Lung Cancer Genomics and Patient Individualization

Transcription

1 Lung Cancer Genomics and Patient Individualization Ming Sound Tsao, MD, FRCPC Qasim Choksi Chair in Lung Cancer Translational Research University Health Network OCI/PMH

2 Leading Causes of Deaths (WHO) In 2002: 1. Ischaemic heart disease 2. Cerebrovascular disease 3. Lower respiratory infection 4. HIV/AIDS 5. COPD 6. Perinatal conditions 7. Diarrheal diseases 8. Tuberculosis 9. Lung cancer 10. Road traffic accidents In 2030: 1. Ischemic heart disease 2. Cerebrovascular disease 3. HIV/AIDS 4. COPD 5. Lower respiratory infection 6. Lung cancer 7. Diabetes Mellitus 8. Road traffic accidents 9. Perinatal conditions 10. Stomach cancer Mathers CD, Loncar D, PLosMed 2006;3:e442

3 Canadian Cancer Statistics 2009 Estimated New cases Estimated Deaths Lung Breast Prostate Colorectal 22000

4 5-year survival rate (%) Cancer Survival Rates ( ) Cancer Facts & Figures 2008

5 HIGH DEATH RATES: 70% of Lung Cancer Patients are Diagnosed at Advanced Stage NSCLC Lung cancer survival local distant regional SCLC SEER STATISTICS (US NCI Surveillance Epidemiology and End Results)

6 BY 20% IN 5-YEARS June 29, 2011,

7 80% of Lung Cancers Detected by LDCTS are Potentially Resectable 505 (80%) NLST, NEJM June 29, 2011,

8 Major Types of Lung Cancer Small cell lung cancer: 20% Non-small cell lung cancer (NSCLC): 80% Adenocarcinoma (45%) Adeno (~ 50%) Squamous cell carcinoma (35%) Squamous (~ 25%) Others (15%)

9 Cumulative Percent Surviving Two Third of NSCLC Patients are Diagnosed at Advanced Stage Stage I A Stage I B Stage II A Stage II B 35% [EARLY STAGE] 20 Stage III A Stage III B Stage IV 65% [ADVANCED STAGE] Months After Treatment

10 Stage: Extent of Disease Spread at Diagnosis Early stage: Tumors limited to involvements of same lobe of lung or immediate draining lymph nodes Late stage: Tumor has spread outside the lung into mediastinal lymph nodes or distant organs

11 Before 2004 Most important to distinguish small cell from non-small cell carcinoma Small cell lung cancer patients are treated mainly by chemotherapy ± radiotherapy Early stage NSCLC patients are treated by surgery only Advanced stage NSCLC patients are treated by platinum doublet chemotherapy ± radiotherapy

12 2004 Beginning of Paradigm Changes in Lung Cancer Treatment and Diagnosis EARLY STAGE NON-SMALL CELL LUNG CANCER ASCO 2004 Winton T, et al. N Engl J Med 2005;352:

13 Landmark Discoveries and Studies Leading to Paradigm Shift in Lung Cancer Diagnosis SCIENCE April 29, 2004 NEW ENGLAND JOURNAL OF MEDICINE, MAY 20, 2004

14 Epidermal Growth Factor Receptor (EGFR/HER/ErbB) Burgess AW, et al. Molec Cell 2003;12: Roskoski Jr, BBRC 2004;319:1-11

15 Activation Follows Dimerization Induced by Ligand Binding Phosphorylated tyrosine Kumar A, et al. J Clin Oncol 26:

16 EGFR Signaling Pathway EGFR RAS RAS-GTP TKR PI3K Tiam1 RalGDS RAF NF1 Rassf1A Akt/PKB Rac Rac MEK RasGAP Anti-apoptosis/Cell Survival Gene expression Protein synthesis Mitosis - Proliferation Motility-Invasion Angiogenesis

17 EGFR TK Domain Mutations Exon 19 Deletion Exon 21 Point Mutation Lynch T, et al. NEJM 350: , 2004

18 Structural Modeling of EGFR Kinase Domain A INACTIVE CONFORMATION ACTIVE CONFORMATION Kumar A, et al. J Clin Oncol 26:

19 Reported EGFR TK Domain Mutations Resistant Mutations Sensitizing Mutations 90% Sharma SV, et al. Nat Rev Cancer 2007;7:169-81

20 EGFR TK Domain Mutations Adeno > Squamous (<5%) Women > Men East Asian (40-50%) > Caucasian (10-20%) Never smokers > smokers

21 Inhibitors to Epidermal Growth Factor Receptor (EGFR) IRESSA TARCEVA

22 EGFR Mutant Lung Cancer Cells are more Sensitive to EGFR TK Inhibitors EGFR Normal Mutant EGFR Activation Wild Type Mutant Paez et al: Science 2005;304:

23 Oncogene Addiction Theory (Weinstein IB. Science 2002;297:63-4) Dependency of tumor cells on single and predominant oncogenic activity to sustain their proliferation and/or survival Oncogene addiction can be the Achilles heel of cancer.

