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R. McCormack



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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-022 - Investigating the utility of plasma derived circulating free DNA for the detection of epidermal growth factor receptor (EGFR) mutations in European and Japanese patients with advanced non-small-cell lung cancer (NSCLC): ASSESS study design (ID 1801)

      09:30 - 09:30  |  Author(s): R. McCormack

      • Abstract

      Background
      In patients with NSCLC, accurate and accessible EGFR mutation testing is important for guiding treatment decisions. Current procedures involve the testing of biopsy or cytology samples, which are not always available from all patients. However, plasma of patients with advanced NSCLC contains circulating-free tumor-derived DNA (cfDNA) that is suitable for mutational analysis. The large, multi-center, non-interventional, non-comparative ASSESS diagnostic study (NCT01785888) will evaluate the utility of plasma-based testing compared with tissue or cytology-based testing as a less invasive methodology by which to assess EGFR mutation status in patients with NSCLC.

      Methods
      A total of 1300 patients (age ≥18 years in Europe; ≥20 years in Japan) with newly diagnosed locally advanced/metastatic (Stage IIIA/B/IV) chemotherapy-naïve NSCLC who are not eligible for curative treatment, or patients with recurrent disease after surgical resection with/without adjuvant chemotherapy, will be screened for EGFR mutation status in tumor and plasma across Japan and 7 European countries over 18 months. To allow determination of sensitivity between tumor and plasma-based EGFR screening (95% confidence interval [CI] 40-60%, assuming 50% sensitivity), 100 patients each with mutation-positive NSCLC in Europe (EGFR mutation frequency: ~10%) and Japan (EGFR mutation frequency: ~30%) will be required; 1000 and 300 patients will therefore be enrolled from Europe and Japan, respectively. Provision of tumor (biopsy/cytology/other tumor cell sample) and plasma samples for EGFR mutation testing will be mandatory. Precise clinical phenotyping will be performed, and clinical information about first line (all patients) and second line (patients with mutation-positive NSCLC) therapy decisions will be recorded. EGFR testing will be performed according to local practices, with Exon 19 deletions and L858R point mutations assessed as a minimum. The primary objective is determination of concordance between EGFR mutation status obtained via tissue/cytology and plasma-based testing (concordance rate, sensitivity, specificity, positive and negative predictive values, and exact 2-sided 95% CIs). Secondary objectives: determination of EGFR mutation frequency (including mutation subtypes) in patients with adenocarcinoma/non-adenocarcinoma NSCLC; description of first-line (all patients) and second-line (all available patients) therapy following mutation testing; characterization of current EGFR testing practices; correlation between EGFR mutation status identified in tumor/plasma samples and demographic/disease status data. Pre-planned exploratory objective: investigation of exploratory biomarkers which may help to define molecular features of NSCLC (prevalence, co-occurrence, correlation with demographic data) using optional, additional tumor (biopsy/cytology/other) samples. The secondary analyses from the study will help define the current status of EGFR mutation testing procedures across Japan and Europe, and provide further information regarding mutation frequency across patient subgroups, and the relationship between EGFR mutation status and therapy decisions.

      Results
      Not applicable.

      Conclusion
      Not applicable.

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    P1.21 - Poster Session 1 - Diagnosis and Staging (ID 169)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P1.21-002 - A survey of EGFR mutation frequency and testing practices in Asia Pacific (ID 1213)

      09:30 - 09:30  |  Author(s): R. McCormack

      • Abstract

      Background
      The efficacy of EGFR TKIs in EGFR mutation-positive NSCLC patients has led to a need for accurate, timely EGFR mutation testing worldwide. Although EGFR mutation testing has been adopted by many laboratories in Asia, accurate data are lacking on the proportion of NSCLC patients tested in each country, and the most commonly used testing methods. The objectives are to investigate the practice of EGFR mutation analysis in Asian Pacific countries and document the prevalence of routine testing in this population.

      Methods
      This is a retrospective database survey of records from NSCLC patients tested for EGFR mutations from 1 January 2011 to 1 January 2012 at participating sites across the Asia Pacific region. The majority of eligible hospitals/laboratories that participated had performed ≥ 100 EGFR mutation tests during that period. Accessible patient records were used to complete an online questionnaire, with data being stored in a central database. Primary objectives were to determine the number of NSCLC patients tested for EGFR mutations and the rate of EGFR mutation positivity: overall, by histological subtype, and by demography. Other variables included the number of NSCLC cases diagnosed, EGFR mutation testing methods used, and tumour sample characteristics and processing. The proportion of EGFR mutation-positive patients and 95% CI were calculated; other variables will be summarized descriptively. An interim analysis has been conducted using data collected from more than 18,000 newly diagnosed NSCLC patients at 29 sites.

