Gli studi clinici nell era delle terapie personalizzate Highlights da Sidney

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1 Gli studi clinici nell era delle terapie personalizzate Highlights da Sidney Massimo Di Maio S.C. Sperimentazioni Cliniche Istituto Nazionale Tumori Fondazione G.Pascale IRCCS Napoli

2 Gli studi clinici nell era delle terapie personalizzate Highlights da Sidney Qualche progresso ma anche fallimenti! siamo sicuri che il target sia sempre driver? aspettando i risultati delle nuove metodologie di studio Bisogna fare i conti con l eterogeneità intratumorale!

siamo sicuri che il target sia sempre driver?

3 Mark Kris PL03.07 Sidney 2013

4 Mark Kris, PL03.07, Sidney 2013

5 Mark Kris, PL03.07, Sidney 2013

6 D. Gandara, The Future of RCTs in the Molecular Era? Sidney 2013

7 D. Gandara, The Future of RCTs in the Molecular Era? Sidney 2013

8 Alcuni risultati negativi con la vecchia strategia all comers Drug Mechanism of action Selection Author (abstract) Necitumumab Anti-EGFR Non- Paz-Ares Phase III: squamous (O03.02) 02) Cis/Pem +/- Neci Cixutumumab Anti-IGF-1R Nonsquamous Scagliotti (P ) Phase II random: Cis/Pem +/- Cix

9 1 line treatment: Cis/Pem +/- cixutumumab (anti IGF-1R) Scagliotti, P , Sidney 2013

10 Gli studi clinici nell era delle terapie personalizzate Highlights da Sidney Qualche progresso ma anche fallimenti! siamo sicuri che il target sia sempre driver? aspettando i risultati delle nuove metodologie di studio Bisogna fare i conti con l eterogeneità intratumorale!

11 Matthew Meyerson. What can we learn from lung cancer sequencing? Sidney 2013

12 Matthew Meyerson. What can we learn from lung cancer sequencing? Sidney 2013

13 Lawrence et al, Nature 489, (27 September 2012) Matthew Meyerson. What can we learn from lung cancer sequencing? Sidney 2013

14 Lawrence et al, Nature 489, (27 September 2012) Matthew Meyerson. What can we learn from lung cancer sequencing? Sidney 2013

15 Matthew Meyerson. What can we learn from lung cancer sequencing? Sidney 2013

16 Gli studi clinici nell era delle terapie personalizzate Highlights da Sidney Qualche progresso ma anche fallimenti! siamo sicuri che il target sia sempre driver? aspettando i risultati delle nuove metodologie di studio Bisogna fare i conti con l eterogeneità intratumorale!

17 Statistics of Personalised Medicine Clinicali l Ti Trial ldesigns for Biomarker Di Driven Therapies in Early Disease (Adjuvant) Giorgio Scagliotti Clinical Trial Designs for Biomarker Driven Therapies in Advanced Disease Roy Herbst The Future of RCTs in the Molecular Era? The Future of RCTs in the Molecular Era? David Gandara

Designs for Biomarker Driven Therapies in Advanced Disease Roy Herbst The Future

18 G Scagliotti, Sidney 2013

19 G Scagliotti, Sidney 2013

20 G Scagliotti, Sidney 2013

21 Statistics of Personalised Medicine Clinical Trial Designs for Biomarker Driven Therapies in Early Disease (Adjuvant) Giorgio Scagliotti Clinical Trial Designs for Biomarker Driven Therapies in Advanced Disease Roy Herbst The Future of RCTs in the Molecular Era? David Gandara

22 Roy Herbst, Sidney 2013

23 Roy Herbst, Sidney 2013

24 Roy Herbst, Sidney 2013

25 Roy Herbst, Sidney 2013

26 Roy Herbst, Sidney 2013

27 Roy Herbst, Sidney 2013

28 Clinical Trial Design for Drug Development Adaptive Designs: For J. Jack Lee Adaptive Designs: Against Marc Buyse Pro/Con session, Sidney 2013

29 Adaptive randomization: pro Jack Lee, ASCO 2012

30 Adaptive randomization: contra Adaptive randomization, which consists of allocating more patients to the treatment that appears to have more efficacy ("play-the-winner"), is justified neither statistically ti ti nor ethically. This strategy may produce slight reductions in the number of patients t exposed to the inferior i treatment, t t but it may increase the total sample size of the trial as compared to using a fixed allocation ratio. More importantly, this adaptive strategy conveys the misleading impression that one treatment is known to be better than the other, a situation in which equipoise is not maintained and randomization no longer ethical. Marc Buyse, Sidney 2013

31 Rationale for Master Protocol Design Multi-arm Master Protocol Homogeneous patient populations & consistent eligibility from arm to arm Each arm independent of the others Infrastructure facilitates opening new arms faster Phase II-III III design allows rapid drug/biomarker testing for detection of large effects Screening large numbers of patients for multiple targets by a broad-based NGS platform reduces the screen failure rate Provides a sufficient hit rate to engage patients & physicians Bring safe & effective drugs to patients faster Designed to faciliate FDA approval of new drugs Roy Herbst, Sidney 2013

