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C. Toh



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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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      P1.01-016 - Treatment Outcomes among Elderly Lung Cancer Patients > 65 Years following Clinical Use of EGFR Tyrosine Kinase Inhibitor  (ID 2552)

      09:30 - 09:30  |  Author(s): C. Toh

      • Abstract

      Background:
      Elderly patients (pts) with lung cancer pose significant challenges in cancer treatment because of concurrent comorbidities and age. We examined treatment patterns and outcomes in elderly pts with advanced lung cancer prior to and after introduction of epidermal growth factor receptor (EGFR) inhibitors into clinical use.

      Methods:
      Clinical data for pts > 65 yrs derived from two databases, cohort 1(1998-2003) and cohort 2(2004-current), were used. Demographics, clinical characteristics and treatment outcomes were compared between these 2 cohorts with stage III/IV lung cancer. Chi-square and Mann-Whitney-U tests were used to compare differences between cohorts. Overall survival (OS) from the time from diagnosis to death from any cause was estimated using Kaplan-Meier method and differences were defined using the logrank test. Pairwise comparisons were analyzed with Sidak’s adjustment applied to account for multiple testing. The Cox proportional hazards model was used to model the association between survival end-points and patient cohort, with the resulting hazard ratios assessed using the Wald test. The proportional hazards assumption was verified by fitting an alternative model with inclusion of a covariate-by-time interaction term and inspection of the p-value of the interaction term for categorical variables. A 2-sided p-value of <.05 was considered statistically significant.

      Results:
      There were 397 pts (cohort 1) and 1584 pts (cohort 2) with complete data for analysis. The median age of diagnosis was not significantly different between the cohorts (72.5 yrs vs 72.8 yrs), p: 0.252. Median follow-up times were comparable. Cohort 1 had poorer ECOG at diagnosis, more males and a higher proportion of current smokers. For cohort 1, cytotoxic chemotherapy was standard of care and EGFR TKI use was minimal. In contrast, for cohort 2, 50% of pts received EGFR TKI monotherapy in 1[st] line, 30% of pts in 2[nd ]line and 33.3% of pts in 3[rd] line and beyond. There was a significant difference in OS between the both cohorts (p <.001), HR 0.75 in favor of cohort 2. Specifically women, good ECOG, never smoker status, and adenocarcinoma were associated with significantly reduced hazard of death.

      Conclusion:
      Routine EGFR TKI use in elderly > 65 yrs of age clinical setting has improved OS over the last decade. This benefit is reflected in the reduced hazards of death for specific patient subsets. Elderly pts where targeted therapies are indicated should not be deprived of therapy.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-026 - Reflex Testing of EGFR and ALK in Non-Squamous Non-Small Cell Lung Cancer (ID 476)

      09:30 - 09:30  |  Author(s): C. Toh

      • Abstract
      • Slides

      Background:
      Reflex molecular testing has affirmed the paradigm shift in the classification of tumors by genetic profile, in addition to conventional histopathology. It plays a critical role in identifying actionable targets and prompt allocation of patients to the appropriate treatment. We sought to compare the clinical characteristics and treatment outcomes between patients with genetic alterations against wild-type (WT) tumors for both EGFR and ALK in non-squamous non-small cell lung cancer (NSCLC) to examine the impact of reflex testing which was recently implemented in the National Cancer Centre Singapore.

      Methods:
      We analyzed all NSCLC patients diagnosed between Jan 2010 and Mar 2014 from a prospective database maintained by the Lung Cancer Consortium Singapore. Patients underwent reflex Sanger-based EGFR analysis from 2010 and ALK-FISH analysis from 2012. These analyses were undertaken upon histological diagnosis, regardless of the AJCC stage at presentation. Clinical characteristics of the mutant and WT groups were compared using chi-squared and Mann Whitney U tests. Overall survival(OS) was estimated using Kaplan-Meier method. Survivals were compared using log-rank test, and prognostic factors were determined using multivariate cox regression.

      Results:
      The overall EGFR mutation rate in our cohort (n=1308) was 51.4%. The corresponding rates in adenocarcinoma and non-adenocarcinoma groups were 52.5% and 34.9% respectively. EGFR mutants were more prevalent among females, never-smokers, and less symptomatic. A higher proportion had better ECOG status, well to moderately differentiated histology, more sites of distant metastases especially in the lungs and bones, presented with Stage IV, , and received more lines of palliative treatment (all p<0.05). The median OS(months) for the mutant group was 24.8 versus 13.3 for the WT group (p<0.001). Prognostic factors included ethnicity, smoking status, stage, histology, number of symptoms, ECOG status, number of metastatic sites, treatment intention and EGFR tyrosine kinase inhibitor (TKI) treatment (all p<0.02). The overall ALK alteration rate (n=405) was 12.6%, 12.4% in adenocarcinoma and 15.2% in non-adenocarcinoma. Contrary to prior reports, there were no differences in gender, diagnosis age, and smoking status between fusion and WT groups. The percentage of ALK fusion among Malays was higher (26.3% vs 7.9%; p=0.031). While ALK fusion had more lines of palliative treatment than WT, there was no significant difference in OS between both groups. Prognostic factors include gender, ethnicity, ECOG status, treatment intent, and number of palliative treatment and metastatic sites (all p<0.02).

