence: 99%

Pharmacodynamic Biomarkers: Falling Short of the Mark?

Gainor

Longo

Chabner

2014

Clinical Cancer Research

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In recent years, the clinical development of targeted therapies has been advanced by a greater understanding of tumor biology and genomics. Nonetheless, drug development remains a slow and costly process. An additional challenge is that targeted therapies may benefit only a subset of patients treatedtypically those patients whose tumors are dependent on the target of interest. Thus, there is a growing need for the incorporation of both predictive and pharmacodynamic (PD) biomarkers in drug development. Predictive biomarkers are important to help guide patient selection, while PD biomarkers can provide information on the pharmacologic effects of a drug on its target. PD studies may provide insights into proof of mechanism (i.e., Does the agent hit its intended target?) and proof of concept (i.e., Does hitting the drug target result in the desired biologic effect?). PD studies may also provide information on the optimal biologic dosing or scheduling of a targeted agent. Herein, we review PD endpoints in the context of targeted drug development in non-small cell lung cancer, highlighting some of the key challenges encountered to date. In doing so, we discuss recent experiences with repeat tumor biopsies, surrogate tissue analysis, alternative clinical trial designs (e.g., window-of-opportunity trials), circulating biomarkers, and mechanism-based toxicity assessments. The application of such technologies and biomarkers in early clinical trials may facilitate rational drug development, while enhancing our understanding of why certain targeted therapies succeed or fail.

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A Phase II Pharmacodynamic Study of Erlotinib in Patients with Advanced Non–Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy

Cited by 67 publications

References 34 publications

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

Reproducibility of Immunohistochemical Scoring for Epidermal Growth Factor Receptor Expression in Non–Small Cell Lung Cancer: Round Robin Test

Pharmacodynamic Biomarkers: Falling Short of the Mark?

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