Lung Cancer - Bimbingan.pptxmnbmbnmnmn mn mn

Oleh:
Rudy Arindra Wijaya
Pembimbing:
Dr. dr. M. Darwin Prenggono, Sp.PD, K-HOM, FINASIM
Bimbingan Stase HOM
Stase Hematologi Onkologi Medik
Program Pendidikan Dokter Spesialis I (PPDS-I) Ilmu Penyakit Dalam
Fakultas Kedokteran Universitas Lambung Mangkurat
RSUD Ulin Banjarmasin
KANKER PARU

Epidemiologi
• Data Globocan 2018 menunjukkan
insidens kanker paru di dunia adalah
sejumlah 2.094 juta (11.6% dari
semua kanker) dan mortalitas kanker
paru di dunia adalah sejumlah 1.8
juta (18.4% dari semua kematian
akibat kanker)
• Laki-laki > perempuan

KANKER PARU
• Menurut WHO 2015, kanker paru diklasifikasikan menjadi dua
kelompok secara biologi, histologi, terapi dan prognosisnya, yaitu
Small Cell Lung Cancer (SCLC) dan Non-Small Cell Lung Carcinoma
(NSCLC).
• NSCLC terdapat sekitar 85% dan 15% lainnya merupakan SCLC dari
semua kasus kanker paru.
• Subtipe yang paling umum dari NSCLC adalah adenokarsinoma,
karsinoma sel skuamosa, dan Large Cell Carcinoma.
• Subtipe kanker paru ini tidak hanya berbeda secara molekuler
tetapi juga memiliki morfologis dan target terapi yang berbeda

Mateus Camargo Barros-Filho et al. Tumour Suppressor Genes with Oncogenic Roles in Lung Cancer. IntechOpen. 2019

Pathogenesis
of Lung Cancer
Sun S, et al. Nat Rev Cancer 2007;7:778-790

Screeni
ng
method
Recommendation LoE, GoR
Screening with
LDCT (low-dose
computed
topography)
Reduces lung cancer-related mortality in high-risk subjects (heavy
smokers [≥ 30 pack-years or ≤ 15 years since cessation] aged
55–74 years)
• Questions remain about the definition of the at-risk
population, screening intervals, age at end of screening,
method of CT
, cost-effectiveness and rate of false-positive
diagnoses
• Anew, non-invasive LDCT protocol shows promise in
reducing the false positive detection rate
I, A
May be offered to well-informed heavy smokers aged 55–74 years
within a dedicated programme in experienced CT centres
I, A
Other screening
methods, such as
chest X-ray,
sputum analysis
or biomarkers
Not recommended for clinical use I, C
© 2017 ESM O . All rights reserved. esm o.org/G uidelines/Lung-and-Chest-Tum ours/Early-Stage-and-Locally-Advanced-non-metastatic-Non-Sm all-Cell-Lung-Cancer
Screenin
g

a Multidisciplinary evaluation including thoracic surgeons, thoracic radiologists, and pulmonologists to determine the likelihood of a cancer diagnosis and the optimal
diagnostic or follow-up strategy.
b Risk calculators can be used to quantify individual patient and radiologic factors but do not replace evaluation by a multidisciplinary diagnostic team with substantial
experience in the diagnosis of lung cancer.
c See Principles of Diagnostic Evaluation (DIAG-A 1 of 3).
CLINICAL PRESENTATION RISK ASSESSMENTb
Incidental
finding of nodule
suspicious for
lung cancer
• Multidisciplinary
evaluationa
• Smoking cessation
counseling
Patient factors
• Age
• Smoking history
• Previous cancer history
• Family history
• Occupational exposures
• Other lung disease (chronic obstructive pulmonary
disease [COPD], pulmonary fibrosis)
• Exposure to infectious agents (eg, endemic areas
of fungal infections, tuberculosis) or risk factors or
history suggestive of infection (eg, immune
suppression, aspiration, infectious respiratory
symptoms)
Radiologic factorsc,d
• Size, shape, and density of the pulmonary nodule
• Associated parenchymal abnormalities (eg,
scarring or suspicion of inflammatory changes)
• Fluorodeoxyglucose (FDG) avidity on PET imaging
Solid nodules
See Follow-up
(DIAG-2)
Subsolid nodules
See Follow-up
(DIAG-3)
Lung nodules in
asymptomatic, high-risk
patients detected during lung
cancer screening with LDCT
NCCN Guidelines for
Lung Cancer Screening
NCCN Guidelines Version 6.2020
Non-Small Cell Lung Cancer
NCCN Guidelines Index
Table of Contents
Discussion
Printed by Loudry Elfa on 9/2/2020 7:07:17 AM. For personal use only. Not approved for distribution. Copyright © 2020 National Comprehensive Cancer Network, Inc., All Rights Reserved.
d The most important radiologic factor is change or stability compared with a previous imaging study.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
DIAG-1
Version 6.2020, 06/15/20 © 2020 National Comprehensive Cancer Network®
(NCCN®
), All rights reserved. NCCN Guidelines®
and this illustration may not be reproduced in any form without the express written permission of NCCN.

