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K. O'Byrne



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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.07 - The prevalence of MET expression by immunohistochemistry (IHC) in the MetLung (OAM4971g) trial: a randomized, placebo-controlled, phase III study with erlotinib + onartuzumab (MetMAb) vs erlotinib + placebo in patients with previously treated non-small cell lung cancer (NSCLC) (ID 2709)

      10:30 - 12:00  |  Author(s): K. O'Byrne

      • Abstract
      • Presentation
      • Slides

      Background
      MET signaling is correlated with a poor prognosis in multiple tumor types, including NSCLC. A randomized, controlled, phase II clinical trial demonstrated a PFS and OS benefit of inhibiting MET signaling with erlotinib + onartuzumab, a humanized monovalent antibody to the MET receptor, in patients whose NSCLC over-expressed MET by IHC (in press). A phase III trial (OAM4971g) is ongoing to confirm the benefit of onartuzumab when combined with erlotinib in patients with previously treated NSCLC whose tumors over-express MET by IHC (2+/3+ only). Here, we present the prevalence rates of MET expression and EGFR mutation status for patients whose tumor tissues were screened and for those enrolled in the phase III study.

      Methods
      Archival or fresh biopsy tumor specimens were submitted to a central laboratory for both MET IHC and EGFR mutation assessment. MET IHC status was determined using the CONFIRM SP44 anti-MET monoclonal antibody (Ventana Medical Systems, Inc., Tucson, AZ). Patients were selected based on expression of MET by IHC, as defined by moderate or strong staining in at least 50% of tumor cells (clinical score 2+/3+). The cobas[®]EGFR mutation test was used to stratify enrollment.

      Results
      Between November 2011 and June 2013, 1605 tumor tissue samples were submitted for MET IHC and EGFR activating mutation analysis, from 188 clinical study centers. The majority of screened and enrolled patients were over 60 years of age, Caucasian, male, and had non-squamous NSCLC histology (see table). MET IHC results are available for 1474 (92%) of all submitted samples: IHC 0 (n=118, 8%), IHC 1+ (n=619, 42%), IHC 2+ (n=575, 39%), IHC 3+ (n=162, 11%). The incidence of MET IHC 2+/3+ in screened patient subgroups is as follows: non-squamous 52.5%; squamous 29.2%; non-Asian 45.9%; Asian 48%; EGFR wild type 50.3%; EGFR mutant 57.5%. Table: Patient characteristics for screened and enrolled patients in the OAM4971g study

      Screened (n=1605) Enrolled (n=443)
      Age (years)
      n 1482 442
      Median 63.0 62.5
      Range 24–89 24–84
      Race
      n 1482 443
      White 1187 (80.1%) 316 (71.3%)
      Asian 185 (12.5%) 72 (16.3%)
      Black or African American 44 (3.0%) 11 (2.5%)
      Sex
      n 1483 443
      Male 937 (63.2%) 244 (55.1%)
      Histology
      n 1451 440
      Non-squamous 1096 (75.5%) 374 (85.0%)
      MET IHC score
      n 1474 443
      3+ 162 (11.0%) 97 (21.9%)
      2+ 575 (39.0%) 346 (78.1%)
      1+ 619 (42.0%) 0 (0.0%)
      0 118 (8.0%) 0 (0.0%)
      EGFR activating mutation
      n 1422 443
      Yes 114 (8.0%) 46 (10.4%)
      No 1308 (92.0%) 397 (89.6%)

      Conclusion
      In this large population, the prevalence of MET IHC 2+/3+ was 50% in screened samples, consistent with prior IHC results for MET prevalence. The prevalence of MET IHC 2+/3+ was higher in non-squamous vs squamous tissue samples, but equally distributed across ethnicity and EGFR mutation status. The ongoing OAM4971g study will prospectively confirm whether blocking MET signaling in patients with MET IHC 2+/3+ over-expressing NSCLC provides clinically meaningful benefit in all enrolled patients and in important clinical subpopulations.

