Targeted therapies in lung cancer - what are the limits?

1. Targeted therapies in lung cancer - what are the limits? D. Ross Camidge, MD PhD Director, Thoracic Oncology Clinical Program University of Colorado Halifax, Nova Scotia, 21st October 2011

2. Disclosures (DRC) • Employment or leadership Position: None • Advisory Role: Ad Hoc Advisory Boards/Consultations (most recent contact last 3 years): • 2011: Ariad, Array Biopharma, AstraZeneca, Aveo, BoehringerIngelheim, Chugai, Clovis, Novartis, Synta • 2010: Millenium, Pfizer • 2009: Imclone, OSI • Stock Ownership: None • Honoraria: Seminar/Talks to Industry (most recent contact last 3 years). • 2011: Ariad, Array Biopharma, Pfizer • 2009: Imclone, BoehringerIngelheim, • Speakers Bureau/Talks for Industry: None • Research Funding: • 2010: Eli-Lilly (Translational) • 2008: Onyx/Merck (IIT) • Expert Testimony: None • Other Remuneration: None

3. Negative phase III trials of new agents in NSCLC 2000-2010 Slide courtesy of JC Soria

4. Targeted therapies? NSCLC Marker A NSCLC Marker B Drug A Drug B

5. EGFR mutant selected NSCLC Spanish Lung Cancer Group (Rosell et al, 2009): Erlotinib in 1st/2nd line EGFR mutant selected NSCLC PFS: 14 months BR.21 (Shepherd et al, 2005): Erlotinib vs. placebo in 2nd/3rd line unselected NSCLC PFS: 2.2 vs 1.8 Months (.4 months difference i.e. < 2 weeks) P<0.001 Unselected NSCLC

6. Rapid and dramatic tumor response in ALK+ NSCLC to crizotinib Ou et al, JTO 2010

7. Best Percent Change from Baseline in Target Lesions 100 Progressive disease Stable disease Partial response Complete response 80 60 40 20 % Decrease or increase from baseline 0 –20 –40 –60 –80 –100 Camidge et al, ASCO 2011

8. Potential predictive biomarkers (both categorical and continuous variables) • Tumor • Mutations • Gene rearrangements • Gene copy number • Protein expression/expression level • Transcript(s) levels • Host • Immune system • Vasculature • Endocrine environment

9. Personalized medicine in oncology Unselected large population, modest overall benefit Selected small population, large benefit

10. From a drug-perspective, the limits will only be partly set by the targets

11. Kinases Protein-ProteinInteractions ImmuneEffectors NucleicAcid • Beyond chemo • Transcriptional repressors (e.g. YM155) • SiRNA • MiRNA • Gene therapy • Challenges set by the methods of drug delivery • But required - given the challenge of most • oncogenic changes being loss of function …

12. Most of the limits are far more immediate and more ‘obvious’ • There are no common cancers • The practical implications of heterogeneity • The financial consequences of heterogeneity • Today’s miracles aren’t curing anyone • The brain is a special place • Addressing molecular mechanisms of resistance • Darwinian oncology The elephant(s) in the room

13. 1. There are no common cancers

14. 516 analyzed cases: Incidence of Oncogenic Drivers Mutation found in 54% (280/516) of Tumors: 97% mutually exclusive Kris et al, ASCO 2011

15. 1.1 The practical implications of heterogeneity in clinical research

16. Have mutation, will travel Origin of lung cancer patients (green circles) who participated in crizotinib clinical trials at the University of Colorado (red circle) (62% from Colorado, 36% from other US States, 2% International (Johannesburg, South Africa; not shown)).

