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Brett G.M Hughes



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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): Brett G.M Hughes

      • 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.

      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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      P1.01-52 - BR-34- Randomized Trial of Durvalumab & Tremelimumab +/- Platinum Chemotherapy in Patients with Metastatic Squamous or Non-Squamous NSCLC (ID 11791)

      16:45 - 18:00  |  Author(s): Brett G.M Hughes

      • Abstract
      • Slides

      Background

      Background- Immunotherapy improves survival of patients with non-small cell lung cancer (NSCLC). Current clinical trials are studying various combinations of PD-1/PD-L1 inhibitors and CTLA-4 agents with or without chemotherapy, to enhance treatment efficacy. This trial will determine the effects of adding platinum chemotherapy to combination of check point blockade with durvalumab and tremelimumab in the first line treatment of advanced non-small cell lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Method- BR-34 is a CCTG led randomized proof-of-concept trial of durvalumab and tremelimumab, with or without platinum-based chemotherapy in patients with metastatic squamous or non-squamous NSCLC. Patients who have histologically confirmed Stage IV NSCLC and wild type EGFR and ALK, PDL-1 unselected, with measurable disease by RECIST 1.1, and available tissue for biomarker testing are eligible and are stratified by stage, histology and smoking status. Primary end point is overall survival. Secondary end points include progression free survival at 1 year, overall response rate, quality of life, cost effectiveness and correlative studies on tissue and blood (including PD-L1, tumour mutation burden and cell-free DNA) with outcomes and response, and PFS by iRECIST (exploratory). In total 300 patients will be recruited from Canada, Australia and Italy. Arm A will receive 4 cycles of fixed doses of tremelimumab (T) 75 mg plus durvalumab (D) 1500 mg every 28 days IV, followed by durvalumab (D) maintenance and Arm B will receive standard platinum-doublet chemotherapy in combination with T+D every 21 days for 4 cycles, followed by maintenance D (with pemetrexed for those with non-squamous histology), until progression.

      4c3880bb027f159e801041b1021e88e8 Result

      Results- BR-34 was initiated in February 2017 in Canada and total 150 patients have been randomized as of April 2018, including 137 from Canada and 13 from Australia. 28 sites are open to accrual in Canada, 15 in Australia the trial will soon be opened in Italy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusion- At the current rate of accrual, the CCTG BR-34 trial should be fully accrued by Q1 2019. This is the first randomized trial of combination checkpoint blockade +/- platinum-doublet chemotherapy in advanced non-small cell lung cancer.

      Acknowledgements: BR-34 is an academic, co-operative group trial led by Canadian Cancer Trials Group (CCTG) in collaboration with ALTG and NHMRC Clinical Trials Centre, with support from AstraZeneca and Canadian cancer society. NCT03057106

      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): Brett G.M Hughes

      • 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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