      Results
      The data from surveyed sites indicates that the overall proportion of NSCLC patients tested for EGFR mutations was 31.9% (95% CI 31.2-32.6%), with an EGFR mutation positivity rate of 40.2% (95% CI 39.1-41.4%) overall, ranging from 28.7% to 53.4% (Table). Additional data on demographic and histological subgroups and current testing practices (methods, sample types, sample preparation) will be presented. [*: Wilson score confidence interval. **: Note that the sites from Vietnam (one site) and Philippines (one site) did not test ≥ 100 patients. N.D.: No data.]

      Table: Proportion of Patients Tested and EGFR Mutation Rates at Participating Sites
      Country Total number of newly diagnosed NSCLC patients Proportion of patients tested, % (95% CI*) EGFR mutation positivity, % (95% CI*)
      Total 18,050 31.9 (31.2-32.6) 40.2 (39.1-41.4)
      Japan 2,379 64.8 (62.9-66.7) 30.2 (28.0-32.6)
      China 12,086 18.3 (17.6-19.0) 38.1 (36.3-39.9)
      Taiwan 2,530 52.9 (50.9-54.8) 53.4 (50.7-56.0)
      Hong Kong 399 31.1 (26.7-35.8) 49.2 (40.6-57.9)
      Malaysia 357 98.6 (96.8-99.4) 45.7 (40.6-51.0)
      Thailand 249 57.8 (51.6-63.8) 45.1 (40.6-49.8)
      Vietnam** 50 100.0 (92.9-100.0) 36.0 (24.1-49.9)
      Philippines** N.D. Not Known 38.9 (29.5-49.2)
      Indonesia N.D. Not Known 28.7 (20.8-38.2)

      Conclusion
      The data collected in this survey indicate that, in 2011, testing practices varied widely across the region, despite the well-known high incidence of the mutation. The data provide an insight into these practices and provide a reference platform on which to compare and build on for the future of EGFR mutation testing and molecular diagnosis of NSCLC in Asia Pacific.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-022 - Phase IV, single-arm study of first-line gefitinib in Caucasian patients with epidermal growth factor receptor (EGFR) mutation-positive, advanced non-small-cell lung cancer (NSCLC): post-hoc exploratory analyses of EGFR mutations in plasma-derived cfDNA samples (ID 1868)

      09:30 - 09:30  |  Author(s): R. McCormack

      • Abstract

      Background
      Study NCT01203917 assessed the efficacy and safety/tolerability of the EGFRTKI gefitinib in Caucasians with EGFR mutation-positive NSCLC (previously reported). Here we report post-hoc EGFR mutation analyses of plasma-derived, circulating-free DNA (cfDNA), including efficacy (objective response rate [ORR] and progression-free survival [PFS]) by mutation subtype (Exon 19 deletions; L858R point mutations).

      Methods
      Patients: Caucasians; ≥18 yrs; PS 0-2; histologically confirmed Stage IIIA/B/IV EGFR mutation-positive NSCLC eligible for first-line treatment. Treatment: 250mg gefitinib once-daily until disease progression. Primary endpoint: ORR (investigator assessment); secondary endpoints: disease control rate, PFS, overall survival, and safety/tolerability (previously reported). Mandatory tumor and plasma samples were collected at baseline (all screened patients). Post-hoc exploratory analyses: correlation between clinical characteristics and baseline plasma cfDNA EGFR mutation status; concordance of plasma cfDNA mutation subtype determination (Exon 19 deletions; L858R) with tumor; gefitinib efficacy by plasma cfDNA mutation subtype (Exon 19 deletions; L858R).

      Results
      Of 1060 screened patients with NSCLC, 118 presented with activating, sensitizing EGFR mutations, 106 of whom were enrolled and treated with gefitinib (Full Analysis Set; 71% female; 97% adenocarcinoma; 64% never-smoker). Mutation rate for samples with known mutation status: 14% (118/859) in tumor, 10% (82/784) in plasma. Among 784 patients with baseline plasma samples of known mutation status, histology (adenocarcinoma vs non-adenocarcinoma; odds ratio [OR] 5.54; p=0.0012), smoking status (never- vs ever-smoker; OR 4.39; p<0.0001), and gender (female vs male; OR 2.68; p=0.0004) independently predicted plasma cfDNA mutation status. Concordance in 652 matched tumor and plasma- Exon 19 deletions: 96% (confidence interval [CI]: 95-98); L858R: 98% (CI: 96-99). Using tumor mutation status as reference, EGFR mutation test sensitivity in cfDNA (Exon 19 deletions) was 68% (CI: 56-78), specificity was 100% (CI: 99-100); positive predictive value: 100% (CI: 93-100); negative predictive value: 96% (CI: 94-98); results were similar for L858R, with numerically lower sensitivity (62%; CI 44-78%). ORR for patients with both EGFR mutation-positive tumor and plasma for Exon 19 deletions (n=45): 82% (CI: 69-91); L858R (n=20): 65% (CI: 41-85) (Table). Median PFS for patients with both EGFR mutation-positive tumor and plasma for Exon 19 deletions (25 events): 10.3 months (CI: 8.5-12.4); L858R (11 events): NC. Table