FINDINGS
d The most important radiologic factor is change or stability compared with a previous
imaging study.
e Low risk = minimal or absent history of smoking or other known risk factors.
f High risk = history of smoking or other known risk factors. Known risk factors include
history of lung cancer in a first-degree relative; exposure to asbestos, radon, or
uranium.
g Non-solid (ground-glass) nodules may require longer follow-up to exclude indolent
adenocarcinoma.
h Adapted from Fleischner Society Guidelines: MacMahon H, Naidich DP, Goo
JM, et al. Guidelines for management of incidental pulmonary nodules detected
on CT images: From the Fleischner Society 2017. Radiology 2017;284:228-243.
i PET/CT performed skull base to knees or whole body. A positive PET result is defined
as a standardized uptake value (SUV) in the lung nodule greater than the baseline
mediastinal blood pool. A positive PET scan finding can be caused by infection or
inflammation, including absence of lung cancer with localized infection, presence
of lung cancer with associated (eg, postobstructive) infection, and presence of lung
cancer with related inflammation (eg, nodal, parenchymal, pleural). A false-negative
PET scan can be caused by a small nodule, low cellular density (nonsolid nodule
or ground-glass opacity [GGO]), or low tumor avidity for FDG (eg, adenocarcinoma
in situ [previously known as bronchoalveolar carcinoma], carcinoid tumor).
j Patients require tissue confirmation of lung cancer before any nonsurgical therapy.
Multidisciplinary evaluation that at least includes interventional radiology, thoracic
surgery, and interventional pulmonology is recommended to determine the safest and
most efficient approach, or to provide consensus that a biopsy is too risky or difficult
and that the patient can proceed with therapy without tissue confirmation. (IJsseldijk
Incidental
finding: solid
nodule(s) on
chest CT
High riskf
Low riske
>8 mm
FOLLOW-UPc,d,g,h
<6 mm No routine follow-
up
6–8 mm CT at 6–12 mo
<6 mm
6–8 mm
>8 mm
Stable
Consider CT
at 18–24 mo
Consider CT at 3 mo,
PET/CT,i,j or biopsy
CT at 12 mo
(optional)
Stable
CT at 6–12 mo Stable
Repeat CT at
18–24 mo
No routine follow-up
Consider CT at 3 mo,
PET/CT,i,j or biopsy
Table of Contents
Discussion
©
Radiological Society of North America. Fleischner Society Guidelines do not direct
whether or not contrast is necessary or if an LDCT is appropriate. LDCT is preferred
unless there is a reason for contrast enhancement for better diagnostic resolution.
MA, Shoni M, Siegert C, et al. Survival after stereotactic body radiation therapy for
clinically diagnosed or biopsy-proven early-stage NSCLC: A systematic review and
meta-analysis. J Thorac Oncol 2019;14:583-595.)
DIAG-2
(NCCN®

d The most important radiologic factor is change or stability compared with a previous
imaging study.
g Non-solid (ground-glass) nodules may require longer follow-up to exclude indolent
adenocarcinoma.
h Adapted from Fleischner Society Guidelines: MacMahon H, Naidich DP, Goo
JM, et al. Guidelines for management of incidental pulmonary nodules detected
on CT images: From the Fleischner Society 2017. Radiology 2017;284:228-243.
©Radiological Society of North America. Fleischner Society Guidelines do not direct
whether or not contrast is necessary or if an LDCT is appropriate. LDCT is preferred
i PET/CT performed skull base to knees or whole body. A positive PET result is defined
as a SUV in the lung nodule greater than the baseline mediastinal blood pool. A
positive PET scan finding can be caused by infection or inflammation, including
absence of lung cancer with localized infection, presence of lung cancer with
associated (eg, postobstructive) infection, and presence of lung cancer with related
inflammation (eg, nodal, parenchymal, pleural). A false-negative PET scan can be
caused by a small nodule, low cellular density (nonsolid nodule or GGO), or low tumor
avidity for FDG (eg, adenocarcinoma in situ [previously known as bronchoalveolar
carcinoma], carcinoid tumor).
j Patients require tissue confirmation of lung cancer before any nonsurgical therapy.
Multidisciplinary evaluation that at least includes interventional radiology, thoracic
surgery, and interventional pulmonology is recommended to determine the safest and
most efficient approach, or to provide consensus that a biopsy is too risky or difficult
and that the patient can proceed with therapy without tissue confirmation. (IJsseldijk
MA, Shoni M, Siegert C, et al. Survival after stereotactic body radiation therapy for
clinically diagnosed or biopsy-proven early-stage NSCLC: A systematic review and
Incidental
finding:
subsolid
nodule(s)
on chest CT
Solitary pure
ground-
glass
nodules
≥6 mm
FOLLOW-UPc,d,g,h
<6 mm
Solitary
part-solid
nodules
Multiple
subsolid
nodules
<6 mm
≥6 mm
• CT at 3–6 mo to confirm no growth or change in solid
component, then annual CT for 5 y
• If solid component ≥6 mm, consider PET/CTi,j or biopsy
• CT at 3–6 mo
If stable, consider CT at 2 and 4 y
CT at 6–12 mo to confirm no growth or
change in solid component, then CT
every 2 y until 5 y
<6 mm
≥6 mm
• CT at 3–6 mo
• Subsequent management
based on most
suspicious nodule(s)
FINDINGS
Table of Contents
Discussion
unless there is a reason for contrast enhancement for better diagnostic resolution. meta-analysis. J Thorac Oncol 2019;14:583-595.)
DIAG-3
(NCCN®

Parameter Mandatory Optional
General
Medical history*
Physical examination*
Assessing comorbidity
Performance status
Imaging
X-ray thorax
CT thorax*
PET-CT thorax*
MRI brain†
Bone scintigraphy
Contrast-enhanced CT brain
Laboratory
Blood cell counts
Renal function
Liver enzymes
Bone
parameters
Cardio-
pulmonary
function
FVC, FEV1, DLCO
ECG
If indicated: CPET
Ejection fraction, CAG
Tissue procurement
Bronchoscopy‡,§
EBUS/EUS mediastinal nodes*
CT-guided biopsy
Mediastinoscopy
Work-up for diagnosis and staging
*T
ests needed for clinical staging
†Screening for brain metastases by MRI might
be useful in patients considered for curative
therapy
‡Dependingon site and size of tumour
with biopsy/aspiration/brush/washing
§
Bronchoscopy is usually sufficient to
diagnose NSCLC,though may notallow a
detailed sub-
classification
Diagnosis and
pathology/molec
ular biology

