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H.A. Wakelee

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    ORAL 22 - Moving Beyond a Smoking Related-Cancer to the Young, Never-smokers and Inherited Disease (ID 117)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 8
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      ORAL22.01 - Increasing Incidence of Never Smokers in Non Small Cell Lung Cancer (NSCLC) Patients (ID 707)

      L. Pelosof, C. Ahn, L. Horn, A. Madrigales, J. Cox, J.N. Roberts, J. Minna, J. Schiller

      • Abstract
      • Presentation
      • Slides

      Background:
      It is estimated that 10-15% of lung cancer cases occur in never smokers. The cause of lung cancer in these patients includes many possible environmental factors but the precise cause in a given case is often uncertain. Additionally, there has been significant debate about whether the rate of lung cancer in these never smokers is increasing. Using our institutions’ cancer registry data, our objective was to determine if the proportion of never smokers with lung cancer is increasing.

      Methods:
      We conducted a retrospective study using lung cancer registry data from The University of Texas Southwestern Medical Center in Dallas, Parkland Hospital in Dallas, and Vanderbilt University in Nashville. These registries were queried between 1990 and 2013 for demographic information including gender, age at diagnosis, diagnosis [non small cell lung cancer (NSCLC) or small cell lung cancer (SCLC)], and self-reported smoking history. A total of 10,568 NSCLC cases and 1504 SCLC cases were analyzed. Logistic regression analysis was performed to assess the incidence of never smokers with lung cancer.

      Results:
      The percentage of never smokers increased among NSCLC pts between 1990 and 2013 [Table 1]. Univariate logistic regression demonstrated an increasing proportion of never smokers among NSCLC cases (p < 0.0001 for year) and multivariate logistic regression also demonstrates this increase (p < 0.0001 for year) after controlling for age and gender. Never smokers with NSCLC were more likely to be female (65.3%, p < 0.0001) than males. The increase in the percentage of NSCLC never smokers was seen at both university hospitals and the Dallas county hospital. In contrast, the percentage of never smokers among SCLC cases did not significantly increase during this time period. Table 1: Percentage of never smokers Figure 1



      Conclusion:
      This multi-institution study demonstrates an increasing proportion of never smokers with NSCLC between 1990 and 2013 in a large, geographically and demographically diverse population. Because the biology and, thus, often the treatment options of lung cancer in never smokers differs from that of smokers, further investigation is warranted as to the etiology of the increasing incidence of never-smoker lung cancer.

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      ORAL22.02 - Spectrum of Cancer Types in Kindreds with NSCLC and EGFR T790M Mutations: Results from INHERIT EGFR (ID 3180)

      G. Wiesner, R. Ashworth, J.C. Heng, I.R. Rainville, K. McReynolds, A. Sable-Hunt, J. Garber, D.P. Carbone, G.R. Oxnard

      • Abstract
      • Slides

      Background:
      EGFR T790M is most commonly seen as a somatic mutation in non-small cell lung cancer (NSCLC) following resistance to EGFR targeted therapies. Rarely EGFR T790M can be seen as a germline mutation where, in case reports, it has been associated with inherited lung cancer risk. However, the penetrance of the T790M germline mutation for NSCLC is not known, nor is it known whether germline carriers are also at risk for other cancers. The INHERIT study (INvestigating HEreditary RIsk from T790M, NCT01754025) is designed to prospectively identify and study individuals and family members with this rare germline mutation.

      Methods:
      Eligible subjects had EGFR T790M identified on routine cancer genotyping (excluding acquired T790M after therapy), or if they or a relative had already been found to carry a germline EGFR mutation. Confirmatory testing of saliva or blood was done to identify germline T790M carriers. Detailed 3-4 generation pedigrees of probands were constructed and analyzed for type of cancer, age at diagnosis, and relationship to proband with T790M mutation.

      Results:
      23 eligible kindreds were enrolled between 12/12 and 4/15, with 17 probands identified to have germline T790M and 6 probands shown to have acquired T790M. Average age at diagnosis for probands with germline T790M mutation was 55.8 (range 29 to 76) compared to 62 years (range 47 to 74) for non-germline probands. Pedigrees from confirmed T790M probands had an average kindred size of 28 members (range 3 to 40). Among the 325 1[st] and 2[nd] relatives, there were a total of 61 (18.7%) cancer diagnoses; 25 (39.7%) in lung, 4 (6.3 %) breast, 3 (4.8 %) colon, 4 (6.3) esophagus, 4 (6.3 %) leukemia/lymphoma, 3 (4.8 %) prostate, 3 (6.8%) bladder, 2 (3.2%) testes with about 1% or less with pancreatic, renal, brain, cervical cancer. Further, 7 of these 17 kindreds (41%) had multi-generational lung cancers consistent with autosomal dominant inheritance. In contrast, the cancer profile from the non-germline T790M kindreds showed high prevelance of breast cancer (61%; 13 of 21 relatives with cancer) and low prevalence of lung cancer (9%; 2 of 21). None of these 6 kindreds showed an autosomal dominant pattern of inheritance.

      Conclusion:
      A wide variety of tumor types were reported in this unique set of kindreds identified by tumor typing of probands for EGFR T790M mutations, with lung cancer as the most frequently reported cancer in close relatives. A high proportion of germline T790M kindreds also had a strong family history consistent with dominant inheritance. Future research will be needed to clarify the cancer risks in relatives of patients with EGFR T790M germline mutations and to develop guidelines and standards for prevention and early detection.

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      ORAL22.03 - Inter-, and Intratumoural Genomic Heterogeneity of Primary Pulmonary Adenocarcinoma in Never Smokers (ID 3231)

      M. Daniels, L. Krause, J. Ellis, I.A. Yang, R.V. Bowman, V. Relan, K. Chee, F. Goh, B. Parris, L. Morrison, M. Martins, E. McCaul, L. Passmore, D. Courtney, E. Duhig, R. Naidoo, K. Fong, M. Windsor

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer in never smokers may be enriched with oncogenic drivers. To explore patterns genomic changes among and within NS-LC, we performed multi-region whole genome sequencing (WGS) of primary pulmonary adenocarcinoma (LUAC).

      Methods:
      An observational study was performed on 8 cases of never-smoking LUAC resected with curative intent. Post-diagnostic residual fresh tumor was procured with informed consent, with constitutional samples from normal lung or blood. Selection criteria included: histologically confirmed LUAC; never-smoker [< 100 cigarettes in a lifetime]; no prior malignancy, cytotoxic therapy or thoracic radiotherapy. Tissue samples were procured by an anatomical pathologist (Table 1). Quality criteria were >40% tumor cellularity and <20% necrosis as assessed visually by 2 anatomical pathologists (Table 1). DNA was extracted using Qiagen AllPrep DNA/RNA Mini Kit and Blood Maxi Kit. WGS was performed on paired end libraries using Illumina's HiSeq 2000 platform (Table 1). Single nucleotide variants (SNVs) called by MuTect, Varscan, Strelka and SomaticSniper were considered ‘high priority’ if their predicted functional significance was ‘moderate’ or ‘high’ according to SNPEff. Genotyping was performed using Illumina’s HumanOmni2.5-8 array for copy number calling using the Genome Alteration Print tool.

