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

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% http://seer.cancer.gov/statfacts/html/lungb.html)

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;6:244-285.

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

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;4:702-709.

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 http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site.

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

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

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

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

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

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.

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.

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.

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

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

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. 22.8 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.

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

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

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

Thank you.