PRINCIPLES OF DIAGNOSTIC EVALUATION
• Patients with a strong clinical suspicion of stage I or II lung cancer (based on risk factors and radiologic appearance) do not require a biopsy
before surgery.
A biopsy adds time, costs, and procedural risk and may not be needed for treatment decisions.
A preoperative biopsy may be appropriate if a non-lung cancer diagnosis is strongly suspected that can be diagnosed by core biopsy or
fine-needle aspiration (FNA).
A preoperative biopsy may be appropriate if an intraoperative diagnosis appears difficult or very risky.
If a preoperative tissue diagnosis has not been obtained, then an intraoperative diagnosis (ie, wedge resection, needle biopsy) is necessary
before lobectomy, bilobectomy, or pneumonectomy.
• Bronchoscopy should preferably be performed during the planned surgical resection, rather than as a separate procedure.
Bronchoscopy is required before surgical resection (see NSCL-2).
A separate bronchoscopy may not be needed for treatment decisions before the time of surgery and adds time, costs, and procedural risk.
A preoperative bronchoscopy may be appropriate if a central tumor requires pre-resection evaluation for biopsy, surgical planning (eg
,
potential sleeve resection), or preoperative airway preparation (eg, coring out an obstructive lesion).
• Invasive mediastinal staging is recommended before surgical resection for most patients with clinical stage I or II lung cancer (see
NSCL-2).
Patients should preferably undergo invasive mediastinal staging (mediastinoscopy) as the initial step before the planned resection
(during the same anesthetic procedure), rather than as a separate procedure. For patients undergoing endobronchial ultrasound (EBUS)/
endoscopic ultrasound (EUS) staging, this may require a separate procedure to allow evaluation if onsite rapid cytology interpretation is
not available.
A separate staging procedure adds time, costs, coordination of care, inconvenience, and an additional anesthetic risk.
Preoperative invasive mediastinal staging may be appropriate for a strong clinical suspicion of N2 or N3 nodal disease or when
intraoperative cytology or frozen section analysis is not available.
• In patients with suspected non-small cell lung cancer (NSCLC), many techniques are available for tissue diagnosis.
Diagnostic tools that should be routinely available include:
Sputum cytology
Bronchoscopy with biopsy and transbronchial needle aspiration (TBNA)
Image-guided transthoracic needle core biopsy (preferred) or FNA
Thoracentesis
Mediastinoscopy
Video-assisted thoracic surgery (VATS) and open surgical biopsy
Diagnostic tools that provide important additional strategies for biopsy include:
EBUS–guided biopsy
EUS–guided biopsy

Table of Contents
Discussion
DIAG-A
1 OF 3
(NCCN®

PRINCIPLES OF DIAGNOSTIC EVALUATION
The least invasive biopsy with the highest yield is preferred as the first diagnostic study.
Patients with central masses and suspected endobronchial involvement should undergo bronchoscopy.
Patients with peripheral (outer one-third) nodules may benefit from navigational bronchoscopy, radial EBUS, or transthoracic needle
aspiration (TTNA).
Patients with suspected nodal disease should be biopsied by EBUS, EUS, navigational bronchoscopy, or mediastinoscopy.
– EBUS provides access to nodal stations 2R/2L, 4R/4L, 7, 10R/10L, and other hilar nodal stations if necessary.
– An EBUS-TBNA negative for malignancy in a clinically (PET and/or CT) positive mediastinum should undergo subsequent
mediastinoscopy prior to surgical resection.
– EUS–guided biopsy provides additional access to stations 5, 7, 8, and 9 lymph nodes if these are clinically suspicious.
– TTNA and anterior mediastinotomy (ie, Chamberlain procedure) provide additional access to anterior mediastinal (stations 5 and 6)
lymph nodes if these are clinically suspicious. If TTNA is not possible due to proximity to aorta, VATS biopsy is also an option.
EUS also provides reliable access to the left adrenal gland.
Lung cancer patients with an associated pleural effusion should undergo thoracentesis and cytology. A negative cytology result on
initial thoracentesis does not exclude pleural involvement. An additional thoracentesis and/or thoracoscopic evaluation of the pleura
should be considered before starting curative intent therapy.
Patients suspected of having a solitary site of metastatic disease should have tissue confirmation of that site if feasible.
Patients suspected of having metastatic disease should have confirmation from one of the metastatic sites if feasible.
Patients who may have multiple sites of metastatic disease—based on a strong clinical suspicion—should have biopsy of the
primary
lung lesion or mediastinal lymph nodes if it is technically difficult or very risky to biopsy a metastatic site.
Table of Contents
Discussion
DIAG-A
3 OF 3
(NCCN®