      Results:
      14 tumour samples and 8 constitutional samples were sequenced (table 1). Figure 1 Common CNVs and SNVs were observed among and within cases (figure 1). Figure 2 In case 1, 3 of 6 (50%) genes harboring high priority variants were altered in all 4 regions. Similarly, for cases 2 and 3, 8/10 (80%) and 4/8 (50%) genes were altered by high priority variants in all regions.





      Conclusion:
      Patterns of SNVs and CNVs in LUAC demonstrate areas of common genomic changes and significant inter-, and intratumoral heterogeneity. These findings have significant implications for our understanding of lung cancer biology, also diagnostic testing of lung cancer and clinical trial design.

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      ORAL22.04 - Discussant for ORAL22.01, ORAL22.02, ORAL22.03 (ID 3356)

      P. Boffetta

      • Abstract
      • Presentation

      Abstract not provided

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      ORAL22.05 - The Genomics of Young Lung Cancer Study (ID 503)

      B.J. Gitlitz, D. Morosini, A. Sable-Hunt, B.J. Addario, M.B. Jennings, S. Novello, T. Vavala, S. Mach, C. Jones, G.R. Oxnard

      • Abstract
      • Presentation
      • Slides

      Background:
      Primary lung cancer is increasingly understood as a heterogeneous disease made up of genomically defined subtypes requiring distinct treatment strategies. We hypothesize young age at diagnosis (< 40 years) is a clinical characteristic associated with an increased chance for a targetable genomic alteration. Our ALCMI study prospectively characterizes the somatic and germline genomics of young lung cancer (GYLC). Our goals are to identify a genomically enriched subtype of lung cancer, facilitate delivery of targeted therapy and lay groundwork for further studies of heritable and environmental lung cancer risk factors.

      Methods:
      Accrual opened July 2014. Patients are eligible if they were diagnosed with bronchogenic lung cancer less than age 40. A study website allows for virtual consenting so patients can participate remotely from anywhere in the world; and use social media to share our trial. We have an integrated data and bio repository that allows for seamless communication and completion of study activities like remote consenting and routing of blood and tumor specimens. We have defined 7 genomic alterations of interest based on the Lung Cancer Mutational Consortium (LCMC) (EGFR, KRAS, HER2, BRAF, ALK, ROS1, RET). We aim to demonstrate that the prevalence of targetable genomic alterations will be greater in our population compared to the LCMC and have powered our study to show an increase from 35% to 50%; and an improvement in use of targeted therapy from 22% to 40%. On study subjects without a known genotype will undergo comprehensive genomic profiling with the FoundationOne test to ensure that all of these genes have been tested. Subjects with advanced adenocarcinoma who are wild type for all 7 genes will receive additional genomic profiling using the FoundationOne Heme test; with the goal of identifying novel oncogenic drivers. Additional investigational genomics will include blood for germline analysis and plasma genomics. All on study genomic analysis is at no cost to the participant.

      Results:
      Preliminary results of the first 33 subjects show: Average age at diagnosis: 33 years; Range 22-39; Histology: adenocarcinoma n=29, squamous cell n=4; Stage at diagnosis: stage 4 n=26 (79%) stages 1-3 n=7 (21%). Of those with stage 4 adenocarcinoma (n=24); 18:24 (75%) have either an ALK re arrangement n=10 (42%), an EGFR activating mutation n=5 (21%) or a ROS1 fusion n=3 (13%).

      Conclusion:
      The trial is currently accruing (NCT02273336) https://www.openmednet.org/site/alcmi-goyl. We have accrued patients from the USA, Europe and Australia. Thus far in our prospective series those diagnosed with primary NSCLC < age 40 tend to have stage 4 adenocarcinoma. Preliminary results exceed our statistical expectation with 75% of our metastatic adenocarcinoma patients having an actionable mutation. We plan on presenting data for the first time at WCLC-2015 on the first 50 subjects. (Study, supported by grants from BJALCF, Beth Longwell Foundation, Peter Barker Foundation, Genentech, Schmidt Legacy Foundation, and Upstage Lung Cancer)

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      ORAL22.06 - Whole Exome Sequencing to Profile the Genomic Landscapes of Young Patients (pts) Diagnosed with Non-Small Cell Lung Cancer (NSCLC) (ID 3073)

      P.C. Ma, Y. Feng, V. Varadan, X. Wu, S. Fink, W. Zhang, L. Yin, A. Liu, S. Remick, Z. Zhang, K. Guda

      • Abstract
      • Slides

      Background:
      The incidence of NSCLC in pts 45 years of age or younger is ~2% of total cases, with annual newly diagnosed cases reaching 4,500 in the United States alone. Majority of these pts are diagnosed at an advanced stage with poor outcomes. Although several specific genomic alterations have been identified in young NSCLC pts particularly in light-/never smokers, e.g. EGFR mutations, the overarching underlying causative mechanisms in the pathogenesis and progression in these young pts remain largely unknown, and likely are different from older pts. The objective of this study is to examine the genomic landscapes of NSCLC in young pts through comprehensive whole exomic survey with the objective to arrive at novel predictive and prognostic genomic biomarkers and therapeutic opportunities in young NSCLC pts.

      Methods:
      We initially identified a cohort of 20 pts (40% male) diagnosed with NSCLC at an age of ≤45, who underwent surgical resection for the primary tumors or metastatic lesions at Cleveland Clinic from 2000-2012. Matching genomic DNA from FFPE lung tumor samples and paired-normal lung tissue/peripheral blood was subjected to whole exome sequencing using Illumina HiSeq 2000 platform. Exome variant calling was performed using GATK and/or SOAPsnp algorithms to identify somatic mutations in individual tumors. Pathway and protein-protein interaction (PPI) network analysis on mutant genes was performed using KEGG/NCI-PID databases and HotNet suite, respectively. Second cohort of young NSCLC tumor cases (n=50) were identified from the Sun Yat-sen University Cancer Center and genomic analysis is underway.

      Results:
      Majority of the tumors from the first cohort had adenocarcinoma (n=12) or squamous cell (n=4) histology. Six (6) pts were never-smokers, while the others had a median 30 pack-year cigarette smoking history. A significantly higher mutation burden was found in smokers (Median, 3.47/Mb) compared to never-smokers (Median, 0.76/Mb). We also found that the G:C→T:A transversions were more common in smokers, and C:G→T:A transitions more common among never-smokers. Key driver cancer genes such as TP53 (50%) and KRAS (17%) harbored mutations exclusively in smokers, whereas EGFR mutations (14%) were observed specifically in never-smokers. Interestingly, global pathway/PPI analysis of the mutant genes revealed distinct sub-networks associated with cell adhesion and epithelial mesenchymal transition (EMT) processes with a 7-fold enrichment in mutation frequency in these young pts when compared to their overall frequencies in the COSMIC/TCGA lung cancer dataset.

      Conclusion:
      Our study nominated novel candidate genes/pathways especially relating to cell adhesions and EMT processes, that potentially play a key role in early-onset NSCLC. Further analysis and validation of our findings could improve our understanding of lung cancer pathogenesis and eventually lead to precision therapies to benefit younger NSCLC pts.

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      ORAL22.07 - Oncogenic Profiling in Lung Adenocarcinoma Emerged in the Youth (ID 686)

      K. Tanaka, Y. Oya, T. Yoshida, J. Shimizu, Y. Horio, T. Hida, Y. Yatabe

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR, Kras mutations and EML4-ALK translocations were frequently positive in adenocarcinoma among lung cancer, and in fewer cases HER2, BRAF mutations or RET, ROS1 translocations were identified. Although adenocarcinomas emerged in the youth are estimatedly associated with some driver oncogenes including these mutations/translocations, the detail remains unknown.

