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  • WCLC 2016

    17th World Conference on Lung Cancer

    Access to all presentations that occur during the 17th World Conference on Lung Cancer in Vienna, Austria

    Presentation Date(s):
    • Dec 4 - 7, 2016
    • Total Presentations: 2466

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    OA13 - Immunotherapy in Malignant Pleural Mesothelioma: Current Status of Trials and New Approaches (ID 392)

    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 8
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      OA13.03 - Long-Term Overall Survival for Patients with Malignant Pleural Mesothelioma on Pembrolizumab Enrolled in KEYNOTE-028 (ID 6165)

      14:40 - 14:50  |  Author(s): E.W. Alley, J. Lopez, A. Santoro, A. Morosky, S. Saraf, B. Piperdi, J.H.M. Schellens

      • Abstract
      • Presentation
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with poor prognosis and limited treatment options after progression on platinum-containing chemotherapy. Pembrolizumab, a humanized anti–programmed death 1 (PD-1) antibody, has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types. Here, we present long-term overall survival (OS) data for patients with malignant pleural mesothelioma enrolled in the KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) study.

      Methods:
      KEYNOTE-028 is a nonrandomized, multicohort phase 1b trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. 25 patients with MPM were treated with pembrolizumab in the mesothelioma cohort. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or intolerable toxicity, death, withdrawal of consent, or physician decision. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary end point was objective response rate (ORR; per RECIST v1.1, investigator assessed). Secondary end points included safety, tolerability, progression-free survival (PFS), and OS.

      Results:
      As of June 9, 2016, median duration of follow-up was 18.7 months (range, 1.5-24.6 months), and 4 patients (16%) are still on treatment. ORR was 28% (n = 7); 12 (48%) patients had stable disease, resulting in a disease control rate of 76%; median duration of response was 9.2 months (range, 2.4-20.5+ months); median PFS was 5.8 months (95% CI, 3.4-8.2 months), with 6- and 12-month PFS rates of 50% and 25%, respectively. Median OS was 18.0 months (95% CI, 9.4 months-not reached) with 6- and 12-month OS rates of 83.5% and 62.6%, respectively. No new safety signals have been identified. Sixteen (64%) patients experienced a drug-related adverse event (DRAE), and 5 (20%) experienced grade 3/4 DRAEs. Three patients required dose interruption because of immune-related adverse events (1 each, ALT increased, iridocyclitis, and pyrexia/arthralgia]). There was no treatment-related mortality or discontinuation due to DRAE.

      Conclusion:
      Single-agent pembrolizumab has significant clinical activity in patients with PD-L1–positive MPM. Responses from pembrolizumab in patients with MPM are durable; the 62.6% 12-month OS rate in this mostly pretreated patient population warrants further investigation. Long-term administration of pembrolizumab is feasible in patients with MPM, and no new safety signals were identified.

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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 98
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      P2.03b-093 - Validation and Performance of a Standardized ctDNA NGS Assay across Two Laboratories (ID 6389)

      14:30 - 14:30  |  Author(s): T. Forshew, A. Lawson, S. Smalley, V. Plagnol, J. Calaway, S. Blais, K. Howarth, G. Jones, M. Pugh, M. Madi, B. Durham, E. Musgrave-Brown, S. Woodhouse, N. Rosenfeld, D. Gale, E. Green, J. Clark

      • Abstract

      Background:
      Molecular profiling of tumors using circulating tumor DNA (ctDNA) in the blood of cancer patients, as a liquid biopsy, is rapidly becoming established as a useful source of information to aid clinical decision-making when a solid tumor biopsy is not available, or is limited in amount or quality. DNA alterations are often found in a small fraction of the total cell free DNA in plasma, and their detection requires specially designed assays that are sensitive and reproducible. Individual hotspot mutations can be assayed using technologies such as droplet/digital PCR, but multiplexing such assays is limited by the small amount of clinical material. This can be addressed by assays based on next generation sequencing (NGS), to create sensitive panels for ctDNA analysis. For clinical application, it is essential that such NGS assays be standardized and reproducible, both intra-and inter-laboratory. Standardization for tissue-based NGS assays has only recently been implemented, after much discussion. We describe a strategy for validation and standardization of a high sensitivity NGS-based ctDNA assay between two laboratories, based in the US and UK.

