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Alastair Greystoke



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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-08 - Clinical Trial in Progress: CONCORDE - A Phase 1B Study of Novel Agents in Combination with Conventional Radiotherapy in NSCLC (ID 600)

      10:15 - 18:15  |  Author(s): Alastair Greystoke

      • Abstract

      Background

      The majority of patients with locally advanced non-small cell lung cancer (NSCLC) treated with curative intent receive radiotherapy (RT) as part of their treatment. Despite considerable technological advances in RT delivery, the survival of these patients has barely changed over the last 60 years. A major factor in this failure to improve outcomes is the relative radioresistance of NSCLC. Attempts to overcome radioresistance by escalating RT doses have demonstrated inferior outcome likely secondary to normal tissue toxicity. Therefore an alternate approach is to exploit genetic dependencies in the DNA damage response of NSCLC, using biological inhibitors to selectively radiosensitise tumours whilst sparing normal tissues. The CONCORDE study is a multi-arm phase 1B platform study to investigate the combination of radical RT with DNA damage response inhibitors (DDR-i) targeting five different proteins: PARP, ATR, WEE1, ATM, DNA-PK.

      Method

      CONCORDE is a hypothesis-driven combination study of novel therapeutics and RT using an innovative adaptive early-phase trial design. The study will address two main research questions:

      - What are the recommended phase 2 doses (RP2D) of individual DDR-i in combination with curative RT in patients with stage IIB/III NSCLC?

      - What are the safety profiles of individual DDR-i combined with curative RT in this population?

      Key inclusion criteria are stage IIB and III NSCLC planned to receive curative intent RT doses (+/- neoadjuvant chemotherapy) and PS 0-1. Participants will be randomised on a 3:1 basis between DDR-i with RT or RT alone. Patients receiving RT alone will be pooled across the arms to provide contemporary data on toxicity. All patients will receive external beam RT with a planned dose of 60 Gy in 30 fractions.

      The study will use a Bayesian adaptive model-based approach to dose-escalation, with separate Time-To-Event Continual Reassessment Method (TiTE-CRM) models in each experimental arm. The primary endpoints are dose-limiting toxicities occurring within 12 months of the start of radiotherapy. Secondary endpoints include safety and toxicity (acute and late toxicity up to 2 years including using patient reported outcome (PRO) measures), treatment compliance, and best overall response (using RECIST 1.1, progression-free, and overall survival).

      Correlative studies will be carried out to identify biomarkers of toxicity and response. We have secured high-level agreement from leading pharmaceutical partners to invest in 5 treatment arms and funding approval from Cancer Research UK is pending. The first participant is estimated to commence treatment in late 2019

      Result

      Section not applicable

      Conclusion

      Section not applicable

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      P2.01-17 - CANOPY-1: Phase 3 Study of Canakinumab/Placebo+Pembrolizumab+Platinum-Chemotherapy in Untreated Stage IIIB-IV NSCLC Pts (ID 1209)

      10:15 - 18:15  |  Author(s): Alastair Greystoke

      • Abstract

      Background

      Interleukin-1β (IL-1β) inhibition with canakinumab reduced the incidence of and mortality due to lung cancer among patients with atherosclerosis in CANTOS trial. Inhibition of IL-1β driven inflammation may lead to a tumor microenvironment more susceptible to anti-PD-(L)1 therapies. Recent studies have shown that low levels of CRP at baseline or decreased levels over time correlated with improved responses to anti-PD-(L)1 agents, providing rationale for combination of canakinumab and Pembrolizumab (PEM).

      Method

      CANOPY-1 (NCT03631199) is a double-blind, randomized, placebo (Pb)-controlled, phase III trial to determine efficacy and safety of PEM + platinum-based chemotherapy (Ctx) ± canakinumab in untreated stage IIIB/IIIC-IV squamous and non-squamous NSCLC pts. It is a 2 part study- In Part 1 [open-label safety run-in with 3 cohorts of ~9 pts each to confirm recommended phase 3 canakinumab regimen], pts will receive canakinumab 200 mg s.c (Q3W) + PEM 200 mg i.v (Q3W) + platinum-based Ctx [Cohort A (non-squamous), carboplatin (CBCDA) + pemetrexed (PTX); Cohort B (non-squamous), cisplatin + PTX; Cohort C (squamous or non-squamous), CBCDA + paclitaxel]. In Part 2 [with ~600 pts) to evaluate efficacy and safety of canakinumab combination], pts will be randomized to receive canakinumab/Pb + PEM + platinum-based Ctx (non-squamous, CBCDA or cisplatin + PTX; squamous, CBCDA + paclitaxel or nab-paclitaxel). PEM and platinum-based Ctx will be administered at their approved doses. Randomization (1:1) will be stratified by PD-L1 status, region and histology. In both parts, pts will receive 4 cycles of induction therapy (canakinumab/Pb + PEM + Ctx) followed by maintenance therapy (PEM + canakinumab/Pb +/- PTX) until progressive disease. Primary objectives: confirm recommended phase 3 regimen for canakinumab combination (Part 1), compare PFS and OS between treatment arms (Part 2). Secondary objectives (Part 1 and 2): ORR, DCR, safety, PK and DOR.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.06 - Mesothelioma (ID 170)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.06-02 - Mesothelioma Stratified Therapy (MiST): A Phase IIA Umbrella Trial for Accelerating the Development of Precision Medicines (ID 2465)

      10:15 - 18:15  |  Author(s): Alastair Greystoke

      • Abstract

      Background

      There are currently no approved therapies for the treatment of relapsed mesothelioma. Recent advances in our understanding of inter-patient genomic heterogeneity, identification of potential drivers, and application of high throughput -omic technologies to clinical trial samples , has created opportunities to explore novel treatments in prospectively biomarker-enriched cohorts.