      Methods:
      We retrospectively screened 55 consecutive patients who were diagnosed as stage I-IV adenocarcinoma at the age of 40 years or less in 2009-2014. We analyzed clinical and genetic characteristics among them.

      Results:
      Out of 55 patients, 21 (38%) were male, 24 (44%) were never-smoker, and 38 (69%) were stage IV, with the median age of 36 years (range; 26-40). Forty-five patients (82%) were identified some driver oncogene. 26 (47%) had EML4-ALK translocation, 13 (24%) had EGFR mutation, and 2 (4%) had Kras mutation. We examined rare oncogenes in 10 out of 14 triple-negative patients, which revealed three patients had HER2 mutation and two had RET translocation.

      Conclusion:
      82% of adenocarcinomas emerged in the youth were identified some targetable driver oncogenes. Not only EGFR mutation or EML4-ALK translocation, rare oncogene examination is necessary especially among these populations.

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      ORAL22.08 - Discussant for ORAL22.05, ORAL22.06, ORAL22.07 (ID 3562)

      B.P. Levy

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI03.10 - Rociletinib in NSCLC Patients with Negative Central Testing for T790M in TIGER-X (ID 951)

      H.A. Wakelee

      • Abstract
      • Presentation
      • Slides

      Background:
      Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. New insights into mutEGFR NSCLC suggest clonal heterogeneity – activating EGFR mutations are truncal (present in all tumor clones) and T790M is a dominant branch mutation with variable clonal frequency between patients and over time. The extent of this clonal heterogeneity may relate to rociletinib efficacy. Here we present preliminary findings to evaluate this hypothesis from an ongoing Phase 1/2 clinical trial.

      Methods:
      TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with metastatic or unresectable locally advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). Screening included mandatory tumor biopsy and T790M testing. For Phase 1, patients could be T790M negative, positive or unknown. For Phase 2, T790M negative patients (by validated central testing) could have a contemporaneous local T790M+ result.

      Results:
      As of March 2015, 36 patients were enrolled in TIGER-X who were T790M central negative by cobas® or Qiagen therascreen® and evaluable for efficacy. Sensitivity analysis indicated that the 2 assay platforms were comparable for T790M detection. 69% (25/36) were T790M negative centrally but positive locally; 4/36 (11%) were negative by both central and local testing; and 7/36 (19%) were centrally negative with no local result. Median number of previous TKIs was 1 and median number of previous therapies was 2; 81% (29/36) were treated with a TKI as their most recent prior therapy. In central negative/local+ patients the ORR was 40% (10/25). In central negative/local negative patients the ORR was 25% (1/4). The most common treatment emergent adverse events in this subset (all grades) were fatigue, diarrhea, nausea and hyperglycemia.

      Conclusion:
      These preliminary findings suggest that patients who test negative for T790M using a sensitive tissue test may still benefit from treatment with rociletinib. In part, this clinical activity may be driven by T790M tumor heterogeneity, demonstrated by the discordant T790M results described. In addition, inhibition of IGF-1R/IR by the previously reported (Soria 2014) rociletinib metabolite M502 may also be driving some of the activity observed. This possible explanation is important, since the response rates reported herein are higher than described for other T790M inhibitors in T790M-negative patients. Furthermore, TKI re-treatment effect is unlikely to be a major driver of these results, since the majority of patients came on study directly after progression on another EGFR TKI. To further explore these findings, the open-label TIGER-2 (NCT02147990) and the randomized Phase 3 TIGER-3 (NCT02322281) studies include T790M negative patients.

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    MINI 08 - Prognostic/Predictive Biomarkers (ID 106)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI08.04 - VeriStrat® and Epidermal Growth Factor Receptor Mutation Status in a Phase 1b/2 Study of Cabozantinib +/- Erlotinib in Non-Small Cell Lung Cancer (ID 552)

      H.A. Wakelee

      • Abstract
      • Presentation
      • Slides

      Background:
      VeriStrat is a blood-based multivariate proteomic test that predicts response to second line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy in non-small cell lung cancer (NSCLC). We report a retrospective blinded analysis of VeriStrat classification in plasma samples from a phase 1b/2 trial of cabozantinib (C) +/- erlotinib (E) in metastatic NSCLC patients who had all progressed after benefiting from EGFR TKI therapy. Cabozantinib inhibits the MET/hepatocyte growth factor (HGF) pathway, and VeriStrat may be a surrogate marker for this pathway.

      Methods:
      Patients enrolled into phase 1b (1A:60 mg C+150 mg E, 2A:60 mg C+100 mg E, 3A:100 mg C+100 mg E, 4A:100 mg C+50 mg E, 2B:40 mg C+150 mg E) and phase 2 (Arm A:100 mg C, Arm B:100 mg C+50 mg E). EGFR mutation (EGFRm) status was tested on archival tissue and/or plasma when available. The primary objective was to determine if pre-treatment VeriStrat (VS) classification, good or poor, was prognostic for patients treated with cabozantinib +/- erlotinib. Kaplan-Meier method and log-rank test was used to compare progression-free survival (PFS) of VS-good v. VS-poor patients. Outcomes were stratified by EGFRm status (mutated v. wild type WT/unknown UNK).

      Results:
      Of 79 evaluable patients, 71 were classified as VS-good and 8 as VS-poor. 55.7% had an activating EGFRm (majority exon 19 del/exon 21 L858R) and 12.7% had UNK EGFRm status. There were no significant differences in patient characteristics between VeriStrat-groups. VS-good patients had a statistically improved PFS: VS-good 3.7 mo. (95% CI 3.5-5.4) v. VS-poor 1.9 mo. (95% CI 1.1-3.4), p=0.014. This was still true after excluding 14 patients who had received cabozantinib alone (p=0.005). There was no difference in PFS for VS-good patients when stratified by EGFRm status. There was also no difference in PFS for VS-poor patients with WT/UNK EGFR v. VS-good patients irrespective of EGFRm status. However, VS-poor patients with WT/UNK EGFR had improved PFS compared to VS-poor patients with an EGFRm (3.1 mo. v. 1.6 mo., HR 0.15, 95% CI 0.03-0.68).

      Conclusion:
      VeriStrat is a strong prognostic marker in this study. This study suggests cabozantinib neutralized the worse prognosis of VS-poor patients with WT/UNK EGFR. Given the heterogeneity of treatment dosing, the small number of VS-poor patients, and a high proportion of unknown EGFRm (including T790M) status, this analysis should be considered exploratory.

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    MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      MINI16.03 - Dose Optimization of Rociletinib for EGFR Mutated NSCLC (ID 967)

      H.A. Wakelee

      • Abstract
      • Presentation
      • Slides

      Background:
      Rociletinib (CO-1686) is a novel, oral, irreversible mutant selective tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. A maximum tolerated dose was not identified in Phase 1 with 1000 mg BID the highest dose studied. Here we assess the efficacy and safety of the three doses of rociletinib (500 mg BID, 625 mg BID and 750 mg BID) selected for Phase 2 study.