      Methods:
      The enhanced TAm-Seq[®] assay (eTAm-Seq™) uses efficient library preparations and bespoke algorithms to identify cancer mutations within a panel of 34 genes, covering cancer hotspots as well as entire coding regions of selected genes. To ensure this complex process is standardised and controlled, a high level ISO and CLIA quality management system is implemented. To perform analytical validation of this assay, we used reference standards and plasma controls to demonstrate the sensitivity, specificity and quantitative accuracy of this ctDNA analysis platform.

      Results:
      We compared performance of the assay between two laboratories, finding a high rate of concordance and reproducibility. Using DNA quantities typical of those found in up to 4ml of plasma from cancer patients, our assay provides high sensitivity for variants that are present at allele fraction 0.25% or higher in plasma, and retains substantial sensitivity at allele fractions as low as 0.1%. Standard dilution curves of well-characterized reference samples show that the accuracy of the eTAm-Seq[®] assay is predominantly limited by stochastic sampling. Analysis of plasma samples from control individuals demonstrates a low false positive rate. Additional data with associated clinical data will be presented at the meeting.

      Conclusion:
      Our data demonstrates eTAm-Seq[TM] assy's robustness and performance in two labs, supporting its use as a basis for clinical applications globally, allowing a high degree of standardization and comparability for molecular profiling of tumors using liquid biopsy.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 126
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      P3.02b-102 - Osimertinib Benefit in ctDNA T790M Positive, EGFR-Mutant NSCLC Patients (ID 5472)

      14:30 - 14:30  |  Author(s): J. Remon, C. Caramella, C. Joelet, L. Lacroix, A. Lawson, S. Smalley, K. Howarth, D. Gale, N. Rosenfeld, E. Green, V. Plagnol, D. Planchard, M.V. Bluthgen, A. Gazzah, C. Pannet, C. Nicotra, J. Soria, B. Besse

      • Abstract
      • Slides

      Background:
      The third generation tyrosine kinase inhibitors (TKIs) osimertinib is approved for patients with acquired epidermal growth factor receptor (EGFR) T790M mutations in advanced non-small cell lung cancer (NSCLC) patients. New tissue biopsy to detect T790M cannot always be performed, due to the size or location of the lesions and risk of complications to the patient. As an alternative, liquid biopsies based on circulating cell-free tumor DNA (ctDNA) analysis have been described. We assess the efficacy of osimertinib in ctDNA T790M-positive, EGFR-mutant NSCLC patients with progression under first- or second-generation EGFR TKIs ineligible for tissue biopsy at progression; and the feasibility of identifying T790M mutations in ctDNA isolated from blood samples in this cohort of patients.

      Methods:
      ctDNA analysis using enhanced eTAm-Seq™ assay (Inivata), and enhanced version of the Tam-Seq ® assay was conducted in 48 eligible patients treated in a single center between April 2015 and April 2016. Patients determined to have T790M mutation were prescribed osimertinib (80mg daily). Objective response rate (ORR) by RECIST 1.1 criteria was centrally reviewed and correlated with (A) T790M allele fraction, (B) EGFR activating mutation allele fraction, and (C) T790M by EGFR activating mutation allele fraction ratio.

      Results:
      T790M status in ctDNA was assessed in 48 EGFR-mutant NSCLC patients. Median age was 65 years (range 37-83); 36 (75%) patients were women and 58% were never-smoker. EGFR mutation status was Del19 in 33 (69%) and L858R in 15 (31%) NSCLC patients. The ctDNA T790M mutation was positive in 24 out of 48 (50%) patients, and 23 out of 24 T790M-positive samples maintained the original activating EGFR mutation in ctDNA analysis. Among evaluable patients (n=16), osimertinib gave a partial response rate of 62.5% and a stable disease rate of 37.5%. Neither correlation between ctDNA T790M AF and RECIST radiological response was observed, nor with the other parameters evaluated. Of the seven cases with best response (decrease of 50% or more in size), 3 cases had T790M detected at <0.25%.