      Conclusion:
      This study demonstrated significant differences in clinical features, management and subsequent response to treatment between genetically altered and WT patients for both EGFR and ALK profiles, reiterating the importance of reflex testing in patient management. While significant survival benefit was demonstrated with EGFR TKI therapy in EGFR cohort, this was not demonstrated for the ALK cohort, which can be attributed to the relative lack of access to ALK TKI (93% treated with EGFR TKI compared to 46.6% treated with ALK TKI). Finally, the considerable rate of EGFR and ALK mutations in non-adenocarcinoma groups reflects the need to extend reflex testing to these patient groups, and not just in patients with adenocarcinoma or adenocarcinoma components.

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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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      PLEN04.05 - Multiregion Whole Exome and Transcriptome Sequencing Defines the Genomic Spectrum of EGFR+ NSCLC and Reveals Novel Mechanisms of TKI Resistance (ID 3118)

      11:29 - 11:41  |  Author(s): C. Toh

      • Abstract
      • Presentation

      Background:
      EGFR mutant (M+) NSCLC is an archetypical oncogene-driven solid tumor, typified by high response rates when treated with a tyrosine kinase inhibitor (TKI), and median progression free survival of 10 months, commonly due to emergence of T790M. The genomic architecture and spectra of EGFR M+ tumours may provide insights to mechanisms of treatment failure and has not been well described to date.

      Methods:
      Paired tumor-normal exome/ transcriptome sequencing and SNP array was performed on 30 tbiopsies from 25 patients with TKI resistance (TKI-R) as well as multiple regions (n=46) of 8 treatment naïve (TKI-N), never smoker East Asian EGFR M+ NSCLC (L858R, n=5; exon 19 del, n=2; exon 20 ins, n=1). Genomic alterations were validated with targeted re-sequencing at a mean depth of 2000x. Alterations were identified and annotated using established pipelines.

      Results:
      Exome sequencing of 46 sectors (4-11 sectors/tumor) from 8 resected NSCLC (Stage IA, n=5; Stage IB, n=3), revealed a median of 52.5 validated mutations (Range: 15-112) per tumor. Primary EGFR mutations (including exon 20 ins) were identified as truncal events in all cases, with the notable absence of T790M even at sequencing depths of 2000x. Private mutations comprised 10-33% of all mutations per tumor, and in some cases harbored potential drivers of subclonal diversity including p53, AKT1 and ATXN1. For the 30 TKI-R tumors (T790M+, n=16; T790M-, n=14), exome sequencing revealed a higher mutation burden (median 80 vs 49 in TKI-N), while SNP array and expression data confirmed ERBB2 and MET as common co-existing resistance mechanisms. We next inferred the relevance of alterations and their hierarchical order (trunk, T; branch, B; private, P). In a TKI-N tumor where 11 sectors were subject to exome-sequencing, 39 of 112 mutations were truncal events – with MAP3K19 and PTEN splice site mutations co-existing with EGFR L858R mutation. Strikingly, when comparing the transcriptomic profiles of TKI-N and TKI-R tumors, all 8 evaluated sectors in this tumor clustered together with the TKI-R signature, suggesting that truncal co-mutations can contribute to primary TKI resistance. Finally, we attempted to curate novel genes in the 46 TKI-N sectors that may be implicated in TKI resistance by identifying genes in common with those altered in TKI-R samples with allele frequency > 0.25. We shortlisted approximately 150 recurrent genes or putative drivers – 85% of which were either trunk or branch mutations including TP53 (T,P), PTEN (B), LRP1B (B), GPRIN3 (B), MAP3K19 (T), ARID3A (P) and MED12 (P).

      Conclusion:
      Multi-region sequencing of 8 never smoker EGFR M+ NSCLC revealed a low mutation burden, with a significant proportion of alterations occurring as trunk or branch events. The different activating EGFR mutations were ubiquitous truncal events and T790M was not found in ultra-deep sequencing across 46 sectors. Mutation hierarchy provides a basis for patterns of TKI treatment failure: with co-occurring truncal events (e.g. MAP3K19, PTEN) potentially contributing to primary resistance, and the low incidence of private subclonal drivers consistent with the relatively high prevalence of T790M mutation in the setting of secondary resistance.

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