Contemporary Treatment of Metastatic NonSmall Cell Lung Cancer

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/p 63 positive = SCC – TTF-1 positive/p 63 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 nonsmall-cell lung cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1986; 4: 702 -709.

Treatment Options • Stage I-II – 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 – 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 progressionfree 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 firstline treatment for patients with advanced EGFR mutation-positive non -small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, openlabel, 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, openlabel, randomised phase 3 trial. Lancet Oncol 2012; 13: 239.

EGFR TKI Toxicities • Rash – 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 ROS 1 RAS MET FGFR 1 PIK 3 ca RET HER 2 AKT 1 BRAF PTEN β-catenin DDR 2 MEK 1

Immunotherapy • Anti-CTLA-4 • Anti-PD 1/PDL 1 • Vaccines

Thank you.