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    MO20 - Preclinical Therapeutic Models II (ID 93)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO20.03 - Development and characterization of a panel of GDC-0980 resistant NSCLC cell lines (ID 2798)

      10:30 - 12:00  |  Author(s): K. O'Byrne

      • Abstract
      • Presentation
      • Slides

      Background
      The PI3K-Akt- mTOR pathway regulates cell growth and proliferation and is often dysregulated in cancer due to mutation, amplification, deletion, methylation and post-translational modifications. PI3K pathway activation in NSCLC has been shown by us and others to lead to a more aggressive disease correlating to poor prognosis for patients. Multiple novel agents, targeting different regulators within the pathway are currently under development. GDC-0980 is a selective dual inhibitor of PI3K and mTOR, which demonstrated excellent downstream inhibition of the PI3K pathway in vitro, with the strongest effects being observed in lung, breast and prostate cancer cell lines. There are 12 clinical trials ongoing for this drug, with Phase I studies in solid tumours and Phase II studies in endometrial carcinoma, renal cell carcinoma, prostate cancer and breast cancer. As with all targeted therapies, acquired resistance to GDC-0980 is anticipated to be a major hurdle in the success of this drug. Multiple mechanisms of resistance to GDC-0980 may develop while a patient is being treated with this drug. The aim of this project is to develop four cell line models of resistance to GDC-0980, each representing a different molecular subtype of NSCLC, in order to predict which mechanisms of resistance may occur in patients. This will allow us to identify biomarkers of response/resistance to the drug that may dictate beneficial treatment strategies.

      Methods
      H460, A549, H1975 and SKMES-1 cells were treated with a dose response curve of GDC-0980 and BrdU proliferation assays determined IC50 values for each cell line. Each cell line was then cultured in GDC-0980 at IC50 concentrations over a period of several months, along with matched ‘parent’ cell lines. Each month, BrdU proliferation assay were carried out in order to track the development of resistance to the drug. When a log fold difference between the parent and resistant IC50s was observed, the cells were deemed to be resistant. Matched parent and resistant cells were then screened for a panel of mutations. Cells lines were also screened for gene alterations using a human cancer drug resistance PCR array. Identified genes of interest were validated at the RNA and protein level by PCR and Western blot, respectively.

      Results
      All four cell lines exhibited a dose-dependent decrease in proliferation when treated with GDC-0980. H1975 cells (adenocarcinoma; PIK3CA mutant) were most sensitive to GDC-0980, however they developed resistance to the drug more rapidly than the other 3 cell lines. Results from mutational analysis and investigation of the gene and protein expression of each of the 4 pairs of parent and resistant cell lines will be presented.

      Conclusion
      While the panel of four NSCLC cell lines all responded well to GDC-0980 treatment initially, resistance to the drug developed rapidly. As such, understanding the mechanisms involved in the development of resistance to this drug will be crucial so that we may design optimal treatment strategies. Specific conclusions regarding the mechanisms of resistance in this panel of cell lines will be drawn based on identified genes and proteins of interest.

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    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.01-012 - Co-targeting the PI3K and MEK pathways in NSCLC: an in vitro evaluation and mutation prevalence in an Irish patient cohort. (ID 2794)

