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Non-small Cell Lung Cancer

Non-small Cell Lung Cancer. Eva Szabo, MD Division of Cancer Prevention, NCI. TRACO 11-14-11. US Lung Cancer Statistics, 2010 227,890 estimated new cases. 158,070 estimated deaths leading cause of cancer deaths greater than breast+prostate+colon

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Non-small Cell Lung Cancer

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  1. Non-small Cell Lung Cancer Eva Szabo, MD Division of Cancer Prevention, NCI TRACO 11-14-11

  2. US Lung Cancer Statistics, 2010227,890 estimated new cases 158,070 estimated deaths leading cause of cancer deaths greater than breast+prostate+colon Death rate per 100,000 decreasing (90.56 in 1990; 67.45 in 2006) Still increasing in women (37.61 in 1991;40.17 in 2006) 16% five year survival 5% in 1950’s, 13% in 1970’s 29% of all male cancer deaths, 26% of all female cancer deaths

  3. Tobacco Use in the US, 1900-2003 Per capita cigarette consumption Male lung cancer death rate Female lung cancer death rate

  4. Radiographic Evidence Linking Tobacco Use to Lung Cancer -●McMullen, DM & Cohen GA, NEJM 354:397, 2006

  5. Risk Factors • Tobacco, tobacco, tobacco (85% lung ca.) • Including passive smoking • Prior aerodigestive malignancy • COPD • Other exposures • Asbestos, radon, polycyclic aromatic hydrocarbons, chromium, nickel, inorganic arsenic – mining, ship building, oil refining • Genetic predisposition • Familial lung cancer – 6q23-25 (Am J Hum Gen, 9/04) • 15q24-25.1 – nicotinic acetylcholine receptor subunits CHRNA3 and CHRNA5, OR=1.3, attributable risk ~14% • Amos et al., Nat Gen 2008;40:616, Hung et al. Nature 2008;452;633, Thorgeirsson et al. Nature 2008;452:638 • CH3NA3/5 is also susceptibility locus for COPD • Pillai et al. PLoS Genet 2009;5:1

  6. Five-year survival by TNM status in NSCLC (old staging system).●In stage 1A, TNM classification T1N0M0 the 5 year survival is 61%.●In stage 1BA, TNM classification T2N0M0 the 5 year survival is 38%.●In stage IIA, TNM classification T1N1M0 the 5 year survival is 34%.●In stage IIB, TNM classification T2N1M0 or T3N1M0 the survival is 24%.●In stage IIIA, TNM classification T1-3NanyM0 or TanyN3M0 the 5 year survival is 13%.●In stage IIIB, TNM classification T4NanyM0 or T3N1M0, the 5 year survival is 5%.●In stage IV, TNM classification TanyNanyM1 the 5 year survival is 1%.

  7. Pathology: Non-small Cell Lung Cancer ●Adenocarcinoma, inc bronchoalveolar 40%● Squamous cell carcinoma 20%● Large cell carcinoma 15%● Others (carcinoid, etc.)

  8. Pathology: Small Cell Lung Cancer ● Small cell lung cancer - 20%

  9. The Continuum of Lung Carcinogenesis Opportunities for Intervention Normal to Hyper/Metaplasia to Dysplasia to Early-Late Cancer

  10. Treatment Strategies for Lung Cancer • Treatment based on stage: • Early stage (Stage I) – surgery • Early stage (Stage II, IIIA resected)-surgery + adjuvant chemo • Regional spread (IIIA/IIIB) – combined modality (chemoradiation, +/- surgery for IIIA) • Metastatic (IIIB “wet”/IV)– chemotherapy, radiation as needed for local control, occasional resection of isolated mets • Small cell lung cancer: chemotherapy (+thoracic radiation for limited stage; prophylactic cranial radiation to prevent brain mets)

  11. Personalizing Therapy for NSCLC:Significantly mutated genes in adenocarcinomas

  12. Epidermal Growth Factor (EGFR) Signaling

  13. EGFR as a Target for NSCLCStandard of Care in 2010 Epidermal growth factor receptor (EGFR) inhibition in advanced NSCLC 10% response rate in advanced disease, 30% prolonged stabilization Survival advantage (erlotinib) Shepherd, F. A. et al. N Engl J Med 2005;353:123-132 Mutually exclusive with K-ras Most benefit for non-smoking related NSCLC, with EGFR mutations (females, adenocarcinomas, Asian) Lynch et al., NEJM 350:2129, 2004; Paez et al., Science 304:1497, 2004; Pao et al., PNAS 101:13306, 2004 Mechanisms of secondary resistance to EGFR inhibitors being identified (T790M mutation-50%, Met amplification-20%) Pao et al., PLoS Med 2:e17, 2005; Engelman et al., Science 316:1039, 2007 Erlotinib approved as single agent for 2nd and 3rd line treatment of NSCLC Also for maintenance after 1st line non-progression after chemo (gefitinib formerly approved in US, failed to show survival advantage)

