1. 1 Precision Medicine in Advanced Non- Small Cell Lung Cancer A therapy that works…so lets get the most out of it that we can Gary Middleton, University of Birmingham

2. Original Article Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib Thomas J. Lynch, M.D., Daphne W. Bell, Ph.D., Raffaella Sordella, Ph.D., Sarada Gurubhagavatula, M.D., Ross A. Okimoto, B.S., Brian W. Brannigan, B.A., Patricia L. Harris, M.S., Sara M. Haserlat, B.A., Jeffrey G. Supko, Ph.D., Frank G. Haluska, M.D., Ph.D., David N. Louis, M.D., David C. Christiani, M.D., Jeff Settleman, Ph.D., and Daniel A. Haber, M.D., Ph.D. N Engl J Med Volume 350(21):2129-2139 May 20, 2004

3. BRAF mutant NSCLC and CRC are both agressive diseases. Antonio Marchetti et al. JCO 2011;29:3574-3579 Gavin P G et al. Clin Cancer Res 2012;18:6531-6541

4. However, dual BRAF/MEK blockade works in NSCLC but doesn’t in CRC Corcoran R. ASCO, 2014 Johnson B. ASCO, 2014

5. Tumor Responses to Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer. Shaw AT et al. N Engl J Med 2014;371:1963-1971

6. Progression-free Survival. Shaw AT et al. N Engl J Med 2014;371:1963-1971

7. Response to ALK Inhibition Kwak EL et al. N Engl J Med 2010;363:1693-1703

8. But there is a problem…. 7524 cases completed successfully for ALK testing between Nov 2011 and May 2015 (included 144 positive cases in total: 2% Centre 1: 1/74 1.35%Centre 2: 3/308 1% Centre 3: 2/170 1.2%Centre 4 4/253 1.6% Centre 5: 3/356 0.85%Centre 6: 7/434 1% Centre 7: 7/401 1.75%Centre 8: 7/200 3.5% Centre 9: 6/361 1.7%Centre 10: 6/275: 2.2% Centre 11: 10/464: 2.1% Phillipe Taniere, UHB.

9. 9 National Lung Matrix Trial A Multi-drug, genetic marker directed, non-comparative multi-arm Phase II trial in NSCLC

10. 10 Trial Design A multi-arm non-randomised design, with treatment allocation according to molecular phenotype No ‘standard’ control arm Each biomarker/drug arm will contain 30 + patients Endpoints are principally objective response rate and duration of response: progression free survival for some drugs The study will be a national study open at all ECMCs The study will be carried out under a single clinical trial protocol and regulatory submission

11. 11 The biology of stratification MATRIX Targets

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14. 14 AZD5363AZD4547 AZD2014 PalbociclibCrizotinibAZD9291Selumetinib + docetaxel MEDI 4736 SUPPLEMENT NO.ABCDENA SCC PIK3CA mutant (11%) SCC PIK3CA amplified (40%) SCC PTEN loss, not mutated (40%) SCC PTEN mutant (6%) Ad - PI3kinase/AKT deregulated (4.5%) NSCLC harbouring AKT1 mutation FGFR (A1) - NSCLC harbouring FGFR mutations (4.0% SCC and <1% Adeno)

15. 15 AZD5363AZD4547AZD2014PalbociclibCrizotinibAZD9291Selumetinib + Docetaxel MEDI 4736 SUPPLEMENT NO.ABCDENA TSC (B1) – NSCLC harbouring TSC1/2 mutations (2.7% SCC and 0.5% adeno) LKB1 (B2 and B3) – NSCLC harbouring LKB1 mutations (Tier 1 - 4.6% Ad and 1.6% SCC: Tier 2 2.4% and <1%) SCC with proficient Rb and p16 loss (C1) (CDKN2A HD 29%) CDK4 amplified NSCLC (C2) (7% Ad and <1% SCC) CCND1 amplified NSCLC (C3) (12% SCC, 5% Ad) Adeno harbouring KRAS mutations (C4) (25.8%)

