In 2006, Dana Reeve – actress, activist, and non-smoker – died of lung cancer. In 2009, Valerie Harper – actress and “Dancing with the Stars” contestant – was diagnosed with lung cancer that has since metastasized to the brain. They are the famous faces of a disease that is the leading cause of cancer deaths. Five-year survival rates for lung cancer, the leading cause of cancer deaths, are very low. Please take a look at some of the ASCO 2014 lung cancer updates on my blog: http://norwalk.patch.com/groups/zeena-nackerdiens-blog/p/american-society-of-clinical-oncology-annual-meeting-2014-key-lung-cancer-abstracts.

1. Lung cancer
Zeena Nackerdien

2. • Basics
• Epidemiology/risk factors
• Three main disease types
• NSCLC
• Disease stages
• Selected mutations
• Some drug-resistance mechanisms
• Management
• ACCP guidelines
• Individualized treatment algorithm
• Genotype-directed therapy in practice
Outline
Lung cancer
(2001-2007): Average 5-year
survival rate for localized
tumor was 52.2% compared
to 15.6 % overall and 3.6 % for
a distant tumor (1)
Most common cancer cause
of death; Rises and declines
in disease parallel smoking
trends (1)
ACCP, American College of Chest Physicians; NSCLC, non-small cell lung cancer
1. American Lung Association Trends in Lung Cancer Morbidity and Mortality. 2012 Available from:
http://www.lung.org/finding-cures/our-research/trend-reports/lc-trend-report.pdf.

3. • Investigational agents (parts 1 and 2)
• Anti-angiogenic agents/immunocheckpoint regulators
• Therapeutic vaccines (NSCLC)
• Summary
Outline
Lung cancer
FISH=fluorescence in situ hybridization; NSCLC=non-small cell lung cancer
Examples of molecular assays (FISH and sequencing)

4. Smoking causes
about 70% of
global deaths
Genetics in early-
onset lung cancer
Radon gas
(20,000 US
deaths/y)
Other
environmental
agents and prior
lung disease
Risk factors
Basics: epidemiology/risk factors
Most commonly diagnosed cancer in the world (2)
2. Wangari-Talbot J, Hopper-Borge E. Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma. Journal of cancer research updates.
2013;2(4):265-82.

5. (A) SCLC
• Respiratory tract
neoplasm
• Aggressive
(B) NSCLC
• Squamous-, adeno-
, and large-cell
carcinomas
• Small (≤20 mm),pre-
defined lung
cancers: no
metastasis outside
tumor-bearing
segment
• Slow and widespread
metastases
(C) Mesothelioma
• Asbestos-related
epithelial
neoplasm
• Aggressive
Three main disease types(1)
(A) SCLC (~14%); (B) NSCLC (85%); (C) Mesothelioma (≤ 1%)
SCLC, small-cell lung cancer
1. American Lung Association,. Trends in Lung Cancer Morbidity and Mortality. 2012 [cited March 2014]. Available from:
http://www.lung.org/findicures/our-research/trend-reports/lc-trend-report.pdf

6. • Occult: cancer cells in sputum
• Stage 0: innermost lining of lung
• Stages IA/IB: Isolated intrapulmonary tumor or cancer has spread to the
lung’s main airways/inner lining
• Stages IIA/IIB: Tumor spread to nearby lymph nodes, chest
wall, diaphragm, membrane around the heart, lining between the lungs
or the main airway
• Stages IIIA/IIIB: Further spread to sites listed in stages IIA/IIB. It may have
spread to the aorta, heart, trachea, sternum, and esophagus. Lung may
be inflamed or may have collapsed
• Stage IV: Malignant growths in more than one lobe of one lung, in both
lungs or cancer has spread to other organs
3. National Cancer Institute, American Cancer Society: lung cancer.org, Principal Health News Centers for Disease Control & Prevention.
Lung cancer infographic. 2014.
NSCLC* stages (3)
*Most common type of lung cancer (85% of
diagnosed cases)
Yur Text Here

