Contemporary Treatment of Metastatic Non-Small Cell Lung Cancer

Jeffrey A. Bubis, DO, FACOI, FACPCancer Specialists of North FloridaBaptist 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– Surgery +/- chemotherapy– Radiotherapy (non surgical candidates)

• Stage III– Surgery + chemotherapy– Chemotherapy+radiation– Chemotherapy

• Stage IV– Systemic therapy +/- radiationNCCN 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 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– 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 InvestigationTranslocation 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.