  14. Effect of Gefitinib on Progression-free Survival and Overall SurvivalMaemondo M et al. N Engl J Med 2010;362:2380-2388230 patients, EGFR mutated, randomized to gefitinib or chemo(carbo/taxol)Results:10 vs. 5 mth PFS74% vs 31% response Median survival 30.5 vs 23.6 mths

  15. EML4-ALK Fusion Gene as a Target for NSCLC Identified in 2007 ~5% NSCLC, mainly never smokers Often with distinct signet cell histology Striking response to inhibitor – crizotinib- 57% RR, 33% stable disease Kwak EL et al. NEJM 2010;363:1693

  16. HER2/neu as a Target for NSCLC Mutations in kinase domain in 4% NSCLC Hunter et al., Nature 2004;30:431 Amplification by FISH in 2-5% Heinmoller P et al. Clin Cancer Res 2003;9:5283 IHC + 30% Langer et al., JCO 2004;22:1180 Trastuzumab in NSCLC with 2+/3+ IHC for Her2 not active (11% of patients eligible, 1/24 PR) Clamon et al., Cancer 2005;103:1670

  17. HER2/neu as Target for NSCLCKelly R J et al. JCO 2010;28:e507-e510 • 50 yo AA nonsmoker with stage IV NSCLC (large cell) in 11/07 • Rx with carbo/taxol/bevacizumab (PR), erlotinib (PD), • PF-00299804 (pan-HER inh, • brief PR) • -found to be HER2 amplified • -Trastuzumab →PD • -Trastuzumab/Vinorelbine→ • near CR x 13 months

  18. Advanced Disease: Targeted TherapiesVEGF Inhibition • Bevacizumab (anti-VEGF antibody) in advanced NSCLC – frontline treatment in combination with chemotherapy (taxol/carbo) – E4599 (Sandler et al. NEJM 2006;355:2542) • Median survival 12.3 vs. 10.3 mths • Response rate 27% vs. 10% • Time to progression 6.4 vs. 4.5 mths • In non-squamous cancers only (life-threatening bleeding higher in squamous cancers)

  19. Controversies in NSCLC Treatment • Choice of agents? • Platinum vs. not (platinum preferred) • Single vs. two vs. three agents (2 conventional chemos) • Treatment of elderly – Yes if good performance • Length of treatment – probably no more than 4-6 cycles of cytotoxic conventional chemo • Second line treatment – yes • Taxotere and pemetrexed better than supportive care • Erlotinib (EGFR inhibitor) for 2nd or 3rd line

  20. Controversies in NSCLC Treatment • Maintenance chemotherapy after first line treatment • Pemetrexed is FDA approved for maintenance in non-squamous NSCLC • Overall survival 13.4 vs. 10.6 mths for all subtypes, 15.5 vs. 10.3 mths for non-squamous histologies • Ciuleanu T et al. Lancet 2009;374:14432 • Erlotinib (SATURN trial) - ~1 mth improvement in survival (12 vs 11 mths) • Data presented b Cappuzzo et al. at 13th World Congress on Lung Cancer, 8/09, San Francisco, CA

  21. Approaches to reducing cancer morbidity and mortality • Prevention (primary, secondary, tertiary) • Early detection • Better therapeutics

  22. The Continuum of Lung Carcinogenesis Opportunities for Intervention Normal to Hyper/Metaplasia to Dysplasia to Early-Late Cancer

  23. Primary Prevention • Smoking cessation • Decline in California lung cancer rates 1988-1997 declined 14%, compared with 2.7% in non-California SEER sites, coincident with declining smoking rates probably due to California tobacco control initiatives • Cowling DW et al., MMWR 49:1066-9, 2000

  24. Effect of Smoking Cessation on Lung Cancer DeathsLung Health Study, 14.5 yr F/U

  25. Cancer Chemoprevention The use of natural or synthetic agents to suppress or reverse carcinogenesis • Regress existing neoplastic lesions (treat intraepithelial neoplasia) • Prevent development of new neoplastic lesions (preneoplastic and cancer) • Suppress recurrence of neoplastic lesions

