Multi-drug, genetic-marker-directed, non-comparative, multi-centre, multi-arm phase II trial in non-small cell lung cancer

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1 Multi-drug, genetic-marker-directed, non-comparative, multi-centre, multi-arm phase II trial in non-small cell lung cancer Sponsor: University of Birmingham Chief Investigator: Gary Middleton Chief Biostatistician: Lucinda Billingham Lead Investigators: Sanjay Popat, Timothy Yap, Yvonne Summers, James Spicer Trial Management Team at CRCTU: Laura Llewellyn, Dee Wherton, Susannah Brown, Kate Davies, Maria Sharif, Peter Fletcher, Ylenia Vigo, Ian Nutt SMP2 Team at Cancer Research UK: led by Rowena Sharpe and Catrin Middleton Trial Management Group: chaired by Sanjay Popat Trial Steering Committee: chaired by Richard Kaplan Current Pharma partners: AstraZeneca, Pfizer Contact: Website: 1

2 What we wanted to achieve, and how we have tried to achieve it The question how many slices of the molecular pie are there in non-small cell lung cancer (NSCLC)? Overarching design adaptive umbrella for economies of scale Endpoints big hitters versus small fry An embedded programme integration of SMP2 with standard NHS practice and making do with what we have 2

3 Developed in partnership with Illumina Panel linked to National Lung Matrix Trial Increased gene spectrum Increased mutation spectrum AKT1 ALK BRAF CCND1 CCND2 CCND3 CCNE1 CDK2 CDK4 CDKN2A EGFR FGFR2 FGFR3 Her2* HRAS KRAS MET NF1 NRAS NTRK1 PIK3CA PTEN RB1 RET ROS1 STK11 TSC1 TSC2 Single test that requires less DNA, analyses more genes, all types of mutational events, better quality result 3

4 Recruiting Sites The National Lung Matrix Trial (NLMT) is being run through all 18 UK Experimental Cancer Medicine Centres (ECMC) with each participating centre operating a hub and spoke model with patients being referred in from nearby hospitals (feeder sites) to the centre. Each centre is linked with one of the 3 Technology Hubs (TH). 10 additional centres have been approved for inclusion in areas of the UK with large populations of lung cancer patients not currently represented in the trial. 4

5 The Current SMP2 Network 5

6 Trial Schema 6

7 Biological Rationale for Arm B & F and Cohorts C5 & C6 Tumour Suppressor Genes Activated Genes Drug targets in the NLMT Signalling intermediaries 7

8 Biological Rationale for Cohorts C1-C4 Tumour Suppressor Genes Activated Genes Drug targets in the NLMT Signalling intermediaries 8

9 Molecular Cohorts and Initial Estimated Prevalence Rates Investigational Medicinal Product(s) AZD4547: Fibroblast growth factor receptor (FGFR) Inhibitor AZD2014 (Vistusertib): Mammalian target of rapamycin complex (MTORC)-1/2 Inhibitor Palbociclib: Cyclin dependent kinase (CDK)- 4/6 Inhibitor Cohorts and Initial Estimated Prevalence Rates A1: FGFR or FGFR3 mutation ADC <1.0% SCC 4.0% B1: TSC1 or TSC2 mutation ADC <1.0% SCC 2.7 % B2: STK11/LKB1 mutation or homozygous deletion ADC 8.8% SCC 1.6% C1: Proficient Rb and homozygous p16 loss SCC 29.0% C2: Proficient Rb and homozygous p16 loss ADC 19.6% C3: Proficient Rb and CDK4 amplification ADC 7.0% SCC <1.0% C4: Proficient Rb and CCND1 amplification ADC 5.0% SCC 12.0% C5: Proficient Rb, STK11/LKB1 mutation or homozygous deletion, with activated KRAS/MAPK pathway (i.e. concomitant KRAS, NRAS or NFI mutation) C6: Proficient Rb and KRAS mutation (no concomitant STK11/LKB1 mutation or deletion, PIK3CA mutation or amplification, PTEN mutation or homozygous deletion, AKT mutation, EGFR mutation, FGFR mutation, TSC1/2 mutation or HER2 mutation) ADC 4.4% SCC 0.8% ADC 25.8% 9