      Methods:
      TIGER-X (NCT01526928) is a Phase 1/2 open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutant NSCLC progressing after ≥1 EGFR tyrosine kinase inhibitor (TKI). Efficacy is assessed using RECIST. Safety is evaluated using standard adverse event (AE) reporting.

      Results:
      As of April 2015, a total of 231 central T790M positive patients were evaluable for efficacy and 343 for safety (any T790M). All patients were enrolled in the USA (85%), Europe (9%) and Australia (6%). Baseline characteristics were similar in each dose group. The median number of prior therapies was 2. 85% had EGFR TKI as their most recent prior therapy and 10% had a history of diabetes/hyperglycemia. Immature ORRs are 53% (500 mg BID), 52% (625 mg BID) and 43% (750 mg BID), with disease control rates of 89% (500 mg BID), 87% (625 mg BID) and 82% (750 mg BID). The most common ≥grade 3 treatment-related AE was hyperglycemia [16% (500 mg BID), 25% (625 mg BID) and 35% (750 mg BID)] which was managed with oral hypoglycemic agents. Only one patient discontinued the study for hyperglycemia. Grade 3 QTc prolongation was uncommon, occurring in 2% (500 mg BID), 7% (625 mg BID) and 10% (750 mg BID) of patients, and demonstrated a relationship to dose. There were no clinically relevant cutaneous toxicities with 7 cases of grade 1 rash and 4 cases of grade 1 stomatitis (no dose relationship) and no paronychia.

      Conclusion:
      All 3 Phase 2 doses of rociletinib are active and well tolerated in a Western patient population with advanced NSCLC. The lack of cutaneous toxicities confirms the selectivity of rociletinib for mutant forms of EGFR and is an important contributor to QOL and maintaining dose intensity (Lacouture et al. 2011). Overall, the adverse event frequency appears to be related to dose, but antitumor activity does not, thus the risk/benefit profile may be optimal at the lowest dose studied.

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      MINI16.04 - Activity of Rociletinib in EGFR Mutant NSCLC Patients with a History of CNS Involvement (ID 965)

      H.A. Wakelee

      • Abstract
      • Presentation
      • Slides

      Background:
      Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) with activity against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). An overall response rate of 67% has previously been reported in this trial for T790M positive patients treated with the 500 and 625 mg BID doses (Soria 2014). Here we provide preliminary data on the activity of rociletinib in the subgroup of patients with a history of CNS disease.

      Methods:
      Patients with a history of CNS disease were permitted if asymptomatic and stable, as defined by steroid requirements. The primary activity endpoint was RECIST overall response rate. However, patients who developed progressive disease (PD) while on study treatment were allowed to continue therapy with rociletinib if deemed clinically beneficial by the investigator.

      Results:
      As of 16 March 2015, a total of 401 patients received therapeutic dose levels of rociletinib (500, 625 and 750 mg BID) including 170 (42%) patients with a history of CNS metastases. Based on this interim analysis, the RECIST overall response rate among these patients with a history of CNS disease is 41%. To date, 42 patients with a history of CNS disease have continued therapy with rociletinib post-progression. Of those who continued for at least 14 days the average treatment duration beyond PD was 89 days (range: 14 - 336 days). Twenty-two of the 42 patients with a history of CNS disease with PD also received brain radiation and continued rociletinib treatment for an average of 120 days (range: 22 – 336 days) after PD. Rociletinib is held on radiation days only. Progression-free survival data for these subgroups is not yet mature. The three most common adverse events in the patient population with a history of CNS disease are similar to those found in the general TIGER-X patient population: hyperglycemia, diarrhea and nausea.

      Conclusion:
      In patients with a history of CNS disease, a factor associated with poor prognosis, rociletinib is active with a RECIST response rate of 41%. Local CNS radiation has been administered safely with rociletinib held on radiation days and continued afterwards. Prolonged use of rociletinib post CNS radiation suggests ongoing systemic benefit is still experienced by these patients. The role of rociletinib in NSCLC patients with CNS involvement is being further explored in the ongoing TIGER clinical development program.

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    MINI 30 - New Kinase Targets (ID 157)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
    • +

      MINI30.04 - A Randomized Phase 2 Trial of Cabozantinib, Erlotinib or the Combination as 2nd or 3rd Line Therapy in EGFR Wild-Type NSCLC: ECOG-ACRIN E1512 (ID 404)

      H.A. Wakelee

      • Abstract
      • Slides

      Background:
      Cabozantinib (C) is a small molecule inhibitor of multiple receptor tyrosine kinases, including MET, VEGFR2 & RET. MET is involved in tumor differentiation & VEGFR2 is a mediator of angiogenesis. Erlotinib (E) is FDA approved for the treatment of NSCLC.

      Methods:
      The primary objective of this randomized phase 2 study was to compare progression-free survival (PFS) of pts treated with E vs. C, & E vs E+C; each comparison had 91% power to detect a PFS hazard ratio (HR) of 0.5 with a 1-sided 0.10-level test stratified on prior number of therapies & ECOG PS. Secondary objectives included overall survival (OS), RECIST 1.1 response & CTCAE v4 toxicity. Pts were selected with previously treated (1-2 regimens) metastatic non-squamous EGFR wt NSCLC. Submission of archival tissue for central MET IHC testing was required. Oral daily dosing was: E-150 mg; C-60 mg; E+C-150 mg E, 40 mg C. Imaging was performed every 8 weeks. Pts optionally crossed over to E+C following progression on E or C.

      Results:
      125 pts were enrolled, of which 115 were eligible & treated (E, n=39; C, n=39; E+C, n=37). Pt characteristics were balanced between arms except for lower rate of brain mets history on E (p=0.02). Median follow up is 8.5 m. Compared with E (median 1.9 m), PFS was significantly improved on C (3.9 m, HR 0.33, p=0.0002, 80% CI 0.22-0.49) & E+C (4.1 m, HR 0.31, p=0.0002, 80% CI 0.21-0.46). Similarly, compared with E (median 4.0 m), OS was significantly improved on C (HR 0.52, p=0.02) & E+C arm HR 0.50, p=0.02). Grade 3-4 treatment-related hypertension & mucositis were higher on C and grade 3-4 diarrhea was higher on E+C. Overall worst grade toxicities were also significantly higher on C and E+C. MET IHC results were available on 88 patients from the primary analysis & 85% were positive (1-3+ membrane or cytoplasm staining with MET4 antibody). There was no correlation between MET status and PFS.

      Conclusion:
      C & C+E significantly improved PFS over E alone in pts with EGFR wt NSCLC. Cabozantinib-based regimens are promising for further investigation in this patient population. Funded by ECOG-ACRIN and NCI Contract No. HHSN261200800001E.

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    MINI 31 - ALK (ID 158)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI31.13 - Symptoms and QOL with Ceritinib in ALK+ NSCLC Patients with/without Brain Metastases (ID 1655)

      H.A. Wakelee

      • Abstract
      • Slides

      Background:
      In the pivotal ASCEND-1 study, ceritinib, an anaplastic lymphoma kinase inhibitor (ALKi), showed clinical activity in patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), including in patients with brain metastases (BrM). Here, patient-reported outcomes (PROs) from the recently reported ASCEND-2 study (NCT01685060) are described for chemotherapy- and ALKi-pretreated patients with ALK+ NSCLC with and without baseline BrM

      Methods:
      In ASCEND-2, adult patients with ALK+ NSCLC previously treated with chemotherapy and an ALKi (crizotinib) received oral ceritinib 750 mg daily. PROs were assessed at baseline and Day 1 of treatment cycles 2, 3, and every two cycles thereafter (1 cycle=28 days), using the Lung Cancer Symptom Scale (LCSS) and EORTC quality of life and lung cancer surveys (QLQ-C30 and QLQ-LC13, respectively). Data were analyzed by presence/absence of baseline BrM. Data beyond cycle 9 are not reported due to small sample sizes.

