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Steven Chuan-Hao Kao



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    OA08 - Mesothelioma: Immunotherapy and microRNA for Diagnosis and Treatment (ID 907)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 201 BD
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      OA08.02 - DREAM - A Phase 2 Trial of Durvalumab with First Line Chemotherapy in Mesothelioma: Final Result (ID 12022)

      15:25 - 15:35  |  Author(s): Steven Chuan-Hao Kao

      • Abstract
      • Presentation
      • Slides

      Background

      We report here the final results of a single-arm, phase 2 trial designed to determine the activity, safety and tolerability of durvalumab, cisplatin and pemetrexed as first line therapy in MPM. ANZ Clinical trial registry number: ACTRN12616001170415

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Participants were considering first line chemotherapy for MPM, were unsuitable for radical surgery, had an un-irradiated target lesion, and had good performance status (ECOG PS 0-1). Objective tumour response (OTR) and progression free survival (PFS) were assessed primarily according to the modified Response Evaluation Criteria in Solid Tumors for MPM (mRECIST) and as secondary endpoints according to RECIST modified for immunotherapy (iRECIST). Study treatment was durvalumab 1125mg, cisplatin 75mg/m2, and pemetrexed 500mg/m2 all given intravenously on day 1, and repeated every 3 weeks for a maximum of 6 cycles, followed by durvalumab 1125 mg every 3 weeks until progression, unacceptable toxicity, or a maximum total of 12 months. The primary endpoint was PFS at 6 months (PFS6). The sample size of 54 provided 90% power to distinguish the observed proportion PFS6 from a null hypothesis of 45% versus an alternative of 65% with a 1-sided alpha of 5%. Tissue and blood samples were required and collected for translational correlative studies.

      4c3880bb027f159e801041b1021e88e8 Result

      We recruited 54 participants from Dec 2016 to Sep 2017. Median age was 68 (range 42-82), 82% were male, 60 had ECOG PS 0, and 82% had epithelioid histology. Dose intensities were 97% for cisplatin and 94% for durvalumab. The proportion PFS6 was 57% (31/54, 90% CI 45-68%); median PFS was 6.9 months (95% CI 5.5-9.0). The OTR rate was 48% (95% CI 35-61%) according to mRECIST and 50% (95% CI 37-63) according to iRECIST. The median duration of response was 6.5 months. Grade 3-5 adverse events occurred in 36 participants, including neutropenia in 13%, nausea in 11%, anaemia in 7%, fatigue in 6% and any grade peripheral neuropathy in 35%. There were 4 deaths on study, none attributed to durvalumab. Immune-related adverse events occurred in 17 participants, and were of grade 3 or worse in 8, including increased lipase (1), pancreatitis (1), and renal impairment (1).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combination of durvalumab, cisplatin, and pemetrexed has demonstrated sufficient activity, safety, and tolerability as first line therapy in MPM to warrant further evaluation in a large-scale, randomised phase 3 trial.

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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • 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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      P1.04-11 - Exploring the Germ-Line Contribution to Exceptional Response to PD-1/PD-L1 Inhibition in Patients with NSCLC by Whole Genome Sequencing (ID 12646)

      16:45 - 18:00  |  Author(s): Steven Chuan-Hao Kao

      • Abstract
      • Slides

      Background

      Responses to immune checkpoint inhibitors (CPI) may vary between individuals because of somatic mutation differences in the tumour and/or germ-line differences in immunological tolerance. To explore the latter, this ongoing study evaluates patients with metastatic non-small cell lung cancer (NSCLC) treated with single agent PD-1 or PD-L1 inhibitors recruited from a treatment pool of 420 patients (total) / 137 (active since 1 August 2017).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Rare and common germ-line DNA variants are analysed in exceptional responders and non-responders by whole genome sequencing (WGS) (Illumina HiSeqX Ten). Exceptional responders are defined as patients with complete or partial response of more than 12 months or stable disease of more than 24 months (per RECIST), and a concurrent immune-related adverse event of any grade. Non-responders are defined as patients with best response of progressive disease, having received at least 4 cycles or 2 months of treatment.

      In these individuals, the burden of rare and common variants in immune tolerance genes is analysed and compared to the Medical Genome Reference Bank (MGRB), comprising WGS of 1144 well-elderly individuals. Comparisons are made with Fisher Exact test. Genetic risk scores for auto-immune conditions are calculated for these cohorts, MGRB and NSCLC patients included in The Cancer Genome Atlas. Scores are calculated using curated risk alleles and OR weightings derived from the NHGRI-EBI GWAS catalogue.

