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Lukas Bubendorf



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    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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      MA26.06 - Crizotinib-Treated ALK Immunopositive Metastasized NSCLC is Associated with an Unfavorable Prognosis when FISH Negative  (ID 13179)

      14:05 - 14:10  |  Author(s): Lukas Bubendorf

      • Abstract
      • Presentation
      • Slides

      Background

      Metastasized NSCLC with an ALK fusion are sensitive to a range of tyrosine kinase inhibitors. ALK-positive NSCLC has been identified in the pivotal phase III trial with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC+ FISH-. The aim of this study was to collect ALK IHC+ cases and compare within this group response to crizotinib treatment of ALK FISH+ cases with ALK FISH- cases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A prospective multicenter investigator initiated research study was started in Europe. Stage IV ALK IHC+ NSCLC cases treated with crizotinib were collected centrally. Slides were validated centrally for ALK IHC (with 5A4 ETOP and D5F3 Ventana protocol) and ALK FISH (Vysis probes).

      4c3880bb027f159e801041b1021e88e8 Result

      The study started April 1, 2014 and closed in November 2017. Fifteen centers participated. Registration of 3523 ALK IHC tests revealed prevalence of 2.6% ALK IHC+ cases. Local ALK FISH analysis resulted in 46 concordant (ALK IHC+/FISH+) and 18 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 6 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The time to treatment failure did not differ for concordant nor discordant cases, and neither for local nor validated ALK testing (HR=0.78; 95% CI= 0.27-2.3; p=0.64) and (HR=2.2; 95% CI= 0.72-6.5; p=0.16), respectively). However, overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010), but not according to local testing (HR=1.7; 95% CI= 0.45-6.2; p=0.44).

      8eea62084ca7e541d918e823422bd82e Conclusion

      ALK IHC+ FISH- NSCLC cases are an infrequent finding. We recommend such cases to be validated carefully because our data indicate that ALK IHC+ FISH- cases have a worse survival when treated by crizotinib compared to ALK IHC+ FISH+ cases.

      This study was funded by an independent research grant by Pfizer

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA26.07 - ROS1 (SP384) Immunohistochemistry Inter-Reader Precision Between 12 Pathologists (ID 12387)

      14:10 - 14:15  |  Author(s): Lukas Bubendorf

      • Abstract
      • Presentation
      • Slides

      Background

      ROS1 positive non-small cell lung cancer (NSCLC) patients can be treated with specific tyrosine kinase inhibitors including crizotinib. ROS1 positivity is often clinically detected by fluorescence in situ hybridization (FISH), however ROS1 IHC can be used to screen samples prior to FISH confirmation of ROS1 status. The ROS1 (SP384) antibody detects ROS1 with high sensitivity, specificity, and consistency. Consistent interpretation of a ROS1 IHC assay between pathologists is important patient evaluation. Here we present inter-reader precision of 12 pathologists across 60 FFPE cases stained with ROS1 (SP384).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort of 60 FFPE NSCLC cases stained with H&E, Rabbit Monoclonal Negative Control Ig, and ROS1 (SP384) were selected to represent positive, negative, and borderline ROS1 IHC status. Twelve practicing lung pathologists independently scored the cases as positive or negative around a cutoff of cytoplasm staining in > 30% tumor cells at a ≥2+ intensity level using Pathotrainer software (Pathomation bvba). Scoring was blinded to other readers and ROS1 status of the cases. Overall percent agreement (OPA), negative percent agreement (NPA), and positive percent agreement (PPA) were calculated in comparison to the group mode. Average overall percent agreement (AOPA), average positive agreement (APA), and average negative agreement (ANA) were calculated pairwise for each reader pair. Following independent assessment, participating pathologists conducted a discordant case review establishing consensus reads for all 60 cases and compared 44 cases to available FISH results.

      4c3880bb027f159e801041b1021e88e8 Result

      OPA of each of the 12 readers to the mode was 96.4% (95% CI 93.9-98.6) with PPA of 96.3% (95% CI 92.7-99.4) and NPA of 96.5% (95% CI 92.8-99.5). Pairwise AOPA between each of the 12 readers was 94.5% (95%CI 91.2-97.7) with APA 94.0% (95% CI 89.5-97.6) and ANA 95.0% (95%CI 91.2-97.9).