PRINCIPLES OF PATHOLOGIC REVIEW
• Pathologic Evaluation
The purpose of the pathologic evaluation of NSCLC will vary depending on whether the sample
1) is a biopsy or cytology specimen intended for initial diagnosis in a case of suspected NSCLC;
2) is a resection specimen; or
3) is obtained for molecular evaluation in the setting of an established NSCLC diagnosis.
In small biopsies or cytology specimens intended for initial diagnosis, the primary purpose is a) to make an accurate diagnosis using the
2015 WHO classification; and b) to preserve the tissue for molecular studies, especially if the patient has advanced-stage disease.
In small biopsies of poorly differentiated carcinomas, the terms "non-small cell carcinoma (NSCC)1" or "non-small cell carcinoma
not otherwise specified (NSCC-NOS)" should be used as little as possible and only when a more specific diagnosis is not possible
by morphology and/or special staining.
The following terms are acceptable: "NSCC favor adenocarcinoma" and "NSCC favor squamous cell carcinoma." "NSCC-NOS" should be
reserved only for cases in which immunohistochemical testing is uninformative or ambiguous (see section on immunohistochemistry).
Preservation of material for molecular testing is critical. Efforts should be undertaken to minimize block reorientation and
the number of immunohistochemistry stains for cases that cannot be classified on histologic examination alone (see section
on immunohistochemistry).
In resection specimens, the primary purpose is a) to classify the histologic type; and b) to determine all staging parameters, as
recommended by the American Joint Committee on Cancer (AJCC), including tumor size, extent of invasion, adequacy of surgical margins,
and presence or absence of lymph node metastases.
The number of involved lymph node stations should be documented since it has prognostic significance (AJCC 8th ed). Direct
extension of the primary tumor into an adjacent lymph node is considered as nodal involvement.
The AJCC, Union for International Cancer Control (UICC), and International Association for the Study of Lung Cancer (IASLC)
recommend that at least six nodes are removed during surgical resection, three from N1 and three from N2 stations (ie, a representative
node from each station) for accurate staging. All lobectomy specimens should be extensively dissected to search for involved lymph
nodes.
In small biopsies or cytology specimens—obtained for molecular testing in the context of an established diagnosis after progression on
targeted therapies, the primary purpose is a) to confirm the original pathologic type with minimal use of tissue for
immunohistochemistry only in suspected small cell carcinoma transformation or a different histology; and b) to preserve material for
molecular analysis.
• Formalin-fixed paraffin-embedded (FFPE) material is suitable for most molecular analyses, except bone biopsies that were previously treated
with acid decalcifying solutions. Non-acid decalcification approaches may be successful for subsequent molecular testing. While many
molecular pathology laboratories currently also accept cytopathology specimens such as cell blocks, direct smears, or touch preparations,
laboratories that do not currently do so are strongly encouraged to identify approaches to testing on non-FFPE cytopathology specimens.
1Non-small cell carcinomas (NSCC, without the L for lung) that show no clear adenocarcinoma or squamous cell carcinoma morphology or immunohistochemical
markers are regarded as NSCC not otherwise specified (NOS). In this setting, it is recommended that pathologists use the term NSCC rather than NSCLC, because
the lack of pneumocyte marker expression in small biopsies or cytology leaves open the possibility of a metastatic carcinoma and the determination of a lung primary
must be established clinically after excluding other primary sites.
Table of Contents
Discussion
Continued
NSCL-A
1 OF 4
(NCCN®

NSCLC Classification
• The types of NSCLC are: adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, large cell carcinoma, and sarcomatoid
carcinoma.
Squamous cell carcinoma: A malignant epithelial tumor that either shows keratinization and/or intercellular bridges, or a morphologically
undifferentiated NSCC that expresses immunohistochemical markers of squamous cell differentiation.
Adenocarcinoma:
For small (<3 cm), resected lesions, determining extent of invasion is critical.
– Adenocarcinoma in situ (AIS; formerly BAC): A small (≤3 cm) localized nodule with lepidic growth, mostly non-mucinous, although
mucinous types can occur. Multiple synchronous AIS tumors can also occur.
– Minimally invasive adenocarcinoma (MIA): A small (≤3 cm) solitary adenocarcinoma with a predominantly lepidic pattern and ≤5 mm
invasion in greatest dimension. MIA is usually non-mucinous, but rarely may be mucinous. MIA is, by definition, solitary and discrete.
– Invasive adenocarcinoma: A malignant epithelial tumor with glandular differentiation, mucin production, or pneumocyte marker
expression. The tumors show an acinar, papillary, micropapillary, lepidic, or solid growth pattern, with either mucin or pneumocyte
marker expression. After comprehensive histologic subtyping in 5%–10% increments, the tumors are classified according to their
predominant pattern. The invasive adenocarcinoma component should be present in at least one focus measuring >5 mm in greatest
dimension.
– Invasive adenocarcinoma variants: invasive mucinous adenocarcinoma, colloid adenocarcinoma, fetal adenocarcinoma, and enteric
adenocarcinoma.
Adenosquamous carcinoma: A carcinoma showing components of both squamous cell carcinoma and adenocarcinoma, with each
component constituting at least 10% of the tumor. Definitive diagnosis requires a resection specimen, although it may be suggested based
on findings in small biopsies, cytology, or excisional biopsies. Presence of any adenocarcinoma component in a biopsy specimen that is
otherwise squamous should trigger molecular testing.
Large cell carcinoma: Undifferentiated NSCC that lacks the cytologic, architectural, and histochemical features of small cell carcinoma,
adenocarcinoma, or squamous cell carcinoma. The diagnosis requires a thoroughly sampled resected tumor and cannot be made on non-
resection or cytology specimens.
Sarcomatoid carcinoma is a general term that includes pleomorphic carcinoma, carcinosarcoma, and pulmonary blastoma. For this reason, it
is best to use the specific term for these entities whenever possible rather than the general term.
Pleomorphic carcinoma is a poorly differentiated NSCC that contains at least 10% spindle and/or giant cells or a carcinoma consisting
only of spindle and giant cells. Spindle cell carcinoma consists of an almost pure population of epithelial spindle cells, while Giant
cell carcinoma consists almost entirely of tumor giant cells.
Carcinosarcoma is a malignant tumor that consists of a mixture of NSCC and sarcoma-containing heterologous elements (eg,
rhabdomyosarcoma, chondrosarcoma, osteosarcoma).
Pulmonary blastoma is a biphasic tumor that consists of fetal adenocarcinoma (typically low grade) and primitive mesenchymal stroma.
Table of Contents
Discussion
Continued
NSCL-A
2 OF 4
(NCCN®