      4c3880bb027f159e801041b1021e88e8 Result

      Recurrent rare variants (Exome Aggregation Consortium (ExAC) frequency < 1%) were found within responders sequenced to date (n=20), including variant A, a frameshift mutation in a protein kinase not present in ExAC, with allelic frequency (AF) of 1.27% in MGRB and 17.5% of our cohort (p<0.0001). Multiple common variants (ExAC ≥1%) were more frequent within the cohort compared with population standard. Among these, three functional variants within gene B, encoding a protein involved in modulating immune-responsiveness, (variant B.1, B.2 and B.3, ExAC AF: 1.3%, 0.99% and 2.3%), were found seven times (total) across six individuals (one compound heterozygous B.2/B.3). The exceptional responders cohort was enriched for subjects with higher genetic risk for Disease A, psoriasis and psoriatic arthritis compared with control groups.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Preliminary findings suggest individuals harbouring functional variants in genes promoting immune tolerance may be more responsive to PD-1/PD-L1 inhibitors. This may be due to higher basal immune activation, requiring greater reliance on inhibitory checkpoints to maintain homeostasis. Ordinarily, this would be clinically undetectable, however the addition of a pharmacological CPI may more effectively break immune tolerance in this primed environment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • 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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      P2.01-50 - Thromboembolism in ROS1 Rearranged Non-Small Cell Lung Cancer (ID 12885)

      16:45 - 18:00  |  Author(s): Steven Chuan-Hao Kao

      • Abstract
      • Slides

      Background

      The risk of thromboembolism (TE) is estimated to be 0.001% per year and hereditary thrombophilia present in 0.2-5% of the general adult population.

      It is estimated that 8-15% of patients with advanced non-small cell lung cancer (NSCLC) will develop thromboembolism throughout their disease course. In ALK rearranged NSCLC this incidence has been reported to be three to four fold higher at 36%.

      We sought to investigate the incidence in TE in a cohort of the rare ROS1 rearranged molecular subgroup.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Electronic records were reviewed in six tertiary hospitals to identify all patients diagnosed with ROS1 NSCLC. Predefined data were analysed in STATA15 software for Kaplan-Meier (KM) plot and Cox-regression modelling.

      4c3880bb027f159e801041b1021e88e8 Result

      Forty-two patients were identified at data cut (31/1/2018). Median follow up was 10.9 months (mo); 38% had died. Median age was 53 years (31-80); 74% were female; 67% non-Asian and 88% non- smokers and 29% CNS disease during diagnosis.

      Median overall survival (OS) overall was estimated 28.8mo (range: 0.1-180.4mo).

      Thromboembolism incidence was 48% (n=20); 19 venous, 11 with pulmonary embolus (PE). One patient presented with fatal arterial TE (ROS1 diagnosed pre-mortem).

      Median time to TE was 2.3mo. In four patients TE was the harbinger for their diagnosis and two had encountered unprovoked TE prior to diagnosis, one then recurrent TE throughout diagnosis.

      Screening for a thrombophilia (TP) was not mandatory, and tested in n=9/20 cases with TE, one without. A co-occurring TP was identified in 15% (n=3/20); two factor V Leiden; one anti-thrombin III (ATIII) deficiency. Of interest, one patient with TE had factor XII deficiency; one thalassaemia minor and one acute-promyelocytic leukaemia without evidence of disseminated intravascular coagulation.

      Age; race; baseline ECOG; smoking history; treatment received; brain metastases at diagnosis; hereditary thrombophilia and neutrophil to lymphocyte ratio were not predictive of TE in this small cohort.

      Median OS in patients with TE was 21.3mo (0.1-180.4) versus 28.83mo (1.2-63.5) with no TE; hazard ratio 1.16 (95%CI 0.43-3.15, p=0.77).

      The ROS-1 fusion partner was known in two cases, both CD74-ROS1, one encountering TE (PE). Twenty-five have archival tissue available to identify the fusion partner and explore an association with TE.

      8eea62084ca7e541d918e823422bd82e Conclusion

      To the best of our knowledge, this is the first report on the incidence of thrombotic events specifically in ROS1-rearranged NSCLC. In this small cohort intriguingly there was a high incidence of TE and a higher incidence than the general population of hereditary thrombophilia.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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