      Consensus IHC scores were concordant with FISH 90.0% (40/44 cases).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Inter-reader precision around a cutoff of >30% tumor cells with cytoplasmic staining at a ≥2+ intensity level was high in interpreting ROS1 (SP384) in NSCLC samples. Case review highlighted confirmation with FISH in questionable cases and staining patterns to be considered when interpreting ROS1 (SP384) IHC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA03 - Advances in Lung Cancer Pathology (ID 897)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
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      OA03.03 - Phase 2B of Blueprint PD-L1 Immunohistochemistry Assay Comparability Study (ID 14530)

      10:50 - 11:00  |  Author(s): Lukas Bubendorf

      • Abstract
      • Presentation
      • Slides

      Background
      PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. a9ded1e5ce5d75814730bb4caaf49419 Method
      Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. 4c3880bb027f159e801041b1021e88e8 Result
      The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. 8eea62084ca7e541d918e823422bd82e Conclusion
      The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible. 6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-04 - Treatment Patterns and Overall Survival Following Biomarker Testing in Real-World Advanced NSCLC Patients (ID 12743)

      16:45 - 18:00  |  Author(s): Lukas Bubendorf

      • Abstract

      Background

      Foundation Medicine (FMI) comprehensive genomic profiling and other next-generation sequencing (NGS) tests are gaining importance in routine clinical management of non-small cell lung cancer (NSCLC). They assess multiple genetic alterations that drive sensitivity or resistance to treatment, enabling optimal therapeutic decisions. We evaluated the effect of biomarker testing on treatment patterns and overall survival (OS) in real-world advanced NSCLC (aNSCLC) patients receiving different test types, and in non-tested patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The Flatiron Health (FH) Database comprises patient-level electronic health records from a large network of US cancer clinics. Patients had aNSCLC diagnoses between 01/2013 and 05/2017, ≥2 clinic visits in the FH network, first treatment starting ≤90 days after aNSCLC diagnosis, and biomarker tests before first treatment. Testing data were abstracted for five biomarkers (EGFR, ALK, KRAS, ROS1, and PD-L1). Patients were hierarchically categorized into three testing groups: FMI, other NGS, and single-biomarker non-NGS. Biomarker status and patterns in first treatment were described. Cox proportional hazards models were used to compare OS among testing groups and non-tested patients.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 11/30/2017, 355 patients had ≥1 FMI test, 780 had ≥1 other NGS test, and 6,363 had ≥1 non-NGS test prior to first treatment; 5,148 patients were never tested. Table 1 summarizes biomarker status, treatment patterns, and results of multivariate survival models adjusted for baseline demographic and clinical differences among testing groups. Patients with FMI tests were more likely to receive NCCN-recommended targeted treatments. Better OS was observed for FMI, other NGS, and non-NGS compared with non-tested patients.

      FMI

      Other NGS

      Non-NGS

      Non-tested

      (n = 355)

      (n = 780)

      (n = 6,363)

      (n = 5,148)

      n

      %

      n

      %

      n

      %

      n

      %

      Biomarker status1

      EGFR mutation

      51

      14.4

      121

      15.5

      853

      13.4

      -

      -

      ALK rearrangement

      8

      2.3

      23

      2.9

      187

      2.9

      -

      -

      ROS1 rearrangement

      0

      0

      3

      0.4

      33

      0.5

      -

      -

      KRAS mutation

      94

      26.5

      189

      24.2

      415

      6.5

      -

      -

      PD-L1-positive

      21

      5.9

      112

      14.4

      234

      3.7

      -

      -

      Patterns in first treatment

      NCCN-recommended
      targeted therapy2,3

      77

      21.7

      129

      16.5

      1,037

      16.3

      112

      2.2

      Non NCCN-recommended targeted therapy2,4

      2

      0.6

      3

      0.4

      11

      0.2

      40

      0.8

      NCCN-recommended ICI2,5

      36

      10.1

      102

      13.1

      381

      6.0

      229

      4.4

      Non NCCN-recommended ICI2,6

      2

      0.6

      0

      0

      8

      0.1

      3

      0.1

      Multivariate Cox proportional hazards model to compare OS, hazard ratio (95% CI)

      All aNSCLC7

      0.72*

      (0.61, 0.85)

      0.74*

      (0.66, 0.83)

      0.78*

      (0.74, 0.83)

      1.00

      (ref)

      aNSCLC, non-squamous
      cell histology8

      0.69*

      (0.61, 0.79)

      0.76*

      (0.70, 0.80)

      0.69*

      (0.57, 0.83)

      1.00

      (ref)

      All aNSCLC9

      0.93

      (0.77, 1.13)

      1.05

      (0.92, 1.21)

      1.00

      (ref)

      -

      -

      aNSCLC, non-squamous
      cell histology10

      0.91

      (0.74, 1.13)

      1.01

      (0.87, 1.17)

      1.00

      (ref)

      -

      -

      aNSCLC, non-EGFR-mutated, non-ALK-rearranged, non-squamous cell histology11

      0.9

      (0.74, 1.10)

      0.94

      (0.82, 1.08)

      1.00

      (ref)

      -

      -


      ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; NCCN, National Comprehensive Cancer Network.