      ORR with gefitinib: baseline tumor vs plasma samples
      Tumor Plasma
      N Responders ORR, % 95% CI N Responders ORR, % 95% CI
      All mutations 106 74 70 61-78 65 50 77 65-86
      Exon 19 deletions 69 50 73 61-82 45 37 82 69-91
      L858R point mutations 33 21 64 47-78 20 13 65 41-85
      Median PFS with gefitinib for baseline tumor vs plasma samples
      Tumor (FAS, N=106) Plasma (N=65)
      Events, N PFS, months 95% CI Events, N PFS, months 95% CI
      All mutations 61 9.7 8.5-11.0 36 10.2 8.5-12.5
      Exon 19 deletions 41 9.6 8.0-11.0 25 10.3 8.5-12.4
      L858R point mutations 19 NC NC 11 NC NC
      NC, not calculated

      Conclusion
      EGFR mutation status assessment of common mutations from plasma-derived cfDNA can be considered when tumor tissue is unavailable. In this context, cfDNA might be used to guide treatment decisions with EGFRTKI therapy, as patients with mutation-positive cfDNA, regardless of mutation subtype, appear to have similar ORR to tumor mutation-positive patients.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-053 - A diagnostic study to determine the prevalence of epidermal growth factor receptor (EGFR) mutations in Asian and Russian patients with non-small cell lung cancer (NSCLC) of adenocarcinoma and non-adenocarcinoma histology: IGNITE study design (ID 1610)

      09:30 - 09:30  |  Author(s): R. McCormack

      • Abstract

      Background
      EGFR mutation status is widely accepted as an important biomarker in NSCLC. To assess the current status of EGFR mutation testing, including testing procedures, sample types, mutation prevalence across demographic/histological subgroups (adenocarcinoma and non-adenocarcinoma histologies), and impact of EGFR mutations on personalized therapy choice, a large, multinational, diagnostic, non-comparative, interventional study (NCT01788163; IGNITE) of EGFR mutation status in patients with locally advanced/metastatic NSCLC of adenocarcinoma and non-adenocarcinoma histology will be conducted across centers in the Asia Pacific region and Russia.

      Methods
      Approximately 3500 patients (age ≥18 years) with chemotherapy naïve, Stage IIIA/B/IV NSCLC (newly diagnosed or recurrent disease after surgical resection) that is not suitable for curative treatment will be recruited over ~18 months from Asia Pacific (including 25 centers in China) and Russia. To give similar precision for the estimation of EGFR mutation frequency in the key non-adenocarcinoma subgroup in Asia Pacific and Russia, 2500 patients from Asia Pacific (assumptions: 20% patients non-adenocarcinoma histology, with 10% EGFR mutation frequency [one-fifth of the 50% prevalence in adenocarcinoma]; precision ±3%) and 1000 patients from Russia (assumptions: 20% patients non-adenocarcinoma histology, with 4% EGFR mutation frequency [one-fifth of the 20% prevalence in adenocarcinoma]; precision ±4%) need to be screened. Provision of diagnostic tumor samples for testing will be mandatory for all patients; additionally, plasma samples, which contain circulating-free tumor derived DNA (cfDNA), will be collected for EGFR mutation testing of plasma from a subset of 2500 patients in Russia, China, Taiwan and Korea. EGFR testing will be performed according to local practices, with Exon 19 deletions and L858R point mutations assessed as a minimum. The first-line (all patients) and second-line (patients with mutation-positive NSCLC; estimated 50% will progress to second-line treatment by study cutoff) therapy choices will be recorded. The primary objective is to determine EGFR mutation (and subtype) frequency in patients with adenocarcinoma and non-adenocarcinoma NSCLC (overall and by country/region). Secondary objectives are: to describe first-line therapy following EGFR mutation testing and second-line therapy following discontinuation of first-line treatment in patients with EGFR mutation-positive NSCLC confirmed by tissue/cytology; to determine concordance between EGFR mutation status determined using tissue/cytology versus plasma; to summarize current EGFR testing practices (methods, sample types, mutation detection rate, turnaround time, and reasons for not performing testing); to determine correlations between EGFR mutation status (derived from tumor or plasma) and demographic data and disease status. The secondary analyses in this study will provide information on current testing and therapeutic practices in advanced NSCLC across the Asia Pacific region and Russia, as well as an assessment of the utility of cfDNA as a less invasive methodology for the assessment of EGFR mutation status in patients with NSCLC.