10 Molecular Cohorts and Initial Estimated Prevalence Rates Investigational Medicinal Product(s) Cohorts and Initial Estimated Prevalence Rates Crizotinib: Anaplastic lymphoma kinase (ALK) Inhibitor D1: Met amplification ADC 2.7% SCC 1.4% D2: ROS1 gene fusions ADC 1.7% SCC <1.0% D3: MET exon 14 mutant including splice, deletion and point mutation NSCLC 3.0% Selumetinib: Mitogen activated protein kinase (MEK) Inhibitor & Docetaxel E1: NF1 mutation SCC 5.8% E2: NF1 mutation ADC 4.6% E3: NRAS mutation ADC 1.0% AZD5363: AKT Inhibitor F1: PIK3CA mutation SCC 11.0% F2: PIK3CA amplification SCC 15.0% F3: PI3K/AKT deregulation: PIK3CA mutation or amplification PTEN mutation or PTEN loss AKT mutation ADC 2.0% ADC 3.0% ADC 0.5% SCC 0.5% F4: PTEN loss or PTEN mutation SCC 20.0% Osimertinib (AZD9291): EGFR mutation positive T790M+ Inhibitor G1: EGFR mutation and T790M+ ADC 8.0 % SCC <1.0% 10

11 How actionability is called the tiering algorithm Carr TH et al. Nature Reviews Cancer 16, (2016) 11

12 Molecular Exclusion Rules Enhancing the Likelihood of Clinical Success by Attention to the pre-clinical data Arm F (AZD5363): PIK3CA, PTEN and AKT aberrations: No concomitant KRAS mutations or gene failures Davies BR et al. Mol Cancer Ther 2012;11: Arm C (palbociclib) cohorts: Proven Rb proficiency is required (no gene failures or aberrations) Cohort C6 (palbociclib: KRAS mutation) Rb Proficient and no activation of PI3K/AKT/MTOR signaling (no concomitant STK11/LKB1, PIK3CA, PTEN, AKT, EGFR, FGFR, TSC1/2 or HER2 aberrations) Puyol M et al. Cancer Cell, 2010; 18: Kennedy AL et al Mol Cell. Apr 8, 2011; 42(1):

13 Ensuring Genes are Wildtype Tumour % Variant present at 10% frequency what % of reads would be mutant Mutant reads 10 mutant reads minimum so minimum read depth required is 5% 0.5% 1/ % 1% 1/ % 2% 1/ % 4% 1/ % 5% 1/ % 10% 1/ Tumour % information critical for analysis Really important to define this to the nearest 10%. Coverage calculator works out % of bases within gene covered to the depth required Gene is passed or failed based on criteria below 13

14 Statistical Design The aim of the trial is to determine whether there is sufficient signal of activity in any drug-biomarker combination to warrant further investigation. A Bayesian adaptive design that gives a more realistic approach to decision-making, and flexibility to make conclusions without fixing the sample size, was chosen. Target recruitment in each drug-biomarker cohort is 30 patients with interim analysis at

15 Stratified Medicine Programme 2 (SMP2) at a Glance >2400 patients with 1+ samples have now been sent for testing through SMP2 31% of SMP2 patients were molecularly eligible for NLMT Arms A-G (Arm G only until 14 th December 2016) 5.4% of SMP2 patients were recruited to NLMT Arms A-G (Arm G only until 14 th December 2016) SMP2 QC failure rate has reduced from 35% in 2015 to 15% in 2016 to 7% in Q SMP2 gene failure rate has reduced from 38% in 2015 to 33% in 2016 Median Technology Hub Turnaround time is in 20 working days Q

16 SMP2 Patient Attrition 2015 vs % of results reported = patients molecularly eligible for an open MATRIX (Arms A-G) 57% of results reported = patients molecularly eligible for an open MATRIX (Arms A-NA) 16

17 SMP2 Results Analysis all samples (2015 vs 2016) 17

18 Monthly SMP2 Testing Figures Month Number of samples tested on the NGS panel (includes NGS fail (6%), NGS pass and NGS partial pass) excludes QC fail. Taken from TH KPIs. Month Number of samples tested on the NGS panel (includes NGS fail (6%), NGS pass and NGS partial pass) excludes QC fail. Taken from TH KPIs. Jan-15 5 Jan Feb-15 0 Feb Mar Mar Apr Apr May May Jun Jun Jul Jul Aug Aug Sep Sep Oct Oct Nov Nov Dec Dec Total (64/month) Total (95/month) Excludes QC fails (15% in 2016) and samples with insufficient tissue to send to TH (39/97 samples at UHB in 2016) 18