      Results:
      All 140 patients enrolled (median age [range] 51 [29–80] years; 50.0% male), had received ≥2 antineoplastic regimens and 100 (71.4%) had BrM at baseline. At data cutoff (13 August 2014), median follow-up was 11.3 months. PRO questionnaire compliance was at least 91.2% up to cycle 9. In the overall patient population, investigator-assessed disease control rate (DCR) was 77.1% and median duration of response (DOR) 9.7 months. Investigator-assessed whole-body DCR [95% confidence interval (CI)] in patients with and without baseline BrM was 74.0% [64.3, 82.3] and 85.0% [70.2, 94.3], respectively, while DOR [95% CI] was 9.2 [5.5, 11.1] and 10.3 [7.4, 16.6] months, respectively. Analysis of PROs data demonstrated that treatment with ceritinib improved lung cancer symptoms in patients with and without baseline BrM (Figure). QLQ-LC13 outcomes were broadly consistent with those of LCSS. In general, mean global quality of life (QLQ-C30) was maintained on treatment for both patient subgroups, with mean change from baseline in QLQ-C30 global health status ranging from -3.06 to +7.25 in patients without baseline BrM and -2.83 to +3.55 in those with baseline BrM. Figure 1



      Conclusion:
      In patients with ALKi-pretreated ALK+ NSCLC who received prior chemotherapy and ceritinib, clinical efficacy was demonstrated and cancer symptoms were mostly improved, with health-related quality of life generally maintained regardless of presence or absence of baseline BrM.

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    MS 03 - Is Tumor Angiogenesis Still a Viable Target in Advanced NSCLC? (ID 21)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MS03.04 - An Update on Clinical Trials: Is Tumor Angiogenesis Still a Viable Target in Advanced NSCLC? (ID 1859)

      H.A. Wakelee

      • Abstract
      • Presentation
      • Slides

      Abstract:
      When the results of E4599 were presented over a decade ago the era of anti-angiogenesis in the treatment of advanced stage NSCLC began. Though the overall survival benefit with the addition of the vascular endothelial growth factor (VEGF) antibody, bevacizumab, to carboplatin/ paclitaxel was only 2 months, it was not only the first randomized phase III trial to show a survival benefit with the addition of any agent to a first line platinum doublet, but also the first to break the 12 months overall survival barrier in a first-line advanced stage NSCLC trial.(Sandler 2006) The enthusiasm lessened with the results of AVAiL, which failed to show an overall survival benefit when bevacizumab was added to cisplatin/gemcitabine.(Reck 2010) However, significant response improvement has been seen in all trials with bevacizumab and many patients benefit from this anti-angiogenesis approach. Recent data from China confirmed the overall survival data from E4599 with a carboplatin/ paclitaxel chemotherapy backbone.(Zhou 2015) The use of bevacizumab with multiple different chemotherapeutics has been explored, and many agents have been added to the E4599 backbone regimen, unfortunately with limited success to date. Ongoing trials continue to utilize this strategy including with everolimus, vorinostat, cixutumumab, GDC-0941, TG4010, and innumerable others. Of particular note, S0819 is a large randomized phase III study in the United States exploring the addition of cetuximab to carboplatin/paclitaxel +/- bevacizumab.(ClinicalTrials.gov Identifier: NCT00946712) A biosimilar bevacizumab (Pf 06439535) is under investigation in a randomized phase III trial of 798 patients in combination with carboplatin/paclitaxel, compared to the E4599 regimen.(ClinicalTrials.gov Identifier: NCT02364999) Key research questions about bevacizumab at this time focus on duration of therapy. E5508 (ClinicalTrials.gov Identifier: NCT01107626), which recently completed accrual, addresses the question of maintenance with bevacizumab. This trial builds on E4599 such that all patients receive carboplatin/ paclitaxel/ bevacizumab for 4 cycles. Those without progression at that time then continue on bevacizumab alone until progression (as per E4599) or stop bevacizumab and start pemetrexed, or receive both agents. The results of this randomized phase III trial of over 1200 patients are eagerly awaited to determine an optimal maintenance approach. The results will also determine the benefit of prolonged bevacizumab use. Earlier work with bevacizumab in a maintenance setting included the AVAPERL trial which showed promising results with the combination of pemetrexed/bevacizumab maintenance compared to bevacziumab maintenance alone after a cisplatin/ pemetrexed/ bevacizumab first line regimen in advanced nonsquamous NSCLC.(Barlesi 2013) Based on positive data in colorectal and ovarian cancer, and retrospective data in lung cancer, demonstrating a survival benefit with continuation of bevacizumab beyond progression, the phase IIIb study AvaALL (MO22097) (ClinicalTrials.gov Identifier:NCT01351415) randomizes patients to continuation of bevacizumab, or not, at the initiation of second line chemotherapy after progression on a bevacizumab containing first-line regimen.(Gridelli 2011) Overall survival is the primary endpoint and a clear survival benefit in this trial will significantly alter the treatment landscape for those patients with adenocarcinoma, without a driver mutation, who are treated with first line bevacizumab. Similar smaller studies are also ongoing. The use of bevacizmab with EGFR targeted therapy in patients with tumors harboring EGFR mutations is an area of particular interest after positive phase II trial results with the combination were published in 2014.(Seto 2014) This Japanese study showed a significant progression free survival advantage with the combination compared to single agent erlotinib as first line therapy in this patient population. Several ongoing trials seek to confirmation these results including a randomized phase II study in the United States (ClinicalTrials.gov Identifier: NCT01532089) and a non-randomized trial in Europe (BELIEF ClinicalTrials.gov Identifier: NCT01562028). Trials looking at bevacizumab in combination with newer immune targeted drugs such as the checkpoint inhibitors targeting PD-1 and PD-L1 are ongoing. The largest is a 3-arm phase III study looking at carboplatin/ paclitaxel with or without bevacizumab PLUS the PD-L1 targeted atezolizumab (MPDL3280A) compared to a control arm of carboplatin/ paclitaxel/ bevacziumab.(ClinicalTrials.gov Identifier: NCT02366143) The study will enroll 1200 patients. Smaller phase I trials of other PD-1 agents in combination with multiple different regimens include carboplatin/ paclitaxel/ bevacizumab arms. Examples include a multi-arm pembrolizumab study (ClinicalTrials.gov Identifier: NCT02039674) and a trial with nivolumab which includes a bevacizumab maintenance with nivolumab arm.(ClinicalTrials.gov Identifier:NCT01454102) Bevacizumab is not the only anti-angiogenesis agent. The VEGFR-2 antibody ramucirumab had recent approval by the US FDA when given in combination with docetaxel in the 2[nd] line setting.(Garon 2014) In contrast to bevacizumab, which is restricted to non-squamous NSCLC, ramucirumab is approved for any histology of NSCLC. Ongoing trials with ramucirumab include a large (N=462) randomized double-blind study of erlotinib with ramucirumab or placebo in EGFR mutation positive NSCLC (ClinicalTrials.gov Identifier: NCT02411448) and a phase 1 study of the agent in combination with pembrolizumab.(ClinicalTrials.gov Identifier: NCT02443324) The VEGFR TKIs continue to have unrealized potential in NSCLC. Combination studies with first-line chemotherapy have been universally negative for an overall survival benefit, though response rates and progression free survival were positive in many studies. Second line trials with docetaxel have also shown response and PFS benefit and subset overall survival benefits, particularly with nintedanib.(Reck 2014) Single agent activity of many is seen, but in a small percentage of patients. However, enthusiasm for these agents in NSCLC has waned and current trials with these drugs are limited. Bevacizumab remains an important component of first-line platinum combination therapy for many patients with advanced stage NSCLC. Ongoing trials are exploring duration of therapy questions with this drug and best ways to incorporate its use with newer immunotherapeutics. Combinations with molecularly targeted agents hold promise. Ramucirumab use may also be expanded to combinations with targeted agents pending results of ongoing trials. Resurrection of the VEGFR-TKIs in NSCLC will require further understanding of best combination therapies and better understanding of how to target them to the proper patients. The biggest challenge with anti-angiogenesis therapy remains a lack of reliable biomarkers. REFERENCES: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al.; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, et al. BEYOND: A randomized, double-bline, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer.J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. Gridelli C, Bennouna J, de Castro J, Dingemans AM, Griesinger F, Grossi F, Rossi A, Thatcher N, Wong EK, Langer C. Randomized phase IIIb trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the AvaALL (MO22097) trial. Clin Lung Cancer. 2011 Nov;12(6):407-11. Epub 2011 Jun 25. Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): An open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014 Oct;15(11):1236-44. Epub 2014 Aug 27. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. Lancet. 2014 Aug 23;384(9944):665-73.. Epub 2014 Jun 2. Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55.