24 EGFR Mutations Predict Higher Response Rates to EGFR TKI Treatment W ild T y p e M u ta n t 100 R esp o n se R ate (% ) 50 0 Huang (16) Tokumo (21) Mitsudomi (59) Zhang (30) Mu (22) Takano (66) Endo (27) Kim (27) Han (90) Chou (54) Uram oto (20) Shih (62) Cortes-Funes (83) Cappuzzo (89) E ast Asian C au casian M ix Taron (68) Bell (79) S tu d y (N u m b er o f p atien ts)

25 EGFR TKI Improves Survival of EGFR Mutant Compared to Wild Type Patients Study No. Pts Ethnicity Agents Superior survival HR (95% CI); p value Mitsudomi 59 Japanese G Yes 0.34 ( ); p=0.05 Cortes- Funes 83 Spanish G Yes 0.32 ( ); p=0.03 Takano 66 Japanese G Yes 0.27 ( ); p=0.001 Han 90 Korean G Yes mutant 0.16 ( ); p=0.05 Shih 62 Chinese G Yes 0.39 (0.17 wild type ); p=0.03 Bell/ IDEAL 79 Worldwide G No Not calculated Cappuzzo 89 Italian G No Not calculated Han S-W et al. J Clin Oncol 2005;23: Takano T et al. J Clin Oncol 2005;23:

26 Clinical Question Standard practice for advanced non-small cell lung cancer patient treatment is chemotherapy Would targeted therapy such as the EGFR inhibitor, which has milder toxicities than chemo be used as an alternative therapy with the same efficacy?

27 IPASS (Iressa Pan-ASia Study)

28 IPASS Progression Free Survival Result

29 N Engl J Med 2009;361:

30 Phase III studies of EGFR-TKI vs. Platinum doublet in EGFR Mutant Patients Group EGFR mutation Primary endpoint N (TKI vs. CT) TKI Control WJOG 3405 EX19, L858R PFS 172 (HR=0.49) G CDDP+DOC NEJ 002 EX19, L858R, G719X, L861Q PFS 320 (HR=0.69) G CBDCA+PAC EURTARC EX19, L858R PFS 174 (HR=0.37) E Pt doublet Optimal EX19, L858R PFS 165 (HR=0.16) E CBDCA+GEM Adapted from Mitsudomi, 2011

31 EGFR-TKIs Improve Progression Free Survival vs. Platinum Doublets in EGFR Mutant Patients WJOG 3405 NEJ 002 Gefitinib (HR 0.49) Gefitinib (HR 0.30) EURTARC OPTIMAL Erlotinib (HR 0.37) Erlotinib (HR 0.16)

32 Gefitinib Labelling in Canada

33 Predictive Biomarkers Patient or tumor characteristics that can predict response of tumor (shrinkage, prolonged survival, etc) to treatment Predictive markers can be POSITIVE (select patients to get treatment) or NEGATIVE (not to receive therapy)

34 EGFR Mutation Testing Advanced NSCLC patients being considered for treatment with gefitinib: First line therapy When TKI is considered an option against chemotherapy Mainly for non-squamous tumors: adeno, large cell and poorly differentiated NSCLC (NOS)

35 Almost All Patients Treated with TKI Eventually Progress

36 T790M Resistant Mutation

37 HGF/Met EGFR Cross-talk

38 Met Amplification as Mechanism of Secondary Resistance to TKI Engleman JA et al. Science 2007;14:

39 Mechanisms of TKI Resistance 37 patients with re-biopsy of tumor that progress during EGFR TKI therapy Sequist LV, et al. Sci Transl Med March 23; 3(75): 75ra26.