      Conclusion:
      Osimertinib efficacy in a real-world setting among T790M-positive tumours detected in ctDNA from liquid biopsy support the use of such liquid biopsies as a surrogate marker for T790M in tumour tissue, avoiding the need for invasive tumor biopsies for personalising treatment in lung cancer patients

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 103
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      P3.02c-028 - Outcomes of Nivolumab in Elderly Patients (pts) with Non-Small Cell Lung Cancer (NSCLC) (ID 5084)

      14:30 - 14:30  |  Author(s): S.J. Bagley, S. Kothari, C. Aggarwal, J. Bauml, E.W. Alley, T.L. Evans, J. Kosteva, C. Ciunci, J. Thompson, S. Stonehouse-Lee, V.E. Sherry, E. Gilbert, B. Eaby-Sandy, F. Mutale, G. Dilullo, R.B. Cohen, A. Vachani, C. Langer

      • Abstract

      Background:
      In randomized trials of nivolumab in NSCLC, less than 10% of pts were ≥75 years old, and all had Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1. The effectiveness of nivolumab in elderly pts with NSCLC treated in routine practice has not been previously described.

      Methods:
      We conducted a retrospective cohort study of pts with advanced NSCLC treated with nivolumab outside of clinical trials at the University of Pennsylvania between March 2015 and March 2016. Logistic regression and Cox proportional hazards models were used to evaluate the association of age (≥75 vs. <75 years) with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), adjusting for ECOG PS (0-1 vs. ≥2), sex, smoking history [heavy (≥10 pack-years) vs. light/never (<10 pack-years)], and number of prior systemic therapies (1 vs. ≥2).

      Results:
      Of 175 pts treated with nivolumab, 43 (25%) were ≥75 years old and 42 (24%) had ECOG PS ≥2. Ninety-five pts (54%) were female, 147 (84%) had heavy smoking history, and 81 (46%) had received ≥2 prior systemic therapies. ORR was 19.4%, with median PFS and OS of 2.1 and 6.5 months, respectively. Age ≥75 years was not associated with ORR (OR 1.0, 95% CI 0.4-2.5; p=0.97), PFS (HR 0.71, 95% CI 0.5-1.1; p=0.12), or OS (HR 0.8, 95% CI 0.5-1.4; p=0.4; Figure 1). ECOG PS ≥ 2 was associated with lower ORR (7.1% vs. 23.3%; OR 0.25, 95% CI 0.07 – 0.88; p=0.03), inferior PFS (median 1.8 vs. 2.3 months; HR 1.9, 95% CI 1.3 – 2.8; p=0.001), and inferior OS (median 3.6 vs. 7.8 months; HR 2.6, 95% CI 1.6 – 4.1; p<0.001). Figure 1



      Conclusion:
      In a large NSCLC cohort treated outside of clinical trials, elderly pts gained similar benefit from nivolumab compared to younger pts. Pts with poor performance status had inferior outcomes regardless of age.

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      P3.02c-029 - Immune-Related Adverse Events and Their Effect on Outcomes in Patients (pts) with Non-Small Cell Lung Cancer (NSCLC) Treated with Nivolumab (ID 5206)

      14:30 - 14:30  |  Author(s): S. Kothari, S.J. Bagley, C. Aggarwal, J. Bauml, E.W. Alley, T.L. Evans, J. Kosteva, C. Ciunci, J. Thompson, S. Stonehouse-Lee, V.E. Sherry, E. Gilbert, B. Eaby-Sandy, F. Mutale, G. Dilullo, R.B. Cohen, A. Vachani, C. Langer

      • Abstract

      Background:
      Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs). While the incidence of irAEs in routine practice and their effect on outcomes have been well characterized in melanoma, a similar analysis has not been previously reported in NSCLC pts treated with anti-programmed death 1 (PD-1) therapy.

      Methods:
      We conducted a retrospective cohort study of pts with advanced NSCLC who received nivolumab outside of clinical trials between March 2015 and March 2016 at the University of Pennsylvania. irAEs were graded using the Common Terminology Criteria for Adverse Events version 4.0. Data collected included demographics, timing and treatment of irAEs, and dates of disease progression and death or last follow-up. To analyze the effect of irAEs on progression-free survival (PFS) and overall survival (OS), landmark analyses were used beginning from 3 months after start of treatment. Pts who reached the PFS or OS endpoints prior to 3 months were excluded. Cox proportional hazards models were used to assess for differences in PFS and OS according to the occurrence of an irAE, adjusting for age, sex, and Eastern Cooperative Oncology Group Performance Status (ECOG PS).

