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
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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
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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 nonsmall-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
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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.