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    ORAL 11 - Clinical Trials 1 (ID 100)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 2
    • +

      ORAL11.05 - Phase II Trial of Single Agent Amrubicin in Patients with Previously Treated Advanced Thymic Malignancies (ID 1288)

      H.A. Wakelee

      • Abstract
      • Presentation
      • Slides

      Background:
      Limited treatment options exist for patients with thymic malignancies (TM), and chemotherapy efficacy is often restricted by cumulative toxicity such as neuropathy (taxanes) and cardiomyopathy (anthracyclines). Single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor with minimal cardiac toxicity, was investigated in TM pts in this trial.

      Methods:
      This was an open-label single drug trial at 2 institutions. Eligible pts had TM (thymoma (T) or thymic carcinoma (TC)) with progression or relapse after at least 1 prior chemotherapy regimen, and adequate organ function including left ventricular ejection fraction (LVEF) of >50%. The initial treatment plan consisted of amrubicin at 40 mg/m[2] IV days 1-3 repeated in 3-week cycles.

      Results:
      From 7/11 to 4/14, a total of 33 patients (14T/19TC) were enrolled. There were 14 women and 19 men; age range of 30-81 years; 9 Asian, 1 African-American, 1 Hispanic and 22 non-Hispanic White pts. A high rate of febrile neutropenia (FN) led to an amended starting dose of 35 mg/m[2] days 1-3 repeated in 3-week cycles. In total, 7 pts experienced FN with 1 related death. Other grade 3/4 related events included: thrombocytopenia (n=2), neutropenia without fever (n=3), hyponatremia (n=2), hypokalemia (n=2), anemia (n=7), lethargy/fatigue (n=7), perirectal abscess (n=2), palmar-plantar erythrodysesthesia (n=3), syncope (n=2), venous embolism (n=2), and 1 pt each with sepsis, oral abscess, mucositis, chest pain, and epigastric pain. Other toxicities were generally mild and well tolerated. No significant changes in LVEF were noted on serial echocardiograms. There were 6 partial responses (4T/2TC), 21 with stable disease, and 4 with progressive disease (PD) or death at or before first assessment for a response rate (RR) of 18% and a disease control rate (DCR) of 88% (29%/11% RR in T vs TC and 100%/78% DCR in T vs TC). All but 5 patients received at least 4 cycles, and 15 tolerated >10 cycles, with 36 cycles as the highest number to date. Five patients remain on therapy.

      Conclusion:
      Amrubicin, at 35 mg/m[2 ]IV days 1-3 on a 3-week cycle, shows promise as a single agent in pre-treated patients with thymoma and thymic carcinoma with an 18% RR and no unexpected toxicity. Response rate and disease control rate was higher in the thymoma patients compared to the thymic carcinoma patients. Further exploration of amrubicin as a single drug or in combination is warranted in thymic malignancies.

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      ORAL11.07 - Computed Tomography (CT) Characteristics Associated with the Proposed IASLC/ITMIG TNM Pathologic Staging System for Thymoma (ID 1603)

      H.A. Wakelee

      • Abstract
      • Presentation
      • Slides

      Background:
      Preoperative CT imaging assists in the management of thymic malignancies (TMs), discerning resectability and the need for neoadjuvant chemotherapy. Here, we examine preoperative CT imaging characteristics in relation to the newly proposed IASLC/ITMIG TNM pathologic staging system for TMs.

      Methods:
      Inclusion criteria for this retrospective study were as follows: 1) diagnosis of thymoma, thymic carcinoma, or thymic carcinoid, 2) definitive primary surgery performed at Stanford University, and 3) pretreatment CT imaging available for review. From 01/1997-03/2015, we identified 119 TM patients who had surgery, and 47 TM patients met all inclusion criteria. The most common reason patients were excluded was for either a missing pretreatment CT (outside imaging not routinely uploaded until 2008) or having surgery for biopsy or recurrent disease. The radiologist (D.T.) was blinded to clinical data, and examined baseline CT imaging per the International Thymic Malignancy Interest Group (ITMIG) standard report terms: contour, calcification, internal density, size of longest diameter, infiltration of mediastinal fat, abutment of mediastinal vessels, vascular endoluminal invasion, abutment/invasion of mediastinal structures, elevated hemidiaphragm, pleural nodules, pleural effusion, mediastinal lymph node enlargement. A univariate analysis and a Lasso regularized general transformation prediction model were performed with all variables to examine the association with pathologic IASLC/ITMIG TNM stage (p<0.05 significant; p<0.10 trend).

      Results:
      Of 47 TM patients, 9 received neoadjuvant chemotherapy. IASLC/ITMIG pathologic stage included 35 I, 1 II, 7 IIIA, 2 IIIB, 1 each of IVA and IVB. By T stage, there were 36 T1 (encapsulated or unencapsulated+extension into mediastinal fat or mediastinal pleura), 1 T2 (pericardium), 8 T3 (lung, brachiocephalic vein, SVC, chest wall, phrenic nerve, or hilar pulmonary vessels) and 2 T4 (aorta, arch, main pulmonary artery, myocardium, trachea, or esophagus). Only one patient each had N2 and M1a disease (separate pleural or pericardial nodule). Histologies included 5 A/micronodular thymoma, 13 AB, 5 B1, 14 B2, 5 B3, and 5 C/carcinoid. There was a significant positive association with aggressive histology and higher stage (OR=10.0;p=0.02). The following CT characteristics had a statistically significant positive association with higher stage (stage 1 vs. others, T1 vs. others) in a univariate analysis: lobulated contour, infiltration of mediastinal fat, invasion of mediastinal structures, vascular endoluminal invasion, elevated hemidiaphragm. There was a trend for higher stage with larger size and the presence of calcification. In a prediction model, vascular endoluminal invasion and elevated hemidiaphragm were the most important for predicting higher stage followed by invasion of mediastinal structures>abutment of mediastinal vessels>calcification>lobulated contour> mediastinal lymph node enlargement. When excluding clearly invasive CT characteristics, only abutment of mediastinal vessels was significantly associated with higher stage.

