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Kenneth O’byrne



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    MA10 - Considerations in Immunotherapy / Real World (ID 911)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 105
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      MA10.07 - Discussant - MA 10.05, MA 10.06 (ID 14614)

      11:10 - 11:25  |  Presenting Author(s): Kenneth O’byrne

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
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      OA02.05 - CK-101 (RX518), a Third Generation Mutant-Selective Inhibitor of EGFR in NSCLC: Results of an Ongoing Phase I/II Trial (ID 11982)

      11:15 - 11:25  |  Author(s): Kenneth O’byrne

      • Abstract
      • Presentation
      • Slides

      Background

      CK-101 (also known as RX518) is a novel, oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and resistance mutations, with minimal activity on wild-type EGFR. CK-101 is being studied in an ongoing first-in-human, multicenter, Phase I/II trial in advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations and other advanced malignancies in the US, Australia, New Zealand and Thailand (NCT02926768). Following dose escalation in which 18 pts received CK-101 in dose groups ranging from 100 mg to 1200 mg/day, a first dose-expansion cohort was enrolled at 400 mg bid.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible pts in dose escalation had a confirmed diagnosis of NSCLC or any advanced solid tumor where targeting EGFR was reasonable. Eligible pts in dose-expansion had a confirmed diagnosis of either (1) EGFR mutation-positive advanced or metastatic NSCLC without prior exposure to EGFR-TKI therapy, or (2) T790M-positive advanced or metastatic NSCLC with disease progression on previous EGFR-TKI therapy, with no limit on number of prior lines of systemic therapy.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 25 June 2018, 37 pts were treated in dose escalation and expansion and evaluable for safety; median age 59 years, 51% male, 51% Asian, 84% ECOG PS 1. No DLTs or treatment-related SAEs were reported. Most common treatment-emergent adverse events: nausea (16%), diarrhea (14%), lacrimation increased (14%) and vomiting (11%), all grade 1/2 except one grade 3 diarrhea; no grade 4. In dose-expansion, 19 pts were treated with CK-101 at a dose of 400 mg bid and evaluable for response; 8/19 (42%) pts were treatment-naïve, 6/19 (32%) pts had brain metastases; 16/19 (84%) pts remained on treatment. Disease control rate was 100% (19/19), with 16/19 pts (84%) experiencing target lesion reduction versus baseline and 8 pts achieving a partial response (7 confirmed, 1 pending confirmation). In treatment-naïve pts, 6/8 (75%) pts achieved a partial response. In pts with brain metastases, 3/6 (50%) pts achieved a partial response. Higher drug exposures were associated with higher response rate with a confirmed ORR of 55% (6/11) in pts achieving Cmax >400 ng/mL. Median duration of response and progression-free survival were not reached as of the data cutoff.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CK-101 was well tolerated with a manageable safety profile. Durable anti-tumor activity was observed, particularly in treatment-naïve pts. Further study is ongoing to establish the optimal dose to maximize therapeutic effect in a planned Phase 3 study in treatment-naïve EGFR-mutant NSCLC pts.

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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): Kenneth O’byrne

      • 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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    P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.01-74 - Clinical and Radiological Predictors of Efficacy to Nivolumab in NSCLC: A Multi-Institutional, Retrospective Cohort Study.  (ID 14377)

      12:00 - 13:30  |  Author(s): Kenneth O’byrne

      • Abstract

      Background

      Identification of sub-populations of patients with a greater likelihood of response to anti-programmed death-1 (PD1) inhibitors in non-small cell lung cancer (NSCLC) would enable treatment to be directed to those most likely to benefit, thereby increasing efficacy and cost effectiveness. The relationship, however, between clinical and radiological parameters with efficacy of single agent Nivolumab remains unclear in advanced NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective analysis was conducted for patients who received second-line Nivolumab following progression after platinum based chemotherapy for advanced NSCLC on a Compassionate Access Program across seven oncology institutions in Queensland, Australia.

      ECOG Performance status (PS), immune related adverse events (IrAEs), and baseline CT texture analysis (as a surrogate for tumour heterogeneity) was assessed. The endpoints were overall survival (OS), progression free survival (PFS) and objective response rate (ORR). An institutional ethical approval was obtained.

      4c3880bb027f159e801041b1021e88e8 Result

      Two hundred and fourteen patients were enrolled over two years, median age 67 (range 42 to 84 years). PS 0-1 (64 %); PS 2-3 (36%).

      The median OS was 8.9 months (95% CI, 6.6 to 11.67); 13.3 months in PS 0-1 patients and 4.9 months in PS 2-3 patients. At 1 year, the OS rate was 41%; 55% in patients with PS 0-1 and 19% in PS 2-3 patients. ORR was recorded in 23% of patients (50/214), an additional 27% (58/214) had stable disease.

      Toxicity data was available for 90% of patients (N=194). The presence of IrAEs of any grade occurred in 36% of patients and was associated with a longer median PFS of 5.9 months versus 2.3 months in patients with no immune toxicity (P value <0.01, 95% CI). In patients with IrAE the ORR was 32% versus 18%, 1 year OS 59% versus 29% in those without any immune mediated toxicity.

      CT texture analysis findings (N=47) consistent with increased tumour heterogeneity showed significantly longer PFS (median NR versus 1.5 months, Hazard Ratio: 2.05, p=0.018).

      8eea62084ca7e541d918e823422bd82e Conclusion

      We found Nivolumab had clinically significant long-term benefits in the treatment of locally advanced and metastatic NSCLC with 12 month survival rates in keeping with clinical trials in PS 0-1 patients. An ECOG PS 0/1, the development of IrAEs and increased tumour heterogeneity by CT texture analysis was associated with a significantly longer PFS and increased clinical benefit in this cohort. The combination of these clinical and radiological parameters may identify subgroups of patients benefitting from this therapy.

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