32 Master Protocol: Potential targets and drugs Target Drug Biomarker Prevalence IGFR LDK378 IGFR expression 60% PI3K BKM120 PI3K expr/ amplif, 25%. (PI3Ka) MLN1117 (AKT)GSK PIK3CA mut PTEN loss AKT, PIK3CA fus. 16% 15% FGFR LY JNJ FGF Trap GSK FRGFR expr FGFR1, 2 amplif, 15%. FGFR 1, 2 mut 10% p53 MK 1775 (+gem) TP53 mut 81% MET AMG337 MET expression 50% LY JNJ Foretinib ib (GSK ) HGF AMG102 HGF expression PD 1 MEDI4736 (PD L1) PDL 1 expression 50% Roy Herbst, Sidney 2013

33 Target Drug Biomarker Prevalence HDM2 Anti HDM2 HDM2 amplif RANKL Denosumab RANK/RANKL expr Notch LY Notch1 mut 8% EGFR CO1686 L858R, Del(19), T790M RAS MEKi+panPI3K RAS CKN2A LY (CDK4/6) CDKN2A mut, deletion, methylation CCND1 amplif HER3 HER3mAb HER3 expression mtor1/torc2 MLN0128 STK11,TSC1, TSC2 mut Raf MLN2480 TBD Roy Herbst, Sidney % 15%, 30% 21% 13% 2%, 3%, 3%

34 S1400: MASTER LUNG-1: Squamous Lung Cancer- 2 nd Line Therapy Biomarker A Biomarker Β Biomarker Profiling (NGS/CLIA) Biomarker C Biomarker Non Match Multiple Phase II III Arms with rolling Opening & Closure Biomarker D CT* Non Match Drug TT A CT* TT B CT* TT C+CT CT* TT D+E E* Endpoint (Interim PFS) OS Endpoint (Interim PFS) OS Endpoint (Interim PFS) OS Endpoint (Interim PFS) OS TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib PI: V. Papadimitrakopoulou p (SWOG) Steering Committee Chair: R. Herbst (YALE, SWOG) Roy Herbst, Sidney 2013

35 S1400: MASTER LUNG-1: Squamous Lung Cancer- 2 nd Line Therapy Biomarker Profiling (NGS/CLIA) Biomarker Non Match CT* PD L1i Multiple Phase II III Arms with rolling Opening & Closure PiK3CA Mut CCND1 ampl or CDKN2 loss + RB WT FGFR ampl, Mut, Fusion MET Expr PI3Ki CT* CDK 4/6i CT* FGFRi+CT CT* HGFi+E E* Endpoint (Interim PFS) OS Endpoint (Interim PFS) OS Endpoint (Interim PFS) OS Endpoint (Interim PFS) OS TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib Roy Herbst, Sidney 2013

36 Gli studi clinici nell era delle terapie personalizzate Highlights da Sidney Qualche progresso ma anche fallimenti! siamo sicuri che il target sia sempre driver? aspettando i risultati delle nuove metodologie di studio Bisogna fare i conti con l eterogeneità intratumorale!

37 Unmet Needs in Future NSCLC Clinical Trials when viewed as a Multitude of Genomic Subsets How to develop drugs for uncommon-rare genotypes? How to apply broad-based genomic screening (NGS)? How to initiate therapy with an acceptable turn- around time for molecular l testing? (<2 weeks) How do you account for both inter- and dintra-tumor t heterogeneity? D. Gandara, The Future of RCTs in the Molecular Era? Sidney 2013

38 Charlie Swanton, Sidney 2013

39 Implications for Therapy and Outcome Intertumour Heterogeneity Intratumour Heterogeneity Intercellular Heterogeneity Review principles p of intratumour heterogeneity learned from Renal Cancer Apply methods to study cancer evolution in Non Small Cell Lung Cancer Charlie Swanton, Sidney 2013 Burrell, Mcgranahan, Bartek and Swanton Nature 2013

40 Charlie Swanton, Sidney 2013

42 Charlie Swanton, Sidney 2013 Yap, Gerlinger, Pusztai, Futreal and Swanton Sci Trans Med 2012

43 Target Tumour Phylogenetic Trunks and Resolve Branches Branched Genetic Events Present in Some Cancer Cells not others Dynamic during disease course Monitor subclonal events to define drug resistance mechanisms Trunk Genetic Events Present in Every Cancer Cell DEFINE TRUNK DRIVERS Charlie Swanton, Sidney 2013

44 Roy Herbst, Sidney 2013

45 Gli studi clinici nell era delle terapie personalizzate Highlights da Sidney Qualche progresso ma anche fallimenti! siamo sicuri che il target sia sempre driver? aspettando i risultati delle nuove metodologie di studio Bisogna fare i conti con l eterogeneità intratumorale!

46 Grazie per l attenzione! Massimo Di Maio S.C. Sperimentazioni Cliniche Istituto Nazionale Tumori Fondazione G.Pascale IRCCS Napoli dimaiomax@libero.it

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