      Conclusion:
      Preoperative CT characteristics, especially those indicating clear invasion, are most useful in delineating more advanced stage disease by ITMIG/IASLC criteria in TMs. Other primary tumor characteristics including contour, calcification, and abutment of mediastinal vessels are moderately helpful. This study is limited by the small sample size, the predominance of stage I disease, the inclusion of patients who received neoadjuvant chemotherapy, and the inherent bias of a definitive surgically treated population.

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P1.01-086 - TIGER-3: A Phase 3 Open-Label, Randomized Study of Rociletinib vs Chemotherapy in NSCLC (ID 949)

      H.A. Wakelee

      • Abstract
      • Slides

      Background:
      Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) that has demonstrated efficacy against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X, a Phase I/II dose-ranging trial, has provided evidence that rociletinib is associated with durable response and is well tolerated in patients with NSCLC and positive T790M status following progression on a TKI.[1 ]Efficacy has also been noted for patients with T790M negative status in TIGER-X.[2] TIGER-3 is designed to investigate single agent rociletinib vs chemotherapy in patients who have failed EGFR therapy and platinum-based doublet chemotherapy, which is a setting of acquired resistance and high unmet need for targeted therapeutic options. TIGER-3 will evaluate patients with T790M positive and negative status based on tumor biopsies and plasma, and biomarkers of response and/or resistance.

      Methods:
      Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC, with radiological progression on the most recent therapy will be enrolled in this phase 3, randomized, open-label study (NCT02322281). Patients must have documented evidence of a tumor with ≥1 EGFR activating mutations excluding exon 20 insertion, and prior treatment with an EGFR TKI and platinum-containing doublet chemotherapy. Patients will be randomized 1:1 to receive rociletinib twice daily (500 mg) or single agent cytotoxic chemotherapy (investigator choice specified before randomization) until disease progression according to RECIST 1.1. Patients will be stratified by presence or absence of brain metastases, ECOG performance status (0 vs 1), and race (Asian vs non-Asian). The primary endpoint is progression-free survival (PFS). Secondary endpoints include safety, objective response rates, duration of response, disease control rate, and overall survival. Kaplan-Meier methodology will assess time to event variables. The stratified log-rank and the hazard ratio will be used for comparing PFS distributions. Serial assessment of safety will be carried out based on standard adverse event reporting. Planned enrolment is 600 patients; enrolment has been open since March 2015. Sequist LV J Clin Oncol. 2014 Soria J-C EORTC-NCI-AACR 2014

      Results:
      Not applicable

      Conclusion:
      Not applicable

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-025 - Lung Cancer Incidence by Histology, Gender, Race/Ethnicity and Socioeconomic Status (ID 266)

      H.A. Wakelee

      • Abstract
      • Slides

      Background:
      The incidence trends of lung cancer (LC) by histology, gender, race/ethnicity and neighborhood socioeconomic status (nSES, derived from US Census data) have not been reported. To examine these trends, we conducted a population-based study, using data from the California Cancer Registry across three discrete time periods to correspond with Census data on nSES: 1988-1992; 1998-2002; 2008-2011.

      Methods:
      Incidence data for invasive LC were abstracted for the three time periods. In each time period, male and female age adjusted incidence rates of LC and incidence rate ratios were calculated by histologic cell type and stratified by nSES.

      Results:
      A total of 240,307 LC cases were identified across the three time periods. Histology incidence trends by race/ethnicity are shown in Figure 1 and by nSES in Table 1 for males and females. Larger declines in incidence were seen over the 3 time periods among males than females. Among males, incidence rate declines over time were seen in all race/ethnic and nSES groups, but were largest among Blacks and Hispanics. Across all races/ethnicities among males, there was a slight increase over time in the incidence of adenocarcinoma histology. Among females, incidence rate declines were seen among Hispanics regardless of nSES, mid- and high-nSES Whites, and low- and mid-nSES Blacks; incidence trends among Asian/Pacific Islander females did not change significantly over time, regardless of nSES. Among females, there were variations in incidence trends by histology with a slight increase in the adenocarcinoma histology. Figure 1Figure 2





      Conclusion:
      Our findings demonstrate differences in LC incidence over time by histology, gender, race/ethnicity and SES. While incidence rates consistently declined for males, there were greater declines in incidence for the high SES patient populations. For females, there were variations in trends by histology, race/ethnicity, and SES. These findings warrant further investigation.

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      P2.01-081 - Case Series of HER2 Mutated Metastatic Lung Adenocarcinoma and Response to HER2 Targeted Therapies (ID 799)

      H.A. Wakelee

      • Abstract
      • Slides

      Background:
      HER2 has long been recognized as an oncogenic driver in some breast and gastro-esophageal cancers. More recently, somatic mutations in HER2 have been reported in 1-2% of patients with lung adenocarcinoma, and the promise of HER2 as a treatment target in lung cancer has been suggested using anti-HER2 small molecules and antibodies.

      Methods:
      Here we report the outcomes of three patients with metastatic lung adenocarcinoma with HER2 mutations being treated with HER2 targeted therapies at a single institution.

      Results:
      The first patient is a 65yo Caucasian woman, minimal smoking history, with stage IIIA lung adenocarcinoma who then developed recurrent metastatic disease mainly in the liver after completing definitive chemoradiotherapy. She progressed through three lines of chemotherapies, with near replacement of liver with tumor. At that time she was found to have HER2 exon 20 insertion mutation (A775_G776 insSVMA) and was started on vinorelbine and trastuzumab. The main side effect was fatigue, which was tolerable. She achieved radiographic stable disease with 13% reduction of her liver metastasis as her best response by RECIST v1.1 for 6 months and significant clinical improvement before progression of disease in all sites. The second patient is a 60yo Caucasian woman, former smoker, diagnosed with stage IV lung adenocarcinoma with HER2 exon 20 insertion mutation (unknown exact sequence) with extensive bony disease. She was treated with carboplatin, paclitaxel, bevacizumab, and an investigational anti-Met therapy with initial mild decrease in lung mass and nodules after one month, then mild progression for 14 months. She was taken off trial then and started on vinorelbine and trastuzumab, and so far shows no measurable growth after 5 months on therapy. The third patient is a 35yo Asian woman, non-smoker, diagnosed with stage IV lung adenocarcinoma with HER2 exon 20 insertion mutation (unknown exact sequence) with malignant pleural effusions, bilateral lung and brain lesions, and extensive lymph node involvement. She was treated with carboplatin, pemetrexed, and bevacizumab first followed by pemetrexed and bevacizumab maintenance, with initial mild improvement then progression after 4.5 months. She was then treated with erlotinib with rapid progression within 1 month. She was then treated with afatinib 40mg daily based on the HER2 mutation, improved disease after 2 months with best response 21% reduction, then progression after 3 more months (5 months total of clinical benefit). She was then started on vinorelbine and trastuzumab. Treatment was interrupted due to one new brain lesion requiring stereotactic radiation treatment. She has shown partial response with best response of 31% on the latest imaging done 4 months after starting therapy.