40 Afatinib (BIBW 2992) F Afatinib is an irreversible EGFR and HER2 inhibitor with preclinical activity against H1975 (L858R/T790M) (EC 50 : 99 nm) Cl N N N N O O O N Designed to irreversibly bind to the ATP binding pocket of EGFR and HER2 F EGFR or HER2 + ATP binding pocket S N O Highly specific for EGFR and HER2 EGFR IC 50 : 0.50 nm HER2 IC 50 : 14 nm Cl N N N N O O S N N O O

41

42

43 Mechanism of Resistance More complicated than resistant mutant clones or amplification

44 Parent DTP DTEP Induction of DTP and DTEP appears linked to chromatin alteration DTP: Drug-Tolerant Persisters; DTEP: Drug-Tolerant Expanded Persisters

45 New Therapies in NSCLC Drug (Target) Gefitinib (EGFR) Erlotinib (EGFR) Cetuximab (EGFR) Crizotinib (ALK) Bevacizumab (VEGFR) Pemetrexed (Folate Pathway) Molecular Selection Marker EGFR mutation (1 st line) EGFR protein by IHC (potential) ALK rearrangement None (currently)

46 Nature 2007 (Aug 2);448: cdna prepared from lung cancer specimen of a 62 year old smoker man negative for EGFR and KRAS mutation Mouse 3T3 fibroblast Transformed foci

47 EML4-ALK v1

48 ALK Break Apart FISH e20 ALK ~12 Mb EML4

49 Sasaki T, et al, Eur J Cancer Jul;46(10):

50 (EML4)-ALK Fusion Gene Tumors Occur Mainly in Adenocarcinoma First author Adeno (total no.) Squamous (total no.) Others (total no.) Imamura (2008) 3.4% (149) 0% (48) 0 (24) Shinamura (2008) 4% (50) 0% (20) 0% (7) Takeuchi (2008) 4.3% (253) 0% (71) 0% (19) Koivunen (2008) 3.8% (208) 0% (88) 0 (100) Martlelli (2009) 4.8% (63) 8.3% (48) 22.2% (9) Wong (2010) 5.3% (209) 0% (34) 8.7% (23) Salido (2010) 4.3% (69) 0% (30) 0% (8) Tumors studied

51 N Engl J Med 2010;363: Overall Response Rate for ALK rearranged patients to Crizotinib (ALK inhibitor): 57% Before TX After TX Disease Control Rate (CR+PR+SD) at 8 weeks= 87% 5% of adenocarcinoma Kwak EL, et al. NEJM 2010;363:

52 In ~1% of NSCLC cases (also found in some GBMs and cholangiocarcinomas) Enriched in younger, never or light smokers with ADC histology No overlap with other oncogenic drivers

53

54 Genome Res 2012;22: (Epub December 22, 2011)

55 188 lung adenocarcinoma analysed for mutations in 623 cancer associated genes 1013 somatic mutations identified in 163 tumors Ding L, et al. Nature vol. 455 (23 October 2008): pg. 1069

56 Molecular Classification of Adenocarcinoma Western (Adeno) East Asian Sun Y, et al. J Clin Oncol 2010;28: Pao W, Girard N. Lancet Oncol 2011;12:175-80

57 8p12 Science Trans Med 2010;2:1-7 FGFR1 amplification: 15/155 (9.7%) et al FGFR inhibitor PD173074

58 Candidate Driver Oncogenes for Squamous Cell Carcinoma et al 22% 3.2%

59 768R 11/290 (3.8%) samples screened; 9/277 (3.2%) primary SqCC Hammerman PS, et al. Cancer Discovery 2011;1:79-89.

60 Nature September 9 (published on line) Potentially Targetable Mutated/Amplified Genes PI3KCA PTEN AKT 1-3 FGFR 1-3 EGFR ERBB2 BRAF NOTCH RAS 16% 8% 20% 12% 9% 4% 4% 13% 6%

61 Histology Classification Non-Small Cell Lung Cancer Classification Molecular Classification North America, Europe East Asia Global Adenocarcinoma Squamous cell ca

62 Mutations Involve Genes with Important Roles in Cancer Cell Biology

63 Short List of Targeted Agents in Non-Small Cell Lung Cancer VEGF targeted agents EGFR targeted agents mtor inhibitors Proteasome inhibitors Cell cycle targeted agents PARP inhibitors CDK inhibitors Novel chemotherapy Proapoptotic agents Vaccine Therapy Sundry Kinase Inhibitors: PI3K AKT MAP kinase MEK (Ras, Raf) SRC Aurora kinase Polo-like kinases PKC HSP 70, 90 targeted agents HIF1-alpha antagonists C-met inhibitors

64 Future Cancer Therapy Treatment A Treatment B NSCLC Treatment C Treatment D Treatment decisions will be based on prognostic and predictive biomarkers of patients and their tumors

65 Conclusions Targeted therapies work best when the tumor is addictive/dependent on a specific pathway Tailoring treatments according to the genetic abnormality of individual patient s tumor is the only way to achieve the most effective cancer therapy