17. PFS by molecular status on pemetrexed-based therapy Camidge et al., J Thoracic Oncol. (2011)

18. Ongoing randomized trials of crizotinib in ALK+ NSCLC RANDOMIZE • Crizotinib 250 mg BID (n=159) • [continuous] • PROFILE 1007 (N=318) • ALK-FISH positive • 1 prior chemotherapy (platinum-based) • pemetrexed 500 mg/m2or • docetaxel 75 mg/m2 (n=159) • infused on day 1 of a 21-day cycle RANDOMIZE • Crizotinib 250 mg BID (n=167) • [continuous] • PROFILE 1014 (N=334) • ALK-FISH positive, non-squamous NSCLC • No prior treatment for advanced disease Crossover on PD • pemetrexed/cisplatin orpemetrexed/carboplatin (n=167) • infused on day 1 of a 21-day cycle

19. Tumor samples available from negative phase III trials of chemo vs new agent or chemo +/- new agent in NSCLC?

20. 1.2 The financial consequences of heterogeneity

21. Every cancer is an orphan? • Orphan disease status: • US = Prevalence <200,000 cases • EU = Prevalence <5/10,000 population • 20% lung adenocarcinomas • < 20,000 cases/year • 1% lung adenocarcinomas • <1000 cases/year KRAS Mt NSCLC BRAF Mt NSCLC

22. You can’t change the benefit from the drug in the marker positive population, so to be more cost effective either: 1. Reduce cost of drug 2. Reduce price of screening test per person positive 3. Screen more enriched populations When low biomarker frequency, cost of screening test dominates over cost of drug in cost effectiveness analysis. Lower screening test cost (red line ($500/person) vs blue line ($1,500/person screened)) shifts this inflexion point further to the left. Flat line if screening cost = $0/person Atherley and Camidge, Submitted

23. The ‘savings’ and ‘cost’ of enrichment policies Atherley and Camidge, Submitted

24. 2. Today’s miracles aren’t curing anyone

25. Is there a median PFS ceiling in targeted therapy for oncogene addicted NSCLC?

26. Potential mechanisms of ‘acquired’ resistance: • Fail to deliver drug to target • E.g. Non compliance • E.g. PK sanctuary sites (e.g. CNS) • Alter target • E.g. Gate-keeper or conformational change mutations in drug target • Bypass target • E.g. Develop second oncogenic drivers • E.g. Downregulateeffector pathways

27. 2.1 The brain is a special place

28. EGFR MT disease: CNS progression Grommes et al, Neuro-Oncology 2011

29. 1500 mg erlotinib weekly (high dose intermittent) 44% ORR Median CNS PFS 2.7 months (range: 0.8-14.5 m) Grommes et al, Neuro-Oncology 2011

30. ALK progression within brain • 29 y/o male with ALK+ NSCLC • Systemic (body) control but • brain progression • Blood and cerebrospinal fluid • (CSF) sampling 5 hours after taking • 250mg crizotinib • CSF:plasma ratio = 0.0026 • (i.e. <0.3% gets into brain) • ?too low to work on ALK • Caveats: One patient, blood brain ‘barrierness’ may vary, ‘free’ drug may differ Costa et al, JCO 2011

31. Who needs new targets? The brain in clinical trials • Only first progression considered. • OS follow may continue in any scenario • Mandates baseline and routine CNS surveillance on study

32. 2.2 Addressing molecular mechanisms of resistance

33. EGFR Mutant: acquired resistance mechanisms Sequist et al, Science Translational Medicine 2011

34. Natural selection of resistant clones while most disease still controlled by crizotinib Baseline: July 2009 Crizotinib response:Sept 2009 November 2009 April 2010: New right adrenal - SBRT & crizotinib continues August 2010: New LN – More SBRT & crizotinib October 2010: New LN – More SBRT & crizotinib

35. Drugs for AR: Rapid Deployment Forces vs. Armies of Occupation? • Adding in/replacing with each new drug at time of AR? • Or combine up front? • Tolerability of new drug(s)?

36. Afatinib + cetuximab at MTD. Responses by mutation Abstract 7525 ASCO 2011 N = 45 40% confirmed response rate and a clinical benefit rate of 90% Appears independent of T790M status as assessed in study

37. 2.3 Darwinian Oncology

38. Pt 9 T790M present [low levels] in CTCs – still ‘responds’ to reversible TKIs as T790M is not an all/none event Turke et al, Cancer Cell 2010 Maheswaran et al, NEJM 2008 Diversity pre-exists (?hard- wired) In patients who manifested MET gene amp as mechanism of acquired resistance, rare amplified cells were seen pre-EGFR TKI treatment Number of CTCs (micropost) and frequency of different alleles (L858R/Del/T790M) relative to control, alters with treatment and parallels radiographic response (Top panels – [X] = low frequency allele) (Bottom panels – number of amplification cycles for detection – left to right panel at different points in treatment)

39. Why is the TKI naïve molecular status as it is? • Why don’t T790M and MET amplified EGFR mutants dominate prior to EGFR TKI? • Easier to develop the basic model? • T790M and/or MET plus EGFR MT have some disadvantage in the absence of a specific selection pressure?