Immunohistochemistry
• Judicious use of immunohistochemistry is strongly recommended to preserve tissue for molecular testing, most notably in small specimens.
When adenocarcinoma or squamous cell carcinomas are poorly differentiated, the defining morphologic criteria that would allow for specific
diagnosis may be inconspicuous or absent. In this case, immunohistochemistry or mucin staining may be necessary to determine a specific
diagnosis.
• In small specimens, a limited number of immunostains with one lung adenocarcinoma marker (TTF1, napsin A) and one squamous
carcinoma marker (p40, p63) should suffice for most diagnostic problems. Virtually all tumors that lack squamous cell morphology and show
co-expression of p63 and TTF1 are preferably classified as adenocarcinoma. A simple panel of TTF1 and p40 may be sufficient to classify
most NSCC-NOS cases.
• Testing for NUT expression by immunohistochemistry should be considered in all poorly differentiated carcinomas that lack glandular
differentiation or specific etiology, particularly in non-smokers or in patients presenting at a young age, for consideration of a pulmonary
NUT carcinoma.
• Immunohistochemistry should be used to differentiate primary lung adenocarcinoma from squamous cell carcinoma, large cell carcinoma,
metastatic carcinoma, and primary pleural mesothelioma (particularly for pleural specimens).
• Primary pulmonary adenocarcinoma:
In patients for whom the primary origin of the carcinoma is uncertain, an appropriate panel of immunohistochemical stains i
s
recommended to assess for metastatic carcinoma to the lung.
TTF1 is a homeodomain-containing nuclear transcription protein of the Nkx2 gene family that is expressed in epithelial cells of the
embryonal and mature lung and thyroid. TTF1 immunoreactivity is seen in primary pulmonary adenocarcinoma in the majority (70%–90%)
of non-mucinous adenocarcinoma subtypes. Metastatic adenocarcinoma to the lung is nearly always negative for TTF1 except in metastatic
thyroid malignancies, in which case thyroglobulin and PAX8 are also positive. Rare cases of TTF1 positivity in tumors of other organs
(gynecologic tract, pancreatobiliary) have been noted, and may be dependent on the specific TTF1 clone utilized, stressing the importance
of correlation with clinical and radiologic features.
Napsin A—an aspartic proteinase expressed in normal type II pneumocytes and in proximal and distal renal tubules—appears to be
expressed in >80% of lung adenocarcinomas and may be a useful adjunct to TTF1.
The panel of TTF1 (or alternatively napsin A) and p40 (or alternatively p63) may be useful in refining the diagnosis to either adenocarcinoma
or squamous cell carcinoma in small biopsy specimens previously classified as NSCC NOS.
Table of Contents
Discussion
Continued
NSCL-A
3 OF 4
(NCCN®

• Immunohistochemistry should be used to confirm neuroendocrine differentiation when there is morphologic evidence of neuroendocrine
morphology (eg, speckled chromatin pattern, nuclear molding, peripheral palisading):
NCAM (CD56), chromogranin, and synaptophysin are used to identify neuroendocrine tumors in cases in which morphologic suspicion of
neuroendocrine differentiation exists.
A panel of markers is useful, but one positive marker is enough if the staining is unambiguous in more than 10% of the tumor cells.
• Malignant mesothelioma versus pulmonary adenocarcinoma
The distinction between pulmonary adenocarcinoma and malignant mesothelioma (epithelioid type) can be made by correlation of t
h
e
histology with the clinical impression, imaging studies, and a panel of immunomarkers.
Immunostains sensitive and specific for mesothelioma include WT-1, calretinin, CK5/6, and D2-40 (usually negative in adenocarcinoma).
Immunostains sensitive and specific for adenocarcinoma include pCEA, Claudin 4, TTF1, and napsin A (negative in mesothelioma). Other
potentially useful markers that can be considered include B72.3, Ber-EP4, MOC31, and CD15, but these generally do not have the sensitivity
and specificity of the above markers.
A pancytokeratin such as AE1/AE3 is also useful, as a negative result suggests the possibility of other tumors.
Other markers can be helpful in the differential diagnosis between mesothelioma and metastatic carcinoma, and will also help determine
the tumor origin. Examples include markers for lung adenocarcinoma (TTF1 and napsin A), breast carcinoma (ERα, PR, GCDFP15,
mammaglobin, and GATA-3), renal cell carcinoma (PAX8), papillary serous carcinoma (PAX8, PAX2, and ER), adenocarcinomas of
the gastrointestinal tract (CDX2), and prostate cancer (NKX3.1). Additionally, p40 (or p63) is helpful for distinguishing epithelioid
mesotheliomas with pseudosquamous morphology from squamous cell carcinomas.
Table of Contents
Discussion
NSCL-A
4 OF 4
(NCCN®

