2. Outline
• Basics
• Epidemiology/risk factors
• Three main diseasetypes
• NSCLC
• Disease stages
• Selected mutations
• Some drug-resistance mechanisms
• Management
• ACCP guidelines
• Individualized treatmentalgorithm
• Genotype-directed therapy inpractice
Lungcancer
(2001-2007):Average 5-year
survival rate for localized
tumor was 52.2%compared
to 15.6 %overall and3.6 %for
a distant tumor (1)
Most common cancer cause
of death; Rises and declines
in disease parallel smoking
trends (1)
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/riskfactors
Most commonly diagnosed cancer in the world (2)
5. (A) SCLC
• Respiratory tract
neoplasm
• Aggressive
(B)NSCLC
• Squamous-, adeno-
, and large-cell
carcinomas
• Small (≤20mm),pre-
defined lung
cancers: no
metastasis outside
tumor-bearing
segment
• Slow and widespread
metastases
(C) Mesothelioma
• Asbestos-related
epithelial
neoplasm
• Aggressive
Threemaindisease types(1)
(A) SCLC (~14%);(B) NSCLC (85%);(C) Mesothelioma (≤1%)
6. • Occult: cancer cellsin sputum
• Stage 0:innermost lining oflung
• Stages IA/IB:Isolated intrapulmonary tumor or cancer has spread to the
lung’s main airways/innerlining
• StagesIIA/IIB:Tumor spread to nearbylymph 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.Itmay 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
NSCLC*stages (3)
*Most common type of lung cancer (85%of
diagnosed cases)
Yur
11. • OPTIMAL (erlotinib vs.
chemotherapy; 83 vs. 82
randomized pts.): one of
the Phase IIItrialsshowing
value of TKIplus
chemotherapy
Initialtrialsshowingutilityofgenotype- directed
treatments(7)
EGFR*as 1stline TKI
(Trialacronyms:
IPASS,WJTOG3405,OPTIMAL)
• LUX-lung 3 (afatinib vs.
cisplatin/pemetrexed; 345/1,269
pts randomized to intervention):
PFS prolongation & acceptable
safety profile
• LUX-lung7 (1stvs. 2nd generation
TKIs;264 pts. to be recruited);
awaiting data
EGFRas 2nd- line TKI
and 1stvs.2ndgeneration TKIs
(selected patients)
• Slightly better outcomes
with chemotherapy in
mutation-negative patients
EGFRvs.chemo in 2nd-line
therapy (Trialacronyms:
INTEREST,V-15-
32,ISTANA,TITAN,HORG, TAIL
OR,unselected patients)
12. Genotype-directedtherapyinpractice
Suggestions by Verma etal(7)
• 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
13. 2000 2005 2010 2015 2020
Ipilimumab (NCT01331525)
Ipilimumab (NCT00527735)
Ramucirumab (NCT00735696)
Nivolumab (NCT01673867)
Tremelimumab (NCT02000947)
MK-3475 (NCT01840579)
Nivolumab (NCT01642004)
MPDL3280A (NCT02008227)
Estimatedcompletion date
ActiveIntervention
The CTLA-4
antibody, ipilimumab
(Yervoy™)(8,9), was the first
treatment provento extend
survival in metastatic
melanoma. Itisnow being
tested for NSCLC and SCLC.
Based on promising early
results, PD-1 (eg, nivolumab
and MK-3475) andPD-L1
(eg, MPDL3280 and MEDI4736)
immunocheckpoint regulators
are also being tested in lung
cancer patients.In
addition, combinationimmune
checkpoint and therapeutic
vaccine approachesare
being evaluated in separate
trials.
Investigationalagents(part1)
Anti-angiogenics/Immunocheckpoint regulators
14. 2000 2020
Onartuzumab (NCT01456325)
Ganetespib (NCT01348126)
Cixutumumab (NCT00955305)
MK2206 (NCT01294306)
PX866(NCT01204099)
Sirolimus(NCT00923273)
Sorafenib (NCT00863746)
Crizotinib (NCT01154140)
Crizotinib (NCT00932893)
BVD523 (NCT01781429)
Trametinib (NCT01192165)
Dabrafenib (NCT01336634)
2005 2010 2015
Estimatedcompletion date
ActiveIntervention
Trial results showed that EGFR
tyrosine kinase inhibitors and
crizotinib were effective
targeted therapies inmetastatic
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.
Investigationalagents(part2)
Chaperones and other targeted therapies(10-11)
15. NSCLCand therapeuticvaccines(12)
Fullprotein vaccine (MAGE-A3 vs. placebo); Ph. II(N=182, stageII*)
Peptide (L-BLP25vaccine vs placebo; Ph III;N=1514, stageIII)
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)
Fullprotein vaccine (chemo. +TG4010 vaccine vs. chemo); PhII
(N=148;stage IIIB/IV)
Trialsdid notmeet primary endpoints,butsignificant benefits seen in sub-groups.
17. LUNGCANCER MANAGEMENT
• Lung cancer 5-yearsurvival 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 TRKIsmay be one
path to improving
outcomes
INDIVIDUALIZEDTREATMENT
Summary
1
