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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

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
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

tobacco use in the us 1900 2003
Tobacco Use in the US, 1900-2003

Per capita cigarette consumption

Male lung cancer death rate

Female lung cancer death rate

radiographic evidence linking tobacco use to lung cancer mcmullen dm cohen ga nejm 354 397 2006
Radiographic Evidence Linking Tobacco Use to Lung Cancer -●McMullen, DM & Cohen GA, NEJM 354:397, 2006
risk factors
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
slide6

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%.

slide7

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

pathology small cell lung cancer small cell lung cancer 20
Pathology: Small Cell Lung Cancer ● Small cell lung cancer - 20%
slide9
The Continuum of Lung Carcinogenesis Opportunities for Intervention Normal to Hyper/Metaplasia to Dysplasia to Early-Late Cancer
treatment strategies for lung cancer
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)
egfr as a target for nsclc standard of care in 2010
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)

slide14

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

eml4 alk fusion gene as a target for nsclc
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

her2 neu as a target for nsclc
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

her2 neu as target for nsclc kelly r j et al jco 2010 28 e507 e510
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
advanced disease targeted therapies vegf inhibition
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)
controversies in nsclc treatment
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
controversies in nsclc treatment1
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
approaches to reducing cancer morbidity and mortality
Approaches to reducing cancer morbidity and mortality
  • Prevention (primary, secondary, tertiary)
  • Early detection
  • Better therapeutics
slide22
The Continuum of Lung Carcinogenesis Opportunities for Intervention Normal to Hyper/Metaplasia to Dysplasia to Early-Late Cancer
primary prevention
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
cancer chemoprevention
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
rationale for lung cancer prevention
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

when is the best time to intervene during carcinogenesis
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.)

minimal requirements for preventive strategies
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)

efficacy how do we identify new agents
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

optimizing the risk benefit balance
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

targeting inflammation for lung cancer prevention rationale
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

slide32

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

slide33

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%)

slide35

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

slide36

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

adenocarcinoma precursor atypical adenomatous hyperplasia
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)

where do we go from here with steroids
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

myo inositol
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 (+)

rationale for myo inositol in lung cancer prevention
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

slide41

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)

slide42

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)

why is this study so important
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!

slide44

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

slide45
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

pioglitazone in oral leukoplakia
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

slide47

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

slide48

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

slide50

“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

issues in lung cancer screening
Issues in Lung Cancer Screening
  • Lead-time bias=earlier diagnosis but no postponement of death (survival appears longer)
  • Length bias=diagnosis of more indolent disease with longer preclinical phase (better prognosis, better outcome)
  • Overdiagnosis=identification of clinically unimportant lesions that would not be diagnosed otherwise
  • Morbidity/mortality/cost of screening and subsequent work-up
helical ct for early lung cancer detection
Helical CT for Early Lung Cancer Detection

ELCAP (Lancet 1999;354:99)

Low dose helical CT in 1000 asymptomatic smokers

Results:

2.7% lung cancers diagnosed by CT vs. 0.7% by CXR

85% cancers were stage I vs. 22% expected

96% were resectable

I-ELCAP (NEJM 2006;355:1763-71)

Low dose helical CT 31,567 asymptomatic screened “at-risk” individuals (inc. second hand smoke exposed)

Results

85% stage I, estimated 10-yr survival 88%

nlst national lung screening trial nlst research team n engl j med 2011 365 395 409
NLST (National Lung Screening Trial) NLST Research Team. N Engl J Med 2011;365:395-409

NLST design

53,454 smokers (current and former)

30 pack-yr smoking hx; quit <15 yrs ago

Age 55-74

Helical CT vs. chest X-ray (prevalence, then x2)

NLST results

CT - 24.2% ‘positive’ tests, 354 lung cancer deaths

CXR – 6.9% ‘positive’ tests, 442 lung cancer deaths

20.0% reduction in lung cancer mortality

6.7% reduction in all cause mortality