Table 1. Definitions for T, N, M
T Primary Tumor
TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but
not visualized by imaging or bronchoscopy
T0 No evidence of primary tumor
Tis Carcinoma in situ
Squamous cell carcinoma in situ (SCIS)
Adenocarcinoma in situ (AIS): adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension
T1 Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more
proximal than the lobar bronchus (i.e., not in the main bronchus)
T1mi Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5
mm
invasion in greatest dimension
T1a Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the
bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
T1b Tumor >1 cm but ≤2 cm in greatest dimension
T1c Tumor >2 cm but ≤3 cm in greatest dimension
T2 Tumor >3 cm but ≤5 cm or having any of the following features: (1) Involves the main bronchus, regardless of distance to the
carina, but without involvement of the carina; (2) Invades visceral pleura (PL1 or PL2); (3) Associated with atelectasis or
obstructive pneumonitis that extends to the hilar region, involving part or all of the lung
T2a Tumor >3 cm but ≤4 cm in greatest dimension
T2b Tumor >4 cm but ≤5 cm in greatest dimension
T3 Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall
(including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the
primary
T4 Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea,
recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s) in an ipsilateral lobe different from that of
the primary
Table of Contents
Discussion
a Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for
tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a
staging descriptor.
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.
ST-1
(NCCN®

Table 1. Definitions for T, N, M (continued) Table 2. AJCC Prognostic Groups
Stage IA1 T1mi N0 M0 T2a N3 M0
T1a N0 M0 T2b N3 M0
Stage IA2 T1b N0 M0 T3 N2 M0
Stage IA3 T1c N0 M0 T4 N2 M0
Stage IB T2a N0 M0 Stage IIIC T3 N3 M0
Stage IIA T2b N0 M0 T4 N3 M0
Stage IIB T1a N1 M0 Stage IVA Any T Any N M1a
T1b N1 M0 Any T Any N M1b
T1c N1 M0 Stage IVB Any T Any N M1c
T2a N1 M0
T2b N1 M0
T3 N0 M0
Stage IIIA T1a N2 M0
T1b N2 M0
T1c N2 M0
T2a N2 M0
T2b N2 M0
T3 N1 M0
T4 N0 M0
T4 N1 M0
N Regional Lymph Nodes T N M T N M
NX Regional lymph nodes cannot be assessed Occult TX N0 M0 Stage IIIB T1a N3 M0
N0 No regional lymph node metastasis Carcinoma T1b N3 M0
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral Stage 0 Tis N0 M0 T1c N3 M0
hilar lymph nodes and intrapulmonary nodes, including
involvement by direct extension
Metastasis in ipsilateral mediastinal and/or subcarinal
lymph node(s)
Metastasis in contralateral mediastinal, contralateral hilar,
ipsilateral or contralateral scalene, or supraclavicular
lymph node(s)
N2
N3
M
M0
M1
Distant Metastasis
No distant metastasis
Distant metastasis
M1a Separate tumor nodule(s) in a contralateral lobe; tumor
with pleural or pericardial nodules or malignant pleural or
pericardial effusiona
M1b Single extrathoracic metastasis in a single organ (including
involvement of a single nonregional node)
M1c Multiple extrathoracic metastases in a single organ or in
multiple organs
Table of Contents
Discussion
a Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for
tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a
staging descriptor.
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.
ST-2
(NCCN®

*Rami-Porta R, Asamura H, Travis WD, Rusch VW. Lung cancer - major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67:138-
155.
Table 3. Comparison of the Descriptors in the Eighth Edition of the TNM Classification of Lung Cancer Compared with the Seventh Edition*
Descriptor 7th Edition T/N/M 8th
Edition T/N/M
T component
0 cm (pure lepidic adenocarcinoma
≤3 cm in total size)
T1a if ≤2 cm; T1b if >2-3 cm Tis (AIS)
≤0.5 cm invasive size (lepidic predominant
adenocarcinoma ≤3 cm total size)
T1a if ≤2 cm; T1b if >2-3 cm T1mi
≤1 cm T1a T1a
>1-2 cm T1a T1b
>2-3 cm T1b T1c
>3-4 cm T2a T2a
>4-5 cm T2a T2b
>5-7 cm T2b T3
>7 cm T3 T4
Bronchus <2 cm from carina T3 T2
Total atelectasis/pneumonitis T3 T2
Invasion of diaphragm T3 T4
Invasion of mediastinal pleura T3 —
N component
No assessment, no involvement, or
involvement of regional lymph nodes
NX, N0, N1, N2, N3 No change
M component
Metastasis within the thoracic cavity M1a M1a
Single extrathoracic metastasis M1b M1b
Multiple extrathoracic metastasis M1b M1c
Table of Contents
Discussion
ST-3
(NCCN®

l See Principles of Radiation Therapy (NSCL-C).
q See Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D).
r Examples of high-risk factors may include poorly differentiated tumors (including
lung neuroendocrine tumors [excluding well-differentiated neuroendocrine tumors]),
vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement,
and unknown lymph node status (Nx). These factors independently may not be
an indication and may be considered when determining treatment with adjuvant
s See Chemotherapy Regimens Used with Radiation Therapy (NSCL-E).
u R0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic
residual tumor.
v Increasing size is an important variable when evaluating the need for
adjuvant
FINDINGS AT SURGERY ADJUVANT TREATMENT
Stage IA (T1abc, N0)
Margins negative (R0)u
Margins positive (R1, R2)u
Observe
Reresection (preferred)
or
RTl (category 2B)
Surveillance
(NSCL-16)
Stage IB (T2a, N0)
Stage IIA (T2b, N0)
Stage IIB (T1abc–T2a, N1)
Stage IIB (T3, N0; T2b,
N1)
Stage IIIA (T1–2, N2; T3, N1)
Stage IIIB (T3, N2)
Margins positive (R1, R2)u
Margins positive
R1u
R2u
Margins positive
R1u
R2u
Observe
or
Chemotherapyq for high-risk patientsr
Reresection (preferred) ± chemotherapyq,v
or
RTl ± chemotherapyq (chemotherapy for stage IIA)
Chemotherapyq (category 1)
Reresection + chemotherapyq
or
Chemoradiationl (sequentialq or concurrents)
or
Concurrent chemoradiationl,s
or
Sequential chemotherapyq + RTl (N2 only)
Chemoradiationl (sequentialq or concurrents)
Table of Contents
Discussion
chemotherapy. chemotherapy.
NSCL-4
(NCCN®