40. Changes in Unidimensional CT Measurements (RECIST) After Discontinuation and Re-Introduction of EGFR TKI 50% 20% Change from baseline 0% -30% EGFR TKI re-start stop 3 weeks 3 weeks Riely et al ‘07

41. Re-emergence of partial EGFR TKI sensitivity during time off EGFR TKI therapy (relaxation of specific selection pressure) Known L858R 07/07 2nd line erlotinib (PR) 03/09 PD (new MET amp) Sunitinib +/- pemetrexed trial until PD in 04/2010 04/2010 Minor response to erlotinib rechallenge PD in 08/2010 Minor short-lived response to erlotinib rechallenge PD on chemo (MET amp)

42. CMF09048 Sample: N09-633 A2 Received – 3/12/09 Reported – 3/18/09 Mean MET= 13.07; sd= 4.51 Mean CEP7= 3.17; sd= 1.74 Ratio MET/CEP7 = 4.13 L858R EGFR mutation 10 months off erlotinib selection pressure CMF10009 Sample: S10-208 A1 Received – 1/12/10 Reported – 1/15/10 Mean MET= 9.24; sd= 5.17 Mean CEP7= 4.20; sd= 1.41 Ratio MET/CEP7 = 2.20 L858R EGFR mutation PD pleura/lung/ bones 05/2006 = 1 month 12/2010 Doc (PD) Gem (PR) Clinical trial (EGFR/MET) ongoing Consolidative SBRT Gem/Carbo (PR) XRT to bone met Pem/Sut trial (PR) Erlotinib (PR)

43. Biston betularia (morpha typica) 1848 – carbonaria morph first described By 1895 – 98% carbonaria Natural selection, secondary to industrial soot blackening the environment, would not have been obvious if all local insects, rather than just the peppered moth, had been studied together as a single group.

44. Changes in Unidimensional CT Measurements (RECIST) After Discontinuation and Re-Introduction of EGFR TKI 50% Drug sensitive cells survive drug 20% Change from baseline 0% -30% EGFR TKI re-start stop 3 weeks 3 weeks Riely et al ‘07

45. The r apy Relaxation of dark blue specific selection pressure ‘Sleeper’ cell? Sleeper cells or unstable variants (blue can generate white and vice versa)? The r apy ‘Unstable Variants’? Relaxation of dark blue specific selection pressure

46. The r apy Relaxation of dark blue specific selection pressure Stem cell? Repopulation from universal progenitor repeating selection process again?

47. Sharma et al, Cell 2010 9 days 33 days Panel E: DTPs grown without erlotinib for 9 doublings reacquire drug sensitivity Panel F: DTEPs require ~30 passages to reacquire same drug sensitivity PC-9 EGFR exon 19 del NSCLC cell line Sensitive to reversible EGFR TKI 0.3% of starting population survive (drug tolerant persisters – largely quiescent) – that can be expanded From quiescent state over time (drug tolerant expanded persisters). No loss of mutation, no T790M, no MET Drug tolerant persisters

48. Sharma et al, Cell 2010 HDACI then erlotinib did not prevent DTEP Eemergence – HDACI must be present at time of selection pressure as DTPs continuously generated Combine targeted therapy in selected population with additional therapy directed to purge cancer of its reservoir of resistance? Among multiple combinations with Erlotinib, only HDAC inhibitors and an IGF1R inhibtor (AEW541) prevented emergence of DTEPs Clinical outcome: Response duration? PFS? (assessing pattern of failure)

49. The Limits: • Making non-chemo nucleic acid targeted therapies deliverable and addressing loss of function drivers More immediately… • Addressing heterogeneity: • In trial design and interpretation • In the financial aspects of developing new treatments • Giving the CNS credit for being different • Optimally monitoring, defining and treating acquired resistance • Addressing the existence of ‘reservoirs of resistance’

50. The End of the Beginning…