Phase II pharmacodynamic trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients previously treated with platinum-based chemotherapy: FISH results

7160 Background: The HER1/EGFR inhibitor erlotinib significantly prolongs survival of patients with previously-treated advanced NSCLC. Methods for selecting patients most likely to derive clinical benefit from erlotinib are not established. Increased HER1/EGFR gene copy number has been suggested as a potential predictive biomarker of clinical benefit, and was investigated in this phase II study. Methods: Advanced NSCLC patients who failed first line chemotherapy were treated with erlotinib monotherapy, 150 mg/d p.o. Each patient underwent tumor biopsy before start of treatment. Tumor HER1/EGFR gene amplification status was assessed using FISH, and classified as positive (amplification, polysomy, high polysomy) or negative (disomy, trisomy). Results: 83 patients were included: median age 56 (range 35–78); sex: male 72%, female 28%; histology: adenocarcinoma 43%, large cell 31%, squamous cell 19%, others 7%; smoking status: 44 current smokers, 28 former smokers, 11 never smokers. Of 73 evaluable patients, 7 (10%) achieved partial response (PR), 28 (38%) had stable disease (SD) and 38 (52%) had disease progression. PRs were observed in 4 males / 3 females; in 5 adenocarcinomas / 1 large cell/ 1 squamous cell; in 2 current / 3 former / 2 never smokers. Erlotinib was well tolerated and no unexpected toxicities were seen. HER1/EGFR gene copy number was evaluated in 53 patients. 15 patients were FISH +, 10 of whom achieved clinical benefit (PR, or SD for ≥12 weeks). Only 5 of 38 FISH - patients had clinical benefit. FISH + patients achieved a longer median time to progression (137 vs 43 days; p = 0.00011; HR 0.35) as well as overall survival (226 vs 115 days; p = 0.3221, HR 0.722). Conclusion: In this study, increased HER1/EGFR gene copy number was associated with a better outcome on erlotinib therapy. [Table: see text] [Table: see text]

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9167 Outcomes with erlotinib in advanced NSCLC: examining the influence of increased EGFR gene copy number and EGFR mutations

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(09)71880-4 ◽

2009 ◽

Vol 7 (2) ◽

pp. 556 ◽

Cited By ~ 2

Author(s):

D. Soulières ◽

T. Ciuleanu ◽

L. Stelmakh ◽

R. Whittom ◽

P. Delmar ◽

...

Keyword(s):

Copy Number ◽

Advanced Nsclc ◽

Gene Copy Number ◽

Egfr Mutations ◽

Gene Copy ◽

Egfr Gene

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Correlation of the EGFR gene mutation, gene amplification and protein expression in non-small cell lung cancer with clinical outcomes of erlotinib monotherapy: An exploratory analysis of biomarkers by the Korean Cancer Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.7608 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 7608-7608

Author(s):

M. Ahn ◽

J. Ahn ◽

S. Kim ◽

H. Kim ◽

J. Lee ◽

...

Keyword(s):

Gene Amplification ◽

Copy Number ◽

Advanced Nsclc ◽

Gene Copy Number ◽

Egfr Mutations ◽

Gene Copy ◽

Egfr Gene ◽

Cancer Study Group ◽

Rate Of Response ◽

Egfr Gene Mutation

7608 Background: Mutations in epidermal growth factor receptor (EGFR) are considered to be strong predictive marker for response to the EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients. The aim of this study conducted by the Korean Cancer Study Group (KCSG) was to determine the clinical implications of EGFR gene mutation, increased gene copy number or protein over- expression in Korean patients with advanced NSCLC who had been treated with erlotinib. Patients and Methods: A total of 120 patients received erlotinib at a dose of 150 mg daily as part of an open label phase II monotherapy trial between January 2005 and May 2006 in Korea. Ninety-two tissue samples obtained from these patients were analyzed for EGFR mutations (exon 18–21), 88 samples for EGFR gene amplification by real time PCR, and 77 samples for EGFR protein expression by immunohistochemical (IHC) staining. Results: Twenty-four out of 92 patients (26.1%) had EGFR mutations in exon 18, 19, or 21, most commonly in exon 19 (75%, 18/24). A higher frequencies were noted in female patients (40.0% vs 17.5%, p=0.017). Higher rate of response to erlotinib was noted in patients with EGFR mutations compared to wild type (N=14/24 (58.3%) vs 11/68 (16.2%), p<0.001). With the median follow-up duration of 14.5 months, time to progression (TTP) and overall survival (OS) were also significantly longer in patients with mutations than those without mutations (p=0.003, p=0.042). Increased EGFR gene copy number was found in 44.9% (36/88). Patients with increased gene copy number achieved higher rate of response to erlotinib (N=14/36 (38.9%) vs 9/52 (17.3%), p=0.023). Also patients with high gene copy number showed longer TTP and OS (p<0.001, p=0.022). Forty six out of 75 patients showed (+) IHC staining for EGFR protein although there was no relationship between the EGFR expression and the response to erlotinib, TTP or OS (p=0.82, p=0.35, p=0.83). Conclusion: EGFR mutation and gene amplification were shown to be important predictive markers not only for response but also for survival of the Korean patients with advanced NSCLC who had been treated with erlotinib. No significant financial relationships to disclose.

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Molecular marker analysis of SWOG S0636, a phase II trial of erlotinib and bevacizumab in never-smokers with advanced NSCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.7552 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 7552-7552

Author(s):

Philip C. Mack ◽

James Moon ◽

Howard Jack West ◽

Wilbur A. Franklin ◽

Marileila Varella-Garcia ◽

...

Keyword(s):

Protein Expression ◽

Copy Number ◽

Gene Copy Number ◽

Careful Analysis ◽

Gene Copy ◽

Activating Mutations ◽

Molecular Selection ◽

Never Smokers ◽

Molecular Marker Analysis ◽

Nsclc Patients

7552 Background: S0636 investigated the combination of erlotinib and bevacizumab in never-smoking NSCLC patients with confirmed adenocarcinoma histology (H. West ASCO 2011). Patient eligibility was not restricted by molecular selection. Median PFS and OS were encouraging at 8 and 26 months. An analysis of molecular markers was undertaken, focusing initially on the EGFR pathway. Methods: EGFR analysis included gene copy number, mutation and protein expression. Copy number was conducted by FISH using the Colorado scoring system. An immunohistochemistry H score was developed for EGFR protein expression analysis, ranging from 0 to 400. Specimens were evaluable from 42 of the 85 eligible patients. Results: FISH positivity was identified in 17/35 pts (49%), 11 with high polysomy and 6 with true gene amplification. EGFR activating mutations were seen in 10/33 pts (30%). IHC H-score >200 was observed in 17/40 pts (43%). All EGFR markers were significantly correlated with one another. In the EGFR WT subgroup, FISH-positive patients outperformed FISH-negative pts (mPFS 20 vs, 6 months, p=0.06). Conclusions: Careful analysis of EGFR markers (mutation, FISH and IHC) identified S0636 patients with favorable PFS and encouraging trends for OS. EGFR FISH and IHC provided additional predictive information beyond that of EGFR mutation status. Supported in part by DHHS: CA32102 and CA38926, and in part by Genentech. [Table: see text]

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