16. 16 AZD5363AZD4547AZD2014PalbociclibCrizotinibAZD9291selumetinib + Docetaxel MEDI 4736 SUPPLEMENT NO.ABCDENA MET (D1) – Met amplified NSCLC (4% SCC and Ad - Rx effect)) ROS (D2) –NSCLC harbouring ROS fusions (Ad 1.7% and SCC <1%) EGFR mutation and T790M+ NF1 (E1) –SCC harbouring NF1 mutations (5.8%) NF1 (E2) – Ad harbouring NF1 mutations (4.6%) N-RAS (E3) – NSCLC harbouring N-RAS mutations (Ad 0.7%) Biomarker negative cohorts (F)

17. 17 NLMT – rationale for single arm design Crizotinib, EML4-ALK and ROS fusion as exemplars – the bona fide targeted therapy Option for biomarker-specificity testing in biomarker negative patients Allows discrete bio-marker testing Based on strong pre-clinical data (and/or clinical data) and the appropriate implementation of those findings

18. 18 AZD5363AZD4547 AZD2014 PalbociclibCrizotini b AZD9291Selumetinib + docetaxel MEDI 4736 SUPPLEMENT NO.ABCDENA SCC PIK3CA mutant SCC PIK3CA amplified SCC PTEN loss, not mutated SCC PTEN mutant Ad - PI3kinase/AKT deregulated NSCLC harbouring AKT1 mutation FGFR (A1) - NSCLC harbouring FGFR mutations (4.0% SCC and <1% Adeno) NLMT – discrete biomarker/drug cohorts

19. 19 Implementing the implications of the pre-clinical data FGFR – amplifications and mutation types Liao R G et al. Cancer Res 2013;73:5195-5205

20. 20 Implementing the implications of the pre-clinical data 5363 and Palbo molecular exclusion rules These will change with different drugs PIK3CA, PTEN and AKT (5363) – no KRAS mutation Davies BR et al. Mol Cancer Ther 2012;11:873-887 KRAS mutation (Palbo) – no activation of PI3K/Akt/MTOR signaling – genetically simple models and the re-induction of senescence with cdk4 knockdown Puyol M et al. Cancer Cell, 2010; 18: 63 – 73 Kennedy AL et al Mol Cell. Apr 8, 2011; 42(1): 36–49

21. 21 Randomised precision medicine trials in lung cancer SAFIR 02 and LUNG-MAP Assessing the benefits of the novel therapy rather than potential prognostic effects of the biomarker

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23. 23 SAFIR 02 - objectives PRIMARY OBJECTIVE : To evaluate whether treatment with targeted agents guided by high throughput molecular analyses (CGH array, next generation sequencing) improves progression-free survival as compared to standard maintenance therapy in patients with metastatic NSCLC. SECONDARY OBJECTIVES : To explore the efficacy (response rate, progression-free survival, overall survival) of the individual targeted agents To correlate molecular mechanisms in patients with the efficacy endpoints (response rate,progression-free and overall survival)

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25. 25 SAFIR 02, MATRIX and LUNG-MAP – Gene blocks in common Akt 1-3, PIK3CA, PTEN, STK11, TSC1/2 (PIK3R1, mTOR) FGFR 1-4 NRAS, KRAS, NF1 (HRAS, MAP2K1, MAP2K4, MAP3K1) CDKN2A loss, CDK4 amplification, CCND1 amplification

26. 26 Concluding remarks – the importance of sustainability and a unique opportunity to collaborate “Therefore, there is maybe a place for, at least, a European project, supported by the EU, setting up a global platform with adequate resources (informatics, mathematics, statisticians, etc) able to fully combined and interpreted the data, taking into account differences in design and drugs, but aiming to propose a unique interpretation of generated knowledge as soon as it becomes available?” Fabrice Barlesi