  26. Rationale for Lung Cancer Prevention Metastatic cancer is rarely curable US lung cancer 5 yr survival is 15% (5% 1950’s, 13% 1970’s) Cancer is preventable P1, STAR breast cancer prevention trials with tamoxifen and raloxifene(Fisher B et al., JNCI 1998;190:1371; Vogel, VG et al., JAMA 2006;295:2727) Multiple animal studies with multiple agents Long preclinical phase with increasing histologic and molecular abnormalities, identifiable populations at risk

  27. When is the best time to intervene during carcinogenesis? Efficacy of intervention Early stage cancer is more curable than late Are precursor lesions more curable than invasive cancer? Can carcinogen-induced DNA damage be prevented? Multiple pathways of carcinogenesis Toxicity of intervention High toxicity acceptable short-term, in setting of cancer Target population – size and ability to identify Many at risk (smokers), relatively few get cancer/yr Inability to identify non-smokers at risk Cost (resources, psychological impact, etc.)

  28. Minimal Requirements for Preventive Strategies Benefit Efficacy in preventing cancer and associated morbidity/mortality Risk Lack of adverse sideeffects that increase morbidity/mortality from other diseases, short- and long-term (major side effects) Tolerability of intervention (minor side effects affecting compliance)

  29. Efficacy: How Do We Identify New Agents? Knowledge of mechanism Example: HPV vaccine and cervical cancer Need: understanding molecular pathogenesis Preclinical (in vitro and animal models) Example: NSAID treated carcinogenesis and transgenic models Need: models reflective of complexity of human disease Observational epidemiology (cohort and case-control studies) Example: NSAIDs and colon cancer incidence/mortality Secondary endpoints from clinical trials (including other diseases) Example: Tamoxifen/raloxifene and breast cancer

  30. Optimizing the Risk-Benefit Balance Identify individuals most likely to develop cancer in short time frame Highest risk Homogeneous cohorts (current vs. former smokers, FAP vs. HNPCC vs. sporadic colorectal adenomas) Pharmacogenetic considerations Minimize toxicities from drug (e.g., route, schedule, modulators of toxicity) Barriers: Lack of adequate risk assessment models for most cancers Incomplete understanding of carcinogenesis at different target organs # needed to treat NL Initiated Dysplasia Carcinoma Stages of Carcinogenesis

  31. Targeting Inflammation for Lung Cancer Prevention: Rationale Animal data showing role for steroids in cancer prevention 1970’s – skin Early 1990’s – lung (oral steroids) Late 1990’s – lung (inhaled steroids) Epidemiology/Human data – Mainly negative (but studies of short exposure duration) VA cohort with COPD (n=10,474) – HR 0.39 (95% CI, 0.16-0.96) Parimon T et al., AJRCCM 175:712, 2007

  32. Effect of Budesonide on Mouse Lung Tumorigenesis Pereira et al., Carcinogenesis 2002 - ● 82% decrease in tumors ● -Shift from adenoma to carcinoma

  33. DCP Phase IIb Trial of BudesonideLam et al. Clin Cancer Res 10:6502, 2004 ●112 smokers with dysplasia (Bronch)●(Spiral CT) Budesonide vs. Placebo x 6mths (Bronch,Spiral CT) ●1o Endpoint: bronchial dysplasia (#sites/grade)2o Endpoints: multiple biomarkers● # Screened (sputum): 1040Cancers detected: 13 (3.1%)

  34. Effect of Budesonide on Bronchial Histology %

  35. Phase IIb Budesonide Chemoprevention TrialPI: Giulia Veronesi, European Institute of Oncology ●202 participants with persistent spiral CT-detected peripheral nodules (Randomize)●inhaled budesonide vs. placebo x 1 year ●repeat spiral CT ●Primary endpoint: shrinkage of lung nodules

  36. Phase IIb Budesonide Chemoprevention TrialLesion Specific Analysis-Overall response negative, but trend toward regression in non-solid lesions (putative precursors of adenocarcinoma)

  37. Adenocarcinoma Precursor: Atypical Adenomatous Hyperplasia Natural history unknown Localized ground glass opacities on CT: AAH 25%; bronchoalveolar ca 50%; invasive adenoca 10%; fibrosis 15% (Nakajima et al., J Comput Assist Tomogr 2002;26:323) AAH 63%; bronchoalveolar ca 34%; scar 3% (Ohtsuka et al., Eur J Cardio-Thor Surg 2006;30:160)

  38. Where do we go from here with steroids? Potential reasons for negative trial Intervention doesn’t work (animal and human data in conflict) Formulation does not penetrate peripherally enough Intervention given too late Intervention focused on wrong cohort (next study to focus on ground glass opacities only) Plan – further molecular characterization of AAH/ground glass opacities Not in current plan: phase III