      09:30 - 16:30  |  Author(s): K. O'Byrne

      • Abstract

      Background
      PI3K pathway activation in NSCLC has been shown by us and others to lead to a more aggressive disease correlating to poor prognosis for patients. Unfortunately, the success of PI3K targeted inhibition has been hampered by a high rate of innate and acquired resistance. Mutations in KRAS and B-RAF, ERK hyperactivation as well as extensive PI3K-MEK pathway cross-talk allow the MEK pathway to provide a bypass track. Preclinical studies demonstrate a rationale for a PI3K-MEK co-targeted treatment strategy which may provide a more effective response. A Phase I clinical trial is underway investigating the combination of GDC-0941, a pan-PI3K inhibitor, with GDC-0973, a MEK inhibitor. GDC-0980 is a dual PI3K-mTOR inhibitor which may offer improved pathway inhibition compared to GDC-0941. No data has been published to date on the combination of GDC-0980 and GDC-0973, which we believe may offer improved overall inhibition of survival signaling in NSCLC cells. We aim to elucidate the role of mutation status in response to this co-targeted inhibition approach in vitro, as well as investigating the frequency of PI3K and MEK pathway mutations in a well characterized Irish NSCLC patient cohort.

      Methods
      The effects of GDC-0941, GDC-0980 and GDC-0973 on proliferation and apoptosis in a panel of four NSCLC cell lines were analysed by BrdU Assay and HCA Apoptosis Assay, respectively. The four cell lines investigated were H460 (adenocarcinoma, PIK3CA mutant & KRAS mutant), A549 (adenocarcinoma, PIK3CA wild type & KRAS mutant), H1975 (adenocarcinoma, PIK3CA mutant, KRAS wild type & EGFR TKI resistant) and SKMES-1 (squamous cell carcinoma, PIK3CA wild type & KRAS mutant). Further investigation involved expression analysis of pAkt, pGSK-3β, pp70S6K, pS6RP, ERK and pERK in cell lines treated with each inhibitor alone or in combination using Mesoscale technology and Western blot. DNA was extracted from 120 NSCLC patient tissue samples, and screened for 547 mutations in 59 genes (including PI3K and MEK pathway members) using the Sequenom.

      Results
      GDC-0941 and GDC-0980 treatment induced dose-dependent anti-proliferative and pro-apoptotic responses across all four NSCLC cell lines, while GDC-0973 treatment induced only anti-proliferative responses. Protein expression analysis showed that GDC-0980 & GDC-0973 combination treatment induced significantly improved phosphoprotein inhibition compared to treatment with either inhibitor alone in cell lines harbouring PIK3CA mutations, while in one cell line bearing WT PIK3CA (SKMES-1), combination treatment actually increased pathway signalling. NSCLC patient mutational profiling data will be presented.

      Conclusion
      This research underpins the importance of mutation status in sensitivity to targeted therapies. While combination treatment approaches may be beneficial in certain molecular subtypes, in others they may be detrimental. In the era of personalised medicine, patient genotyping is crucial to improve patient survival and reduce toxicities.

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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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      P3.11-023 - Comparative safety profile of afatinib in Asian and non-Asian patients with EGFR mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC) (ID 2141)

      09:30 - 16:30  |  Author(s): K. O'Byrne

      • Abstract

      Background
      Afatinib is an oral, irreversible ErbB Family Blocker which showed superior efficacy to standard first-line chemotherapy in two large randomized Phase III trials in global (LUX-Lung 3) and Asian (LUX-Lung 6) EGFR M+ patients. In both trials, median progression-free survival on afatinib was 11 months by independent review. This was also reflected in median treatment duration of 11–12 months in both trials. With long-term treatment duration, the safety profile of afatinib becomes particularly relevant to patients and physicians, and needs to be well characterized. Furthermore, differences in the pattern of some adverse events (AEs; notably interstitial lung disease [ILD]) have been previously described in Asian and non-Asian patients with reversible EGFR tyrosine kinase inhibitors. Here, we present a detailed review of afatinib’s safety profile in Asian and non-Asian patients.

      Methods
      229 (LUX-Lung 3) and 239 (LUX-Lung 6) EGFR M+ patients were treated with afatinib 40mg daily until progression or intolerable AEs. Afatinib dose could be escalated to 50mg daily or reduced to 30mg or 20mg based on predefined study criteria. Patients from both trials were grouped according to ethnicity: Asian vs. non-Asian. On-treatment AEs were summarized by preferred/grouped terms and graded using NCI-CTCAEv3.0.

