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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: lungmatrix@trials.bham.ac.uk Website: www.birmingham.ac.uk/lungmatrix

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• 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

What we wanted to achieve, and how we have

tried to achieve it

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Single test that requires less DNA, analyses more genes, all types of mutational events, better quality result

– 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

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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.

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The Current SMP2 Network

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Trial Schema

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Signalling intermediaries

Tumour Suppressor Genes

Activated Genes

Drug targets in the NLMT

Biological Rationale for Arm B & F and

Cohorts C5 & C6

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Biological Rationale for Cohorts C1-C4

Signalling intermediaries

Tumour Suppressor Genes

Activated Genes

Drug targets in the NLMT

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Molecular Cohorts and Initial Estimated

Prevalence Rates Investigational Medicinal Product(s)

Cohorts and Initial Estimated Prevalence Rates

AZD4547: Fibroblast growth factor receptor (FGFR) Inhibitor

A1: FGFR or FGFR3 mutation

ADC <1.0% SCC 4.0%

AZD2014 (Vistusertib): Mammalian target of rapamycin complex (MTORC)-1/2 Inhibitor

B1: TSC1 or TSC2 mutation ADC <1.0% SCC 2.7 %

B2: STK11/LKB1 mutation or homozygous deletion ADC 8.8% SCC 1.6%

Palbociclib: Cyclin dependent kinase (CDK)-4/6 Inhibitor

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)

ADC 4.4%

SCC 0.8%

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 25.8%

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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%

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How actionability is called – the tiering algorithm

Carr TH et al. Nature Reviews Cancer 16, 319–329 (2016)

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• Arm F (AZD5363): PIK3CA, PTEN and AKT aberrations:

• No concomitant KRAS mutations or gene failures

• Davies BR et al. Mol Cancer Ther 2012;11:873-887

• 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: 63 – 73

Kennedy AL et al Mol Cell. Apr 8, 2011; 42(1): 36–49

Molecular Exclusion Rules – Enhancing the

Likelihood of Clinical Success by Attention to

the pre-Clinical data

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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% 1/200 2000

10% 1% 1/100 1000

20% 2% 1/50 500

40% 4% 1/25 250

50% 5% 1/20 200

100% 10% 1/10 100 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

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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.

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• >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 14th December 2016)

• 5.4% of SMP2 patients were recruited to NLMT Arms A-G (Arm G only until 14th

December 2016)

• SMP2 QC failure rate has reduced from 35% in 2015 to 15% in 2016 to 7% in Q1 2017

• SMP2 gene failure rate has reduced from 38% in 2015 to 33% in 2016

• Median Technology Hub Turnaround time is in 20 working days Q1 2017

Stratified Medicine Programme 2

(SMP2) at a Glance

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SMP2 Patient Attrition – 2015 vs 2016

35% 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)

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SMP2 Results Analysis – all samples

(2015 vs 2016)

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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-16 107

Feb-15 0 Feb-16 127

Mar-15 26 Mar-16 126

Apr-15 86 Apr-16 85

May-15 104 May-16 47

Jun-15 107 Jun-16 91

Jul-15 83 Jul-16 115

Aug-15 66 Aug-16 99

Sep-15 80 Sep-16 79

Oct-15 74 Oct-16 84

Nov-15 62 Nov-16 89

Dec-15 73 Dec-16 91

Total 2015 766 (64/month) Total 2016 1140 (95/month)

Excludes QC fails (15% in 2016) and samples with insufficient tissue to send to TH (39/97 samples at UHB in 2016)

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• 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

Gene Failures

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Molecularly Eligible Results Released

per Month (Jan 2015 – Mar 2017 inclusive; Arms a-G up to Dec 2016, Arms A-F thereafter)

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

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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

Why if 28% patients are molecularly eligible,

are only 6% being recruited?

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Cumulative & Monthly NLMT Recruitment [28% OF 1340 WITH 21% transition = 7/month]

Data as of 30th June 2017

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Recruitment by Treatment Arm and Cohort

Data as of 30th June 2017

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• LCMC (JAMA, 2014)

• n=1537 33.8% 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)

How does National Lung Matrix Trial compare?

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• 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

How does this compare with frozen?

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• 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 2017.

• Discussions are currently ongoing regarding further new arms to be submitted for funding consideration.

New Arms

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• Predictive biomarkers from tissue and ctDNA

• Resistance mechanisms from ctDNA and PDX

• Integrating the SMP-2 data with NHSE – molecular prognostication and SOC prediction

Translational and Other Outputs

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Trial Milestones Year Milestone

2017 August: Interim analyses of first 2 cohorts to reach n=15 July: Major improvements to trial website www.birmingham.ac,uk/lungmatrix June: 150th patient recruited & funding approved for 2 new cohorts February: 4th Trial Steering Committee (TSC) Interim analysis & funding approved for 2 new cohorts

2016 November: 100th patient recruited September: 3rd TSC Interim analysis June: Approval for funding for further 2 years & 2 new arms from CRUK March: 50th patient recruited February: 2nd TSC Interim analysis

2015 October: Arm F & G opened to recruitment September: 1st 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

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• 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

With Many Thanks to:

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Thank You