CHEMOTHERAPY REGIMENS FOR NEOADJUVANT AND ADJUVANT THERAPY
Preferred (nonsquamous)
• Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1 every 21 days for 4 cycles1
Preferred (squamous)
• Cisplatin 75 mg/m2 day 1; gemcitabine 1250 mg/m2 days 1 and 8, every 21 days for 4 cycles2
• Cisplatin 75 mg/m2
day 1; docetaxel 75 mg/m2
day 1 every 21 days for 4 cycles3
Other Recommended
• Cisplatin 50 mg/m2 days 1 and 8; vinorelbine 25 mg/m2 days 1, 8, 15, and 22, every 28 days for 4 cycles4
day 1; vinorelbine 30 mg/m2
days 1, 8, 15, and 22, every 28 days for 4 cycles5,6
• Cisplatin 75–80 mg/m2 day 1; vinorelbine 25–30 mg/m2 days 1 and 8, every 21 days for 4 cycles
day 1; etoposide 100 mg/m2
days 1–3, every 28 days for 4 cycles5
Useful in Certain Circumstances
Chemotherapy Regimens for Patients with Comorbidities or Patients Not Able to Tolerate Cisplatin
• Carboplatin AUC 6 day 1, paclitaxel 200 mg/m2 day 1, every 21 days for 4 cycles7
• Carboplatin AUC 5 day 1, gemcitabine 1000 mg/m2
days 1 and 8, every 21 days for 4 cycles8
• Carboplatin AUC 5 day 1, pemetrexed 500 mg/m2
day 1 for nonsquamous every 21 days for 4 cycles9
All regimens can be used for sequential chemotherapy/RT.
1Kreuter M, Vansteenkiste J, Fishcer JR, et al. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed
versus cisplatin and vinorelbine: the TREAT study. Ann Oncol 2013;24:986-992.
2Pérol M, Chouaid C, Pérol D, et al. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line
treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2012;30:3516-3524.
3Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for
advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21:3016-3024.
4Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-lung cancer. N Engl J Med 2005;352:2589-2597. 5Arriagada
R, Bergman B, Dunant A, et al. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely
resected non-small cell lung cancer. N Engl J Med 2004;350:351-360.
6Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung
cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006;7:719-727.
7Strauss GM, Herndon III JE, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small cell lung cancer: CALGB 9633
with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008;26:5043-
5051.
8Usami N, Yokoi K, Hasegawa Y
, et al. Phase II study of carboplatin and gemcitabine as adjuvant chemotherapy in patients with completely resected non-small cell lung
cancer: a report from the Central Japan Lung Study Group, CJLSG 0503 trial. Int J Clin Oncol 2010;15:583-587.
9Zhang L, Ou W, Liu Q, et al. Pemetrexed plus carboplatin as adjuvant chemotherapy in patients with curative resected non-squamous non-small cell lung cancer.
Thorac Cancer 2014;5:50-56.
Table of Contents
Discussion
NSCL-D
(NCCN®

g Testing is not listed in order of priority and is dependent on clinical circumstances,
institutional processes, and judicious use of resources.
h Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS,
EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a
clinically (PET and/or CT) positive mediastinum should undergo subsequent
k See Principles of Surgical Therapy (NSCL-B).
m Image-guided thermal ablation is an option for selected patients.
n Patients require tissue confirmation of lung cancer before any nonsurgical
mediastinoscopy prior to surgical resection. therapy. Multidisciplinary evaluation that at least includes interventional radiology, i There is
low likelihood of positive mediastinal lymph nodes when these nodes are thoracic surgery, and interventional pulmonology is recommended to
determine CT and PET negative in solid tumors <1 cm and purely non-solid tumors <3 cm. the safest and most efficient approach, or to provide consensus that a
biopsy is Thus, pre-resection pathologic mediastinal evaluation is optional in these settings. too risky or difficult and that the patient can proceed with therapy without
tissue
j PET/CT performed skull base to knees or whole body. Positive PET/CT scan confirmation. (IJsseldijk MA, Shoni M, Siegert C, et al. Survival after
stereotactic findings for distant disease need pathologic or other radiologic confirmation. If body radiation therapy for clinically diagnosed or biopsy-proven early-
stage PET/CT scan is positive in the mediastinum, lymph node status needs pathologic NSCLC: A systematic review and meta-analysis. J Thorac Oncol
2019;14:583-
CLINICAL ASSESSMENT PRETREATMENT EVALUATIONg INITIAL TREATMENT
Stage IA
(peripheral T1abc, N0)
• Pulmonary function tests
(PFTs) (if not previously
done)
• Bronchoscopy
(intraoperative preferred)
• Consider pathologic
mediastinal lymph node
evaluationh,i
• FDG PET/CT scanj (if
not
previously done)
Negative
mediastinal
nodes
Positive
mediastinal
nodes
Operable
Medically
inoperablek
Surgical exploration
and resectionk +
mediastinal lymph
node dissection or
systematic lymph
node sampling
Definitive RT including
stereotactic ablative
radiotherapy (SABR)l,m,n
See Stage IIIA/IIIB (NSCL-8)
or Stage IIIB/IIIC (NSCL-12)
See Adjuvant
Treatment
(NSCL-4)
Table of Contents
Discussion
confirmation. 595.)
NSCL-2
(NCCN®