      Conclusion:
      From our single institution experience, HER2 targeted therapy can provide disease control for patients with metastatic HER-2 mutated NSCLC that has progressed on previous therapies. Our results are consistent with the study by Mazières et al. Vinorelbine was dosed as 25 mg/m2 and trastuzumab as 2 mg/kg every 1 week (with 4mg/kg first loading dose) or 6 mg/kg every 3 weeks. All three patients were able to tolerate therapies well with no significant toxicities nor cardiac toxicity.

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      P2.01-086 - Ceritinib in ALK+ NSCLC Metastatic to Brain and/or Leptomeninges: The ASCEND-7 Study (ID 290)

      H.A. Wakelee

      • Abstract

      Background:
      Although the anaplastic lymphoma kinase inhibitor (ALKi), crizotinib achieves high responses in patients with ALK-rearranged (ALK+) non–small cell lung cancer (NSCLC), disease progression within 1 year can occur, with the brain/central nervous system (CNS) as a common site of progression and relapse. Ceritinib is a novel oral ALKi with 20-fold greater potency than crizotinib in enzymatic assays and crosses the blood-brain barrier with good CNS penetration in preclinical studies. In the pivotal phase 1 study (NCT01283516), ceritinib was highly active in ALK+ NSCLC patients (regardless of prior crizotinib exposure) and achieved intracranial responses in 7 of 14 patients with measurable baseline brain lesions. The adverse events profile in these patients was similar to that of the full study population.

      Methods:
      This international, prospective, phase 2, open-label study is designed to evaluate the antitumor activity of ceritinib in patients with ALK+ NSCLC metastatic to the brain or leptomeninges (ASCEND-7; CLDK378A2205). Eligible patients must have ALK+ (centrally assessed) NSCLC metastatic to the brain and ≥ 1 extracranial measurable lesion using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients must be neurologically stable ≥ 1 week prior to study drug administration and will be allocated to 1 of 5 arms depending on prior treatment:

      Arms 1-4 (patients with active* brain metastases, without leptomeningeal carcinomatosis [LC]) Prior ALKi treatment No prior ALKi treatment
      Prior whole brain radiotherapy (WBRT) Arm 1 Arm 3
      No prior WBRT Arm 2 Arm 4
      Arm 5: patients with LC with or without evidence of active lesion at baseline
      *Lesion free of local treatment (stereotactic or WBRT) or lesions in unequivocal progression after radiotherapy. Oral ceritinib 750 mg/d will be dosed on a continuous schedule and study assessments are consistent across arms. The primary and key secondary objectives are to evaluate overall response rate and disease control rate, respectively. Other secondary objectives include assessment of intracranial and extracranial responses for all patients and for each of arms 1–4; overall survival and safety for all patients and for each of arms 1–5; and ceritinib pharmacokinetics in all patients. Enrollment is ongoing.

      Results:
      This study is in the activation phase.

      Conclusion:
      This study will demonstrate the efficacy of ceritinib in ALK+ NSCLC brain metastases and leptomeningeal metastases, in both WBRT-naive patients and prior irradiated patients.

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    PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 1
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      PLEN04.03 - Randomized Phase III Trial of Adjuvant Chemotherapy with or without Bevacizumab in Resected Non-Small Cell Lung Cancer (NSCLC): Results of E1505 (ID 1608)

      H.A. Wakelee

      • Abstract
      • Presentation
      • Slides

      Background:
      Adjuvant chemotherapy for resected early stage NSCLC provides modest survival benefit. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, improves outcomes when added to platinum-based chemotherapy in advanced stage non-squamous NSCLC. We conducted a phase 3 study to evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC. The primary endpoint was overall survival and secondary endpoints included disease-free survival and toxicity assessment.

      Methods:
      Patients with resected stage IB (>4 centimeters) to IIIA (AJCC 6th edition) NSCLC were enrolled within 6-12 weeks of surgery and stratified by chemotherapy regimen, stage, histology and sex. All patients were to receive adjuvant chemotherapy consisting of a planned 4 cycles of every 3 week cisplatin at 75 mg/m[2] with either vinorelbine, docetaxel, gemcitabine or pemetrexed. Patients were randomized 1:1 to arm A (chemotherapy alone) or arm B, adding bevacizumab at 15 mg/kg every 3 weeks starting with cycle 1 of chemotherapy and continuing for 1 year. Post-operative radiation therapy was not allowed. The study had 85% power to detect a 21% reduction in the overall survival (OS) hazard rate with a one-sided 0.025-level test.

      Results:
      From July 2007 to September 2013, 1501 patients were enrolled. Patients were 49.8% male, predominantly white (87.9%) with a median age of 61 years. Patients enrolled had tumors that were 26.2% stage IB, 43.8% stage II and 30.0% stage IIIA and 28.2% of patients had squamous cell histology. Chemotherapy options were utilized with the following distribution: vinorelbine 25.0%, docetaxel 22.9%, gemcitabine 18.9% and pemetrexed 33.2%. At a planned interim analysis, with 412 of 676 overall survival events needed for full information (60.9%), though the pre-planned futility boundary was not crossed, the Data Safety Monitoring Committee recommended releasing the trial results based on the conditional power of the logrank test. At the time of interim analysis, with a median follow-up time of 41 months, the OS hazard ratio comparing the bevacizumab containing arm (Arm B) to chemotherapy alone (Arm A) was 0.99 (95% CI: 0.81-1.21, p=0.93). The DFS hazard ratio was 0.98 (95% CI: 0.84-1.14, p=0.75). Completion of treatment per protocol was 80% on Arm A and 36% on Arm B. Statistically significantly increased grade 3-5 toxicities of note (all attributions) included: overall worst grade (67% versus 84%); hypertension (8% versus 30%), and neutropenia (33% versus 38%) on Arms A and B, respectively. There was no significant difference in grade 5 adverse events per arm with 16 (2%) on arm A and 19 (3%) on arm B.

      Conclusion:
      The addition of bevacizumab to adjuvant chemotherapy failed to improve survival for patients with surgically resected early stage NSCLC.

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    PRC 04 - Press Conference 4 (ID 199)

    • Event: WCLC 2015
    • Type: Press Conference
    • Track: Other
    • Presentations: 1
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      Abstract – Randomized Phase III Trial of Adjuvant Chemotherapy with or without Bevacizumab in Resected Non-Small Cell Lung Cancer (NSCLC): Results of E1505 - Dr. Heather Wakelee, Associate Professor of Medicine (Oncology) at the Stanford University Medical Center, Stanford, California (ID 3635)

      H.A. Wakelee

      • Abstract
      • Presentation

      Abstract not provided

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    YIS - Young Investigator Session incl. Q & A with Longstanding IASLC Members (ID 238)

    • Event: WCLC 2015
    • Type: Young Investigator Session
    • Track: Other
    • Presentations: 1
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      YIS.02 - Planning an Academic Career in Lung Cancer (ID 3512)

      H.A. Wakelee

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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