  39. myo-Inositol Glucose isomer Source of several second messengers & signaling molecules Dietary sources (grains, beans, fruits, rice) Studied in psychiatric conditions (+/-), diabetic neuropathy(+/-), polycystic ovary syndrome (+)

  40. Rationale for myo-Inositol in Lung Cancer Prevention Efficacy Multiple animal studies show inhibition of carcinogen induced tumors in mice (40-50%) Estensen and Wattenberg, Carcinogenesis 1993;14:1975 Hecht et al., Carcinogenesis 2002;23:1455 Inhibits carcinogenesis in mainstream/sidestream smoke-exposed A/J mice by 53% Witschi H et al., Carcinogenesis 1999;20:1375 Combination with budesonide  efficacy up to 80% Estensen and Wattenberg, Carcinogenesis 1993;14:1975 Witschi et al. Carcinogenesis 1999;20:1375 Wattenberg et al. Carcinogenesis 2000;21:179 Safety Used in multiple short term trials for psychiatric and diabetic neuropathy indications – no toxicity reported Generally Regarded as Safe (GRAS) by US FDA terminology

  41. Phase I Study of Myo-inositol in Bronchial Dysplasia-Lam et al., CEBP 2006;15:1526 ●Inhibits B[a]P carcinogenesis in mice (53%); combination with budesonide ●Phase I study (26 participants)tolerable 18 g/d91% vs. 48% regression dysplasia, P=0.014 (10 participants)

  42. PI3K pathway activation in the airways of smokers with dysplasiaGustafson A M et al. Sci Transl Med 2010;2:26ra25-PI3K pathway is activated in smokers with dysplasia in airway p<0.001-Myo-inositol inhibited PI3K activation in normal bronchial airways in smokers with regression of dysplasia (p=0.04)

  43. Why is this study so important? Does PI3K activation truly identify smokers at risk for cancer? Easier to get normal brushings than to identify dysplasia (sampling bias); do not remove biomarker with procedure Potential to identify “the right” cohort New potential clinical trial model – pathway analysis pre- and post-treatment, smaller # participants, shorter interventions Identify mechanisms of interventions Needs validation!

  44. Phase IIb myo-Inositol Chemoprevention TrialPI: Stephen Lam, British Columbia Cancer Agency30+ pack yr. Get Bronch, Spiral CT N=110myo-inositol 9g bid vs. placebo x 6 mths Get Bronch, Spiral CT1o Endpoint: bronchial dysplasia (# sites/grade)2o Endpoints: multiple biomarkers (gene expression) Clinical sites: BCCA, Mayo Clinic, New Mexico VA

  45. Peroxisome Proliferator-Activated Receptor  (PPAR  ) as a Target for Prevention of Aerodigestive Carcinogenesis Pioglitazone – PPARγ agonist approved for type II DM Rationale: Cell lines – induces growth arrest, differentiation (NSCLC) Animal carcinogenesis models 4-NQO rat tongue model; incidence and multiplicity ↓ 10-fold Yoshida et al., Cancer Sci 94:365, 2003 Epidemiology 33% ↓ lung cancer in diabetics using TZDs (RR=0.67; 95% CI, 0.51-0.87); Nonsignificant decrease in colon and prostate cancer Govindarajan et al. JCO 2007;25:1476-81 41-55%↓ HNSCC in diabetics using TZDs Govindarajan R et al. JCO 2007;25:63s

  46. Pioglitazone in Oral Leukoplakia DCP phase IIa clinical trial - 22 pts., 81% clinical response rate, 79% average ↓size F. Ondrey, U Minn AACR Frontiers Cancer Prev Res, 2007 New trial – phase IIb, 100 person, 6 mths Rx PIs: J Boyle, MSKCC and F Ondrey, U Minn pre post

  47. Effect of PPARγ Agonists on NSCLC: Animal ModelsTreatment causes tumor volume ↓ 66.7%-growth delay 104 days. Prevention causes56-64% ↓ in tumor burden in wildtype and p53 mutant animals Ming You et al. Mol Cancer Ther 2010;9:30742

  48. Current Pioglitazone Clinical Trials (NCI sponsored) Phase IIb oral leukoplakiaPioglitazone 45 mg qd vs placebo x6 months100 participants; 11 sites1o Endpoint: clinical and pathologic responsePIs: Jay Boyle, MSKCC and Frank Ondrey, UMinnPilot trial presurgical NSCLC trialPioglitazone 45 mg qd for 2-6 weeks prior to definitive surgery 20 participants; biomarker endpointsPI: Dennis Wigle, Mayo

  49. The Continuum of Lung CarcinogenesisOpportunities for Intervention

  50. “For it happens…that in the beginning of the malady it is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”-N. Machiavelli, The Prince

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