7. Selected mutations in NSCLC
(Adenocarcinoma; Patients were smokers or non-
smokers)
Molecular pathology(4)
• KRAS (ALK/BRAF/PI3K)
• EGFR (ALK inhibitors)
• EML4-ALK
• BRAF (EGFR TKI)
• MET (Kinase domain mut.)
• ERBB2/HER2 (EGFR TKI)
• MAP2K1(MEK inhibitor-sens.)
• NRAS (MEK inhibitor-sens.)
BRAF, proto-oncogene B-Raf and v-Raf murine sarcoma viral
oncogene homolog B1; EGFR, epidermal growth factor receptor; EML4-ALK,
echinoderm microtubule-associated protein-like 4-anaplastic lymphoma
kinase; ERBB2/HER2, Receptor tyrosine-protein kinase erbB-2; MAP2K1,
dual specificity mitogen-activated protein kinase kinase 1; MET, proto-oncogene (hepatocyte growth factor receptor); mut., mutation;
NRAS, Neuroblastoma RAS viral oncogene homolog; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; PIKC3A, Phosphatidylinositol-4,5-
bisphosphate 3-kinase, catalytic subunit α; sens., sensitive; TRKI, tyrosine kinase inhibitor
4. Cheng L, Alexander RE, Maclennan GT, Cummings OW, Montironi R, Lopez-Beltran A, et al. Molecular pathology of lung cancer: key to
personalized medicine. Modern pathology 2012;25(3):347-69.

8. .
Some drug resistance mechanisms(2)
AKT, protein Kinase B; HSP90, heat shock protein 90; IGFR, insulin-like growth factor 1 receptor
2. Wangari-Talbot J, Hopper-Borge E. Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma. Journal of cancer arch updates.
2013;2(4):265-82.
Secondary mutations
Acquired resistance
EML4-ALK
Proliferation
EGFR (PI3K/AKT↑;IGFR
crosstalk)
KRAS
Gene
amplification/copy
number gain (C)/fusion
MET
ALK-C/ALK-fusion-
negative tumors
Cellular/Chaperone
HSP90
Epithelial-to-
mesenchymal transition
Multi-drug resistance
proteins

9. .
Management: ACCP guidelines(5)
CT Screening
• Only to smokers age
55-74, with > 30
pack-years of
smoking
• Annual low-dose CT
scanning in NLST-
compliant setting
• Not to pts. with
severe
comorbidities
Stages I & II
• VATS with
systematic lymph
node sampling
preferred
• Better outcomes
with specialty-
trained surgeons
& at high-volume
centers
Stage III
• Chemo +
radiation therapy
for most N2,3 pts
• Trimodal
approach for
toxicity mgmt.
• Tailor treatment
depending on
mediastinal
involvement
Stage IV
• EGFR+-pts: targeted
therapy is 1st line of
treatment
• Appropriate
maintenance
chemotherapy
• VEGF inhibitors safe
& useful
• Doublet
chemotherapy in
selected cases
ACCP, American College of Chest Physicians; chemo, chemotherapy; mgmt., management; NLST, National Lung Cancer Screening Trial;
pts., patients; VATS, video-assisted thoracic surgery; VEGF, Vascular endothelial growth factor
5. Detterbeck FC, Lewis SZ, Diekemper R, Addrizzo-Harris D, Alberts WM. Executive Summary: Diagnosis and management of lung cancer, 3rd
ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):7s-37s.
Advances in treatment for different stages

10. Diagnostic
biopsy
Biomarker
testing
Mutations/Copy
numbers/sequencing
Restaging
Molecular
imaging
Adjust treatment
according to disease
status
Ideally, sufficient
tissue, blood, and other
samples can be collected for
diagnostic purposes.
Validated biomarkers will be
monitored in < 2 weeks and
guide disease management.
Restaging and subsequent
treatment would depend on
disease status, individual
quality of life, and the possible
need for re-biopsy and re-
evaluation of biomarkers.
Individualized treatment algorithm(6)
6. Carrizosa DR, Mileham KF, Haggstrom DE, Brouse GM, Induru R, Kim ES. New Targets and New Mechanisms in Lung Cancer.
Journal of Oncology [Internet]. 2013. Available from: http://www.cancernetwork.com/lung-cancer/new-targets-and-new-
mechanisms-in-lung-cancer.