19 Gene Failures A not insignificant problem due to the stringent requirements for calling wildtype. Why were they occurring? Large regions of interest Extremes in GC content Low tumour content of samples Poor quality of tissue and DNA What was done about it? Addition of probes to failing genes/exons Revision of gene coverage Pre-analytical steps & Sample processing steps fixation time, reverse cross-linking temperature 19

20 Molecularly Eligible Results Released per Month (Jan 2015 Mar 2017 inclusive; Arms a-g up to Dec 2016, Arms A-F thereafter) 20

21 Patients Molecularly Eligible for NLMT (Jan2015 Mar 2017 inclusive; Arms A-G up to Dec 2016, Arms A-F thereafter) 21

22 Why if 28% patients are molecularly eligible, are only 6% being recruited? Birmingham transition data on 92 molecularly eligible patients: 3 lost to follow-up 19 enrolled onto the NLMT (21%), 1 in screening, 4 failed eligibility - 26% (21% of 28% = 6%) 28% not at 2L time-point (on first line, in remission, indolent disease or subsequent radical Rx) 43% not fit for 2L (or for 1L), progressed on 1L with poor PS or rapid PD after 1L (19) or brain mets (6) 2L attrition is the awful reality of advanced NSCLC recruit at SD on 1L, particularly in an immunotherapy era 22

23 Cumulative & Monthly NLMT Recruitment [28% OF 1340 WITH 21% transition = 7/month] Data as of 30 th June

24 Recruitment by Treatment Arm and Cohort Data as of 30 th June

25 How does National Lung Matrix Trial compare? LCMC (JAMA, 2014) n= % fail rate (insufficient tissue/diagnostic) 47.7% tested on all 10 genes MDA ( JCO, 2015) 11/46/50 genes? n=2000 screened with 23% fail due to inadequate DNA quality/quantity 39% potentially actionable in genotype matched trials 11% of these entered (4% total) 25

26 How does this compare with frozen? SAFIR01 (Lancet Oncol, 2014) WG CGH and Sanger PIK3CA and AKT 67% and 70% respectively low % cancer cells Not dependent on time of testing or volume 46% targetable 13% targeted therapy (=28% targetable group) 9% response rate with 21% SD>16/52 26

27 New Arms Incorporation of 2 new treatment arms into protocol for 2 molecular cohorts (already on the NGS panel - an NTRK inhibitor and a BRAF inhibitor), both provided by a new pharmaceutical partner. An additional 2 treatment arms from another pharmaceutical partner for new molecular cohorts (RET, Ch4 12q amplifications, CBL mutation) and a further no-actionable genetic change cohort. 3 of these arms should open to recruitment before the end of Discussions are currently ongoing regarding further new arms to be submitted for funding consideration. 27

28 Translational and Other Outputs Predictive biomarkers from tissue and ctdna Resistance mechanisms from ctdna and PDX Integrating the SMP-2 data with NHSE molecular prognostication and SOC prediction 28

29 Trial Milestones Year Milestone 2017 August: Interim analyses of first 2 cohorts to reach n=15 July: Major improvements to trial website June: 150 th patient recruited & funding approved for 2 new cohorts February: 4th Trial Steering Committee (TSC) Interim analysis & funding approved for 2 new cohorts 2016 November: 100 th patient recruited September: 3 rd TSC Interim analysis June: Approval for funding for further 2 years & 2 new arms from CRUK March: 50 th patient recruited February: 2 nd TSC Interim analysis 2015 October: Arm F & G opened to recruitment September: 1 st TSC interim analysis May: First patient recruited March: Central R&D approval and first site opened 2014 December: MHRA approval received November: Ethics approval received October: Protocol Version 1 submitted for regulatory approval August: Grant Activation Date 2013 September: Initial approval for CRUK Clinical Trials Unit at Birmingham to run the NLMT with Prof Middleton as the Chief Investigator & Prof Billingham as Lead Statistician 29

30 With Many Thanks to: The Cancer Research UK Clinical Trials Unit National Lung Matrix Trial Team The Cancer Research UK SMP2 Team Members of the National Lung Matrix Trial Management Group & Trial Steering Committee Members of the SMP2 Governance Board The NCRI Lung Clinical Studies Group All the Lead Investigators, Principal Investigators, clinical teams and research nurses at all sites The patients and their families 30

31 Thank You 31