      Results
      404 Asian (66% China/Taiwan; 16% Southeast Asia; 13% Japan; 5% Korea) and 64 non-Asian patients (95% Caucasian; 3% American-Indian; 2% African-American) received afatinib, with median exposure of 359 and 261 days, respectively. There was no difference in afatinib pharmacokinetic exposure in Asian vs. non-Asian patients. All patients reported at least one AE. Most common AEs were EGFR-mediated and are summarized in the table. Figure 1 Drug-related AEs leading to discontinuation were slightly higher in Asian patients, but at a rate lower than with chemotherapy (28%). Related ILD-like events occurred in four Asian patients (three Grade ≥3) and no non-Asian patients.

      Conclusion
      Most common drug-related AEs with afatinib were EGFR mediated and occurred at similar frequency in Asian and non-Asian patients. Treatment discontinuation due to EGFR-related AEs was low in both groups, indicating that afatinib has a manageable safety profile in both populations and is suitable for long-term treatment of EGFR M+ NSCLC patients.

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    P3.22 - Poster Session 3 - Epidemiology, Etiology (ID 168)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P3.22-006 - Incidence and 5-year survival of lung cancer in Queensland, Australia: an epidemiological study. (ID 2570)

      09:30 - 16:30  |  Author(s): K. O'Byrne

      • Abstract

      Background
      Lung cancer is the fourth most common invasive cancer in Australia and was the leading cause of cancer death for both males and females in 2007. Five-year relative survival for lung cancer in Australia, which compares the risk of death for that cancer with age- and sex- matched population controls and overestimates absolute survival, is 13%. Gender based disparities have been noted, with men having worse outcomes. In this study, we publish for the first time an analysis of long-term (5 year) survival for lung cancer in Queensland, a northern state of Australia, where cancer is a notifiable disease. Differential outcomes for different tumour histologies, age groups, sex and estimated socio-economic status are compared, across 25 years spanning 1982-2006.

      Methods
      Cancer incidence and survival data on all Queensland residents diagnosed with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) between 1982 and 2009 were derived from the Oncology Analysis System, Queensland Cancer Control Analysis Team. Incidence and overall all-cause survival at five years from diagnosis were aggregated over four time periods to 2006 and stratified by histological subtype, age, gender, and estimated socioeconomic status derived from postcode information. Survival at 5 years from diagnosis was calculated using Kaplan-Meier estimates.

      Results
      The absolute incidence of lung cancer diagnoses in Queensland has increased between 1982 and 2009, from 820 cases per year (in the time period 1982-1990) to 1,632 cases per year (time period 2006-2009). The increased incidence of non-squamous NSCLC accounts for the majority of this and has increased significantly from 322/year to 1,083/year. Approximately one out of eight cases of lung cancer are SCLC. Five year survival for those diagnosed 2002-06 was 14% for all lung cancer, with a significantly worse outcome for SCLC (6%) compared with NSCLC (15%). Survival from squamous NSCLC was marginally better than non-squamous histologies (17% vs 15%). Significant discrepancies are seen in outcome related to gender (16% for women vs 13% for men) (p<0.05) and based on age (17% for those aged less than 65, and 13% for those 65 and older) (p<0.05). The outcomes are favourable compared with the five years 1982-86, where overall 5-year survival from lung cancer was 12% (4% for SCLC and 13% for NSCLC). No significant relationship was seen with outcome based on estimated socio-economic status across the entire time period, although this was not recorded for 34% of patients. For those classed as affluent or middle class, 5-year survival was 14% compared with 12% in disadvantaged areas.

      Conclusion
      Five year survival for lung cancer in Queensland, Australia compares favourably with national and international norms, and has increased over the last 25 years. There is a significantly worse outcome for men seen across all tumour subtypes, which has been noted in other tumour streams. Of note, there is no significant differential in survival based on socioeconomic status, where this could be estimated.