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Timothy A. Yap

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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): Timothy A. Yap

      • Abstract
      • Slides


      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.


      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.


      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.


      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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