      1 Denotes biomarker status overall prior to starting first treatment and represents overall status from all test-types. In case of multiple tests, the following hierarchy is used: positive>negative>pending/unsuccessful/indeterminate/unknown.

      2 Based on the NSCLC NCCN Guidelines, Version 3. 2018; 02/21/2018.

      3 NCCN-recommended targeted therapy implies treatment regimens containing at least one of the following: erlotinib, afatinib, gefitinib, osimertinib, crizotinib, ceritinib, alectinib, brigatinib, dabrafenib+trametinib, cabozantinib, vandetanib, ado-trastuzumab emtansine.

      4 Non NCCN-recommended targeted therapy implies treatment regimens containing at least one of the following: necitumumab, cetuximab, panitumumab, vemurafenib, dabrafenib, trametinib, trastuzumab, pertuzumab+trastuzumab, venetoclax.

      5 NCCN-recommended ICI implies treatment regimens containing at least one of the following: pembrolizumab, nivolumab, atezolizumab.

      6 Non NCCN-recommended ICI implies treatment regimens containing at least one of the following: ipilimumab, avelumab.

      7 Adjusted for age, sex, race, clinic type, payer type, smoking history, stage at initial diagnosis, ECOG performance status, histology, and year of advanced diagnosis.

      8 Adjusted for age, sex, race, clinic type, payer type, smoking history, stage at initial diagnosis, ECOG performance status, and year of advanced diagnosis.

      9 Adjusted for age, sex, race, clinic type, payer type, smoking history, stage at initial diagnosis, ECOG performance status, histology, year of advanced diagnosis, sample type used for the test, and biomarker status.

      10 Adjusted for age, sex, race, clinic type, payer type, smoking history, stage at initial diagnosis, ECOG performance status, year of advanced diagnosis, sample type used for test, and biomarker status.

      11 Adjusted for age, sex, race, clinic type, smoking history, stage at initial diagnosis, ECOG performance status, and year of advanced diagnosis.

      * Indicates a statistically significant estimate (p<0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Complexity of real-world aNSCLC biomarker testing and associated treatments creates challenges when comparing OS among testing groups. In the future, as more treatments targeting a wider array of genomic alterations become available and accessible, the utility of NGS-based assays to guide NCCN-recommended treatments with actionable targets and differences in OS may become more apparent.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-14 - Tumor Mutational Burden Assessed by a Targeted NGS Assay Predicts Benefit from Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer  (ID 14516)

      16:45 - 18:00  |  Author(s): Lukas Bubendorf

      • Abstract

      Background

      Immune checkpoint inhibitors (ICI) improve overall survival in non-small cell lung cancer (NSCLC) in the 2nd-line setting and lead to prolonged disease control in a subgroup of patients (pts). Robust predictive biomarkers for ICI are highly desired. In an exploratory analysis of the CheckMate 026 study, high tumor mutation burden (TMB) assessed by whole-exome sequencing was associated with improved outcome of pts treated with nivolumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From our institutional database, 41 pts with metastatic NSCLC were included in this study and identified as either having clinical benefit (CB; defined as complete/partial response (CR/PR) or stable disease (SD)) or having no clinical benefit. TMB was assessed using a targeted NGS assay that simultaneously detects variants in all coding regions / sequences of 409 cancer-related genes (Oncomine Tumor Mutation Load Assay, Thermo Fisher Scientific, Waltham, MA, USA). TMB values were normalized to tumor cell content. The correlation between TMB and CB rate was assessed. Mann-Whitney test was used and differences were considered significant at a p-value <0.05.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 41 pts (mean age 63.7 years), 73% were male, 87.8% smokers and 71% had adenocarcinoma histology. Nivolumab was the most frequently used ICI (70.7%), and it was most commonly used in the 2nd-line setting (61.0%). PR was observed in 29.2% of patients, and SD in 14.6%. CB rate was 43.8%. The median number of genomic mutations per Megabase (Mb) was 8.81. In pts with CB, median TMB with 11.52 mutations per Mb was significantly higher than in pts without response to therapy (7.71 mutations per Mb; p=0.02).

      8eea62084ca7e541d918e823422bd82e Conclusion

      TMB as determined by a targeted NGS panel comprising the coding regions of 409 cancer-related genes can reliably predict clinical benefit from ICI. These results need further confirmation due to limited sample size of this study. We are currently analyzing a second independent cohort, and results will be presented during the meeting.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    PC06 - Controversies in Immunobiomarker Testing (ID 845)

    • Event: WCLC 2018
    • Type: Pro-Con Session
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 106
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      PC06.04 - Tumor Mutation Burden - CON (ID 11628)

      14:30 - 14:50  |  Presenting Author(s): Lukas Bubendorf

      • Abstract
      • Presentation

      Abstract not provided

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