11. • OPTIMAL (erlotinib vs.
chemotherapy; 83 vs. 82
randomized pts.): one of
the Phase III trials showing
value of TKI plus
chemotherapy
Initial trials showing utility of genotype-
directed treatments (7)
EORTC 08114-GEM intergroup translational research-observational study will focus on the genetics of EGFR+ - NSCLC;
EGFR, epidermal growth factor receptor; PFS, progression-free survival; pts., patients; TKI, tyrosine kinase inhibitors
7.Verma S, Tsao M, Sivjee K. Webinar Archive: Integration of Targeted Therapies in the Management of NSCLC:
oncologyeducation.com; 2014. Available from: http://www.oncologyeducation.com/information/lung/lung-cancer-
videos/webinar-archive-nsclc/
EGFR* as 1st line TKI
(Trial acronyms:
IPASS, WJTOG3405, OPTIMAL)
• LUX-lung 3 (afatinib vs.
cisplatin/pemetrexed; 345/1,269
pts randomized to intervention):
PFS prolongation & acceptable
safety profile
• LUX-lung7 (1st vs. 2nd generation
TKIs; 264 pts. to be recruited);
awaiting data
EGFR as 2nd- line TKI
and 1st vs. 2nd generation TKIs
(selected patients)
• Slightly better outcomes
with chemotherapy in
mutation-negative patients
EGFR vs. chemo in 2nd-line
therapy (Trial acronyms:
INTEREST, V-15-
32, ISTANA, TITAN, HORG, TAIL
OR, unselected patients)

12. • EGFR & ALK testing actionable in
NSCLC
• Images of EGFR signaling pathway &
ALK + crizotinib
• Testing mainly performed on non-
squamous tumors
• Multi-disciplinary approach needed for
molecular testing
• Multiplex-testing by next-generation
sequencing can resolve complexity
associated with molecular testing
Genotype-directed therapy in practice
Suggestions by Verma et al(7)
7. Verma S, Tsao M, Sivjee K. Webinar Archive: Integration of Targeted Therapies in the Management of NSCLC:
oncologyeducation.com; 2014. Available from: http://www.oncologyeducation.com/information/lung/lung-cancer-
videos/webinar-archive-nsclc/.

13. 2000 2005 2010 2015 2020
Ramucirumab (NCT00735696)
Ipilimumab (NCT00527735)
Ipilimumab (NCT01331525)
Tremelimumab (NCT02000947)
Nivolumab (NCT01673867)
Nivolumab (NCT01642004)
MK-3475 (NCT01840579)
MPDL3280A (NCT02008227)
Estimated completion date
ActiveIntervention
The CTLA-4
antibody, ipilimumab
(Yervoy™)(8,9), was the first
treatment proven to extend
survival in metastatic
melanoma. It is now being
tested for NSCLC and SCLC.
Based on promising early
results, PD-1 (eg, nivolumab
and MK-3475) and PD-L1
(eg, MPDL3280 and MEDI4736)
immunocheckpoint regulators
are also being tested in lung
cancer patients. In
addition, combination immune
checkpoint and therapeutic
vaccine approaches are
being evaluated in separate
trials.
Investigational agents (part 1)
Anti-angiogenics/Immunocheckpoint regulators
CTLA-4, Cytotoxic T-Lymphocyte Antigen 4 ; PD-1 or PD-L1, programmed death or programmed death-ligand 1
8. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and
carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter
phase II study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(17):2046-54.
9. Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and
carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter
phase 2 trial. Annals of Oncology 2013;24(1):75-83.