      Method

      MiST is a British Lung Foundation funded, University of Leicester sponsored multicentre national clinical trial. Patients (Pts) harbouring either pleural (any histological subtype) or peritoneal mesothelioma are eligible. Pts must have ECOG performance status 1 or 0, received prior standard chemotherapy and progressed from their last treatment (in any line). The study is designed in three stages. Stage 1 comprises prospective molecular profiling of the tumour suppressors BAP1, BRCA1, p16ink4A and the immune checkpoint inhibitor PDL1 (22C3), using automated immunohistochemistry. Stage 2: Patients meeting eligibility criteria are presently stratified into Arm 1: Rucaparib (PARP inhibitor) for BAP1 inactivated (cytoplasmic or loss of expression) /BRCA1 negative mesothelioma. Arm 2: Abemaciclib (CDK4/6 inhibitor) for p16ink4a negative tumour, Arm 3, Pembrolizumab (anti-PD1) and Bemcentinib (AXL) to patients without biomarker specification. Arm 4, Atezolizumab (anti-PDL1) and Avastin (anti-VEGF) for PDL1 positive MM. Further arms are in development. The primary endpoint is 12 week disease control (12wDCR), with the secondary endpoints, 24wDCR, response rate (modified RECIST1.1) and safety/tolerability. 12wDCR>50% will be considered worthy of further investigation. Stage 3: Genome wide somatic copy number analysis and transcriptomic analysis with in-silico deconvolution of immune cell infiltrates will be used to refine molecular correlates of response. Gut microbiome 16RNA sequencing will be conducted in arms 3 and 4. Patients exhibiting a response to treatment who then progress, will be re-biopsied to facilitate molecular interrogation of acquired resistance mechanisms. MiST is coupled to our laboratory functional genomics programme, aimed at exploring co-clinical trial models, to robustly define or validate mechanisms that underpin drug responses.

      Result

      Section not applicable

      Conclusion

      In summary, MiST is a new clinical research platform that will support proof-of-concept studies capable of testing biomarker enrichment/efficacy hypotheses, with the aim of advancing personalised therapy for mesothelioma.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
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      PL02.09 - National Lung Matrix Trial (NLMT): First Results from an Umbrella Phase II Trial in Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2282)

      08:00 - 10:15  |  Author(s): Alastair Greystoke

      • Abstract
      • Slides

      Background

      Oncogene-addicted NSCLC can achieve substantial clinical benefit with single-agent targeted therapy. Seeking to extend this paradigm to other more genetically complex NSCLC, we report first results of NLMT, an umbrella phase II trial whereby a bespoke next-generation sequencing screening panel (Stratified Medicine Programme 2) stratifies NSCLC patients to rationally selected targeted therapies. Uniquely we present results across the entirety of the platform to enable an assessment of the potential to further stratify medicine in advanced NSCLC. Novel methodology is used to ensure that the integrity of this ongoing platform trial is not jeopardised.

      Method

      NLMT uses a Bayesian adaptive design to screen currently 8 targeted drugs for signals of activity in 22 molecularly defined cohorts. For single agents, pre-specified clinically relevant outcomes are either median progression-free survival (mPFS) >3 months or objective response rate (ORR) and/or durable clinical benefit rate at 24 weeks (DCBR) >30%. Target recruitment for each cohort is 30 with futility analyses at 15. Recruitment continues in 19 cohorts. We report posterior probabilities (PP) of a clinically relevant outcome for closed cohorts and Bayesian predictive probability of success (PPoS) given observed data for open cohorts. This novel approach provides insight into the drug-biomarker combinations that have the strongest potential for further research.

      Result

      Over a 4 year period to end of March 2019, NLMT has recruited 286 patients from >4000 screened. Of 6 palbociclib cohorts (all proficient Rb): mPFS in KRAS mutation (n=30) is 5.8 months (PP>0.99); CDKN2A loss/non-squamous (n=27) passed its interim analysis; we predict >75% PPoS, given current data, in CDKN2A loss/squamous (n=16) and CCND1 amplification (n=13). Data for crizotinib show >90% PPoS in ROS1 gene fusions (n=8) and MET exon 14 skipping mutation (n=8), with less clear signal for MET amplification (n=9). Responses to selumetinib/docetaxel in NF1 mutation (n=16) warrant continuation. Recruitment to vistusertib was halted at interim for LKB1 single mutation (ORR=0/15, PP=0.003; DCBR=1/15, PP=0.026), but DCBR in LKB1/KRAS double mutation (n=23) warrant continuation. 4 cohorts receive capivasertib (n=22): data in PIK3CA amplifications (n=9) indicate <15% PPoS.

      Conclusion

      These first results from the largest stratified medicine dataset in NSCLC indicate further molecular stratifications could benefit from targeted therapies. Reporting interim outputs for all cohorts will allow reappraisal of the global stratified medicine strategy in cancer.

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