1. Contemporary Treatment of Metastatic Non-Small Cell Lung Cancer
Jeffrey A. Bubis, DO, FACOI, FACP
Cancer Specialists of North Florida
Baptist South and Fleming Island

2. Lung Cancer Stats Leading cause of cancer death in U.S.
Predicted 2014 demographics
224,210 new cases
116,000 men and 108,210 women
159,260 deaths
86,930 men and 72,330 women
5 year OS is 16.6%

3. Classification WHO SCLC NSCLC NSCLC is 85% of all lung cancer cases
Squamous cell Carcinoma
Non-Squamous Cell Carcinoma
Adenocarcinoma (Most common)
Large cell
Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:

4. Pathologic Evaluation
Biopsies should be with a core needle or with multiple FNA specimens
All specimens should be tested for:
EGFR
ALK
If limited tissue is available, this is more important than IHC
TTF-1 negative/p63 positive = SCC
TTF-1 positive/p63 negative = NSNSCLC

5. Prognostic Factors Early stage disease
Good performance status (ECOG 0, 1, 2)
Weight loss <5%
Female gender
Finkelstein DM, Ettinger DS, Ruckdeschel JC. Long-term survivors in metastatic non-small-cell lung cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1986;4:

6. Treatment Options Stage I-II Stage III Stage IV
Surgery +/- chemotherapy
Radiotherapy (non surgical candidates)
Stage III
Surgery + chemotherapy
Chemotherapy+radiation
Chemotherapy
Stage IV
Systemic therapy +/- radiation
NCCN guidelines

7. Treatment Options For Metastatic Disease
Cytotoxic chemotherapy
Pros
Reduces symptoms
Improves quality of life
Improves overall survival
Cons
Nonspecific

8. Treatment Options For Metastatic Disease
Targeted Therapy
Pros
Reduces symptoms
Improves quality of life
Improves progression free survival
May have reduced toxicity relative to cytotoxic therapy
Cons
Nonspecific

9. Historic Perspective on Front Line Therapy of NSNSCLC
Until the mid-2000’s
Platinum and non-platinum doublet therapies
Carboplatin + taxane
Carboplatin + gemcitabine
2006
Bevacizumab FDA approved
2009
Pemetrexed FDA approved

10. EGFR Activating Mutations
Seen in 15% of NSCLC in the U.S.
More frequent in non-smokers
Up to 62% of Asian (especially females)
Favorable prognosis
Predicts sensitivity to EGFR tyrosine kinase inhibitors
Erlotinib and afatinib

11. EGFR Positive EGFR TKIs Second line Front line
Improve PFS compared to standard platinum-based therapy
Continue until progression or intolerance
Second line

12. EGFR TKI Data
Meta-analysis of 13 phase III trials with 2620 patients demonstrated
PFS improved
No change in OS
Lee CK, Brown C, Gralla RJ, et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. J Natl Cancer Inst 2013; 105:595.

13. EGFR TKI Data OPTIMAL 154 patients
Erlotinib vs Carboplatin/Gemcitabine
PFS 13.1 vs 4.6 months
ORR 83 vs 36%
Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12:735.

14. EGFR TKI Data EURTAC 174 patients Erlotinib vs. platinum doublet
PFS 9.7 vs 5.2 months
OS 19.3 vs 19.5 months
Crossover design
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13:239.

15. EGFR TKI Toxicities Rash Diarrhea Interstitial pneumonitis
Usually mild
Usually responsive to topical therapies or doxycycline
Diarrhea
Rarely severe
Usually responsive to loperamide
Interstitial pneumonitis
Hepatic toxicity

16. ALK Translocation Present in 4% of NSCLC in the U.S.
More frequent in nonsmokers
More frequent in younger patients
Predicts for sensitivity to ALK tyrosine kinase inhibitors
Crizotinib

17. ALK Trial Data
347 patients with ALK+ NSCLC that was previously treated with a platinum doublet randomly assigned to crizotinib or single agent chemotherapy. Crossover was allowed.
PFS was better with crizotinib (7.7 vs 3.0 months)
RR was better with crizotinib (65 vs 20%)
OS unchanged (20.3 vs months)
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368:2385.

18. ALK TKI Toxicities Visual disturbances (dark to light transitions)
N/V/D/constipation
Transaminitis
Bradycardia
QTc prolongation
Serum testosterone depression
Pneumonitis

19. Other Targets Under Investigation
Translocation
Mutation
Expression
Amplification
Alteration
ROS1
RAS
MET
FGFR1
PIK3ca
RET
HER2
AKT1
BRAF
PTEN
β-catenin
DDR2
MEK1

20. Immunotherapy
Anti-CTLA-4
Anti-PD1/PDL1
Vaccines

21. Thank you.