14. 2000 2005 2010 2015 2020
Dabrafenib (NCT01336634)
Trametinib (NCT01192165)
BVD523 (NCT01781429)
Crizotinib (NCT00932893)
Crizotinib (NCT01154140)
Sorafenib (NCT00863746)
Sirolimus (NCT00923273)
PX866 (NCT01204099)
MK2206 (NCT01294306)
Cixutumumab (NCT00955305)
Ganetespib (NCT01348126)
Onartuzumab (NCT01456325)
Estimated completion date
ActiveIntervention
Trial results showed that EGFR
tyrosine kinase inhibitors and
crizotinib were effective
targeted therapies in metastatic
NSCLC. The following agents
have been approved for the
treatment of advanced NSCLC:
Gefitinib, erlotinib and afatinib
for positive EGFR
mutation, crizotinib for positive
echinoderm microtubule-
associated protein-like 4 (EML4-
ALK) translocation and
bevacizumab. Ceritinib
(LDK378), a new ALK inhibitor
that has shown greater pre-
clinical antitumor potency than
crizotinib, was highly active in
patients with advanced, ALK-
rearranged NSCLC, in a Phase I
trial.
Investigational agents (part 2)
Chaperones and other targeted therapies(10-11)
10. Reungwetwattana T, Dy GK. Targeted therapies in development for non-small cell lung cancer. Journal of carcinogenesis.
2013;12:22.
11. Shaw AT, Kim D-W, Mehra R, Tan DSW, Felip E, Chow LQM, et al. Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer. New
England Journal of Medicine. 2014;370(13):1189-97.

15. NSCLC and therapeutic vaccines(12)
Full protein vaccine (MAGE-A3 vs. placebo); Ph. II (N=182, stage II*)
Peptide (L-BLP25 vaccine vs placebo; Ph III; N=1514, stage III)
Ganglioside vaccine (Racotumomab + BSC vs BSC; Ph III,; N=1082;
stage IIIB/IV*)
Whole tumor cell vaccine (Belagen-pumatucel+BSC vs BSC; Ph III;
N=532)
Full protein vaccine (chemo. + TG4010 vaccine vs. chemo); Ph II
(N=148; stage IIIB/IV)
Trials did not meet primary endpoints, but significant benefits seen in sub-groups.
12. Cuppens K, Vansteenkiste J. Vaccination therapy for non-small-cell lung cancer. Current opinion in oncology. 2014;26(2):165-70.

16. Immune regulators &
suppressive mechanisms(13)
Potential biomarkers/drug targets
IDO, indoleamine 2,3 dioxygenase; GITR, Glucocorticoid-induced tumor necrosis factor receptor; KIR, killer immunoglobulin
receptor ; OX40 (CD134), Tumor necrosis factor receptor superfamily, member 4, P-serine, phosphatidylserine; TAA, tumor-
associated antigen
13. Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer control 2014;21(1):80-9.
P-serine
externalization
KIR 2DL1
promotion
B7-3
overexpression
N-glycolil-GM3
expression
MHC-1
loss
TAA
deletion/
nitrosylation
TIM-3LAG-3
IDO-
upregulation
GITR
PD1-
overexpression
OX40

17. LUNG CANCER MANAGEMENT
• Lung cancer 5-year survival
rates continue to be low
(16.3%)(14)
• Smoking remains the
number one cause of the
disease
• ACCP guidelines
recommend targeted
therapies as part of lung
cancer treatment
• Gene-directed therapies
and Inducing/potentiating
immune responses via
immunotherapies are
viable options for
improving outcomes
• Tailored mono-/combination-
/adjunctive therapies
• Targeted therapies
include promising
immunotherapies & other
drugs
• PDL-1, PD-L1, CTLA-4
immunocheckpoint
regulators combined
with TRKIs may be one
path to improving
outcomes
INDIVIDUALIZED TREATMENT
Summary
1. American Lung Association, Research and Program Services Division, Trends in Lung Cancer Morbidity and Mortality. 2012
Available from: http://www.lung.org/finding-cures/our-research/trend-reports/lc-trend-report.pdf.