      Results:
      175 pts received a median of 5 cycles of nivolumab (range, 1-24, IQR, 3-9). Median age was 68 years (range, 33-88, IQR, 60-74). Forty-six percent of pts were male; 5% had an ECOG PS ≥ 2. Twenty-eight pts (16%) experienced an irAE of any grade and 6 (3%) had a grade 3/4 irAE. Median time to onset of the irAE was 3 cycles (range, 1-18, IQR, 2-6). Of the pts who experienced an irAE, 14 (50%) were treated with systemic corticosteroids. The most common irAEs were hypothyroidism/hyperthyroidism (n=8), pneumonitis (n=6; three grade 4), colitis (n=4; one grade 3), dermatitis (n=4), and arthritis (n=2). Less common irAEs (n=1 each) included hepatitis (grade 4), aseptic meningitis (grade 3), immune thrombocytopenia, and severe hypoalbuminemia that improved with steroids. Overall response rate was 19.4% (34 of 175), and median PFS and OS were 2.1 and 6.5 months, respectively. After adjusting for age, sex, and ECOG PS, landmark analyses revealed no difference in PFS (HR 1.3, 95% CI 0.4-3.8, p=0.7) or OS (HR 0.9, 95% CI 0.3-2.7, p=0.9) stratified by the presence or absence of an irAE.

      Conclusion:
      In NSCLC pts treated with nivolumab in typical practice, irAEs of any grade were uncommon, and grade 3/4 irAEs were rare. The occurrence of irAEs was not associated with PFS or OS.

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      P3.02c-069 - Pretreatment Neutrophil-to-Lymphocyte Ratio (NLR) Predicts Outcomes with Nivolumab in Non-Small Cell Lung Cancer (NSCLC) (ID 5218)

      14:30 - 14:30  |  Author(s): S.J. Bagley, S. Kothari, C. Aggarwal, J. Bauml, E.W. Alley, T.L. Evans, J. Kosteva, C. Ciunci, J. Thompson, S. Stonehouse-Lee, V.E. Sherry, E. Gilbert, B. Eaby-Sandy, F. Mutale, G. Dilullo, R.B. Cohen, A. Vachani, C. Langer

      • Abstract

      Background:
      The NLR, a marker of systemic inflammation, has been associated with outcomes in multiple cancers. In patients (pts) with metastatic melanoma treated with ipilimumab, pre-therapy NLR < 5 has been associated with improved progression-free survival (PFS) and overall survival (OS). However, the utility of NLR as a marker of outcomes in pts with NSCLC treated with programmed-death 1 (PD-1) inhibitors is not known.

      Methods:
      We conducted a retrospective cohort study of pts with advanced NSCLC treated with nivolumab off clinical trials at the University of Pennsylvania between March 2015 and March 2016. NLR was calculated from complete blood counts obtained within two weeks of starting nivolumab. Pts were dichotomized based on a NLR <5 or ≥ 5. We calculated PFS and OS using the Kaplan-Meier method and used multivariate Cox proportional hazards models to adjust for sex, age, histology (squamous vs. non-squamous), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0-1 vs. ≥ 2), smoking history [heavy (≥10 pack-years) vs. light/never (<10 pack-years)], and number of prior systemic therapies (1 vs. ≥ 2).

      Results:
      175 pts received a median of 5 cycles of nivolumab (range, 1-24; IQR 3-9). Median age was 68 years (range 33-88, IQR 60-74), 46% of pts were male, 75% were white, 25% had an ECOG PS ≥ 2, and 46% had ≥ 2 prior systemic therapies. Eighty-four percent of pts had a ≥10 pack-year smoking history, and 76% had non-squamous histology. Median baseline NLR was 5.5 (IQR, 3.1 – 9.4), with NLR < 5 in 73 pts (42%) and NLR ≥ 5 in 102 patients (58%). Through the date of this analysis (June 1, 2016), disease progression had occurred in 124 pts (71%), and 92 pts (53%) had died, resulting in median PFS and OS of 2.1 and 6.5 months, respectively. After controlling for the aforementioned clinical and demographic factors, pts with baseline NLR<5 had significantly improved PFS (median 2.8 vs. 1.9 months; adjusted HR=0.70, 95% CI: 0.50-0.99; p = 0.04) and OS (median 8.4 vs. 5.5 months; adjusted HR=0.54, 95% CI: 0.34-0.84; p = 0.007) compared to pts with NLR ≥ 5.

      Conclusion:
      Pre-therapy NLR is independently associated with PFS and OS in advanced NSCLC pts treated with nivolumab. It is unclear whether this marker is predictive or prognostic. Prospective studies are warranted to determine the utility of NLR in predicting outcome in the context of other biomarkers of PD-1 therapy.