      Results
      Not applicable.

      Conclusion
      Not applicable.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-020 - Epidermal growth factor receptor (EGFR) mutation analyses in tumor and plasma samples from a Phase IV, single-arm study of first-line gefitinib in Caucasian patients with EGFR mutation-positive, advanced non-small-cell lung cancer (NSCLC) (ID 1807)

      09:30 - 09:30  |  Author(s): R. McCormack

      • Abstract

      Background
      Study NCT01203917 assessed the efficacy, and safety/tolerability of the EGFR tyrosine kinase inhibitor gefitinib in Caucasians with EGFR mutation-positive NSCLC, and compared mutation status in tumor-derived DNA and plasma-derived circulating-free DNA (cfDNA).

      Methods
      Patients: Caucasians; ≥18 yrs; PS 0-2; histologically confirmed Stage IIIA/B/IV EGFR mutation-positive NSCLC eligible for first-line treatment. Treatment: 250mg gefitinib once-daily until disease progression. Primary endpoint: objective response rate (ORR; investigator assessment). Secondary endpoints: disease control rate (DCR; complete/partial response or stable disease ≥6 wks), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objectives: comparison of EGFR mutation status in tumor versus mandatory, duplicate plasma samples (all screened patients) collected at baseline (plasma1 and 2) and one optional plasma at progression.

      Results
      Of 1060 screened patients with NSCLC, 118 presented with activating, sensitizing EGFR tumor mutations, 106 of whom were enrolled and treated with gefitinib (Full Analysis Set; 71% female; 97% adenocarcinoma; 64% never-smoker). ORR (70%), DCR (90.6%), median PFS (9.7m), and median OS (19.2m) indicated gefitinib efficacy, with rash (45%), and diarrhea (31%) the most common adverse events (AEs; any grade; serious AEs: 19%) (previously reported at EMCTO 2013). Mutation rate for samples with known mutation status: 14% (118/859) in tumor, 10% (82/784) in plasma1. In 201 screened patients, tumor mutation status could not be detected due to technical reasons; however, 12 had a mutation in plasma1. Mutation status concordance in 652 matched tumor and plasma1: 94% (CI: 92-96; mutation subtype/frequencies in Table). Using tumor mutation status as reference, EGFR mutation test sensitivity in cfDNA was 66% (CI: 56-75), specificity was 100% (CI: 99-100); positive predictive value: 99% (CI: 92-100); negative predictive value: 94% (CI: 92-96). Mutation status concordance in 224 duplicate plasma samples: 97% (CI: 94-99) (subtype/frequencies in Table). ORR (post-hoc) for patients with both EGFR mutation-positive tumor and plasma1 or 2 (n=66): 77% (CI: 66-86); ORR for patients with EGFR mutation-positive tumor and EGFR mutation-negative plasma1 or 2 (n=37): 60% (CI: 44-74). Of 12 patients with baseline and progression plasma samples, 4 differences were observed: no mutations were detected at progression in 3 patients in which exon 19 deletions were detected at baseline; one patient with an exon 19 deletion at baseline acquired an additional mutation, T790M (75% concordance; CI: 43-95). Table

      Baseline tumor EGFR mutation subtype results and corresponding plasma 1 results for 652 patients with matched tumor and plasma1 samples
      Plasma1,n TOTAL
      Positive: Exon 19 deletions Positive: L858R Positive: L858R & T790M Negative
      Tumor, n Positive: Exon 19 deletions 48 0 0 23 71
      Positive: L858R 0 21 0 12 33
      Positive: L858R & T790M 0 0 0 1 1
      Negative 0 1 0 546 547
      TOTAL 48 22 0 582 652
      Baseline plasma1 EGFR mutation subtype results and corresponding plasma2 results for 224 patients with duplicate plasma1 and 2 samples
      Plasma2, n TOTAL
      Positive: Exon 19 deletions Positive: L858R Negative
      Plasma1, n Positive: Exon 19 deletions 43 0 4 47
      Positive: L858R 0 20 1 21
      Negative 1 1 154 156
      TOTAL 44 21 159 224

      Conclusion
      First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. EGFR mutation status assessment from plasma-derived cfDNA can be considered when tumor tissue is unavailable.