CLINICAL ASSESSMENT PRETREATMENT EVALUATIONg
e
Stage IB (peripheral
T2a, N0)
Stage I (central
T1abc–T2a, N0)
Stage II (T1abc–2ab,
N1; T2b, N0)
Stage IIB (T3, N0)
Stage IIIA (T3, N1)
• PFTs (if not previously
done)
• Bronchoscopy
• Pathologic mediastinal
lymph node evaluationh
not previously
done) o
• Brain MRI with contrast
(Stage II, IIIA)
(Stage IB [optional])
Negative
mediastinal
nodes
Positive
mediastinal
nodes
Operable
INITIAL TREATMENT
Surgical exploration
and
resectionk,p +
mediastinal lymph node
dissection or systematic
lymph node sampling
Medically
inoperablek
See Adjuvant
Treatment (NSCL-4)
N0
N1
Definitive RT
including SABRl,n
Consider adjuvant
chemotherapyq
for high-risk
stages IB–IIBr
Definitive
chemoradiationl,s
Durvalumabs,t
(category 1)
(stage III only)
See Stage IIIA/IIIB (NSCL-8)
or Stage IIIB/IIIC (NSCL-
12)
e T3, N0 related to size or satellite nodules.
g Testing is not listed in order of priority and is dependent on clinical circumstances,
institutional processes, and judicious use of resources.
j PET/CT performed skull base to knees or whole body. Positive PET/CT scan
findings for distant disease need pathologic or other radiologic confirmation. If
PET/CT scan is positive in the mediastinum, lymph node status needs pathologic
confirmation.
n Patients require tissue confirmation of lung cancer before any nonsurgical
therapy. Multidisciplinary evaluation that at least includes interventional radiology,
thoracic surgery, and interventional pulmonology is recommended to determine
the safest and most efficient approach, or to provide consensus that a biopsy is
too risky or difficult and that the patient can proceed with therapy without tissue
confirmation. (IJsseldijk MA, Shoni M, Siegert C, et al. Survival after stereotactic
body radiation therapy for clinically diagnosed or biopsy-proven early-stage
NSCLC: A systematic review and meta-analysis. J Thorac Oncol 2019;14:583-
o If MRI is not possible, CT of head with contrast.
p After surgical evaluation, patients likely to receive adjuvant chemotherapy may be
treated with induction chemotherapy as an alternative.
q See Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D). r
Examples of high-risk factors may include poorly differentiated tumors (including
lung neuroendocrine tumors [excluding well-differentiated neuroendocrine tumors]),
vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement,
and unknown lymph node status (Nx). These factors independently may not be
an indication and may be considered when determining treatment with adjuvant
chemotherapy.
t Durvalumab is not recommended for patients following definitive surgical
Table of Contents
Discussion
595.) resection.
NSCL-3
(NCCN®

CLINICAL
ASSESSMENT
PRETREATMENT EVALUATION CLINICAL EVALUATION
Stage IIB (T3 invasion, N0)
Stage IIIA (T4 extension,
N0–1; T3, N1; T4, N0–1)
• PFTs (if not previously done)
• Bronchoscopy
• Pathologic mediastinal lymph node
evaluationh
• Brain MRI with contrasto
• MRI with contrast of spine +
thoracic inlet for superior sulcus
lesions abutting the spine or
subclavian vessels
• FDG PET/CT scanj (if not previously
done)
Superior sulcus tumor
Chest wall
Proximal airway
or mediastinum
Unresectable disease
Metastatic disease
h Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a clinically (PET
and/or CT) positive mediastinum should undergo subsequent mediastinoscopy prior to surgical resection.
j PET/CT performed skull base to knees or whole body. Positive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT
See Treatment (NSCL-6)
See Treatment for Metastasis
limited sites (NSCL-14) or
distant disease (NSCL-17)
Stage IIIA (T4, N0–1) See Treatment (NSCL-7)
Table of Contents
Discussion
scan is positive in the mediastinum, lymph node status needs pathologic confirmation.
NSCL-5
(NCCN®

CLINICAL PRESENTATION INITIAL TREATMENT ADJUVANT TREATMENT
Superior
sulcus tumor
(T3 invasion,
N0–1)
Superior
sulcus tumor
(T4 extension,
N0–1)
Preoperative
concurrent
chemoradiationl,s
Possibly
resectablek
Unresectablek
Preoperative
concurrent
chemoradiationl,s
Definitive concurrent
chemoradiationl,s
Surgical
reevaluation
including chest
CT with or without
contrast ±
PET/CT
Resectable
Unresectable
k
Surgery +
chemotherapyq
Surveillance
(NSCL-16)
Surgeryk +
chemotherapyq Surveillance
(NSCL-16)
Complete definitive RTl
+ chemotherapys
Surveillance
(NSCL-16)
Surveillance
(NSCL-16)
Durvalumabs,t
(category 1)
Table of Contents
Discussion
t Durvalumab is not recommended for patients following definitive surgical resection.
NSCL-6
(NCCN®

u R0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic residual tumor.
CLINICAL
PRESENTATION
INITIAL TREATMENT ADJUVANT TREATMENT
Chest wall,
proximal airway,
or mediastinum
(T3 invasion, N0–1
Resectable T4
extension, N0–1)
Surgeryk (preferred)
or
Concurrent
chemoradiationl,s
or
Chemotherapyq
Margins
negative (R0)u
Margins
positive
Surgeryk
R1u
R2u
Margins
negative (R0)u
Margins positive
(R1, R2)u
Chemotherapyq
or
Chemoradiationl
(sequentialq or concurrents)
or
Observe
Reresectionw
Surveillance
(NSCL-16)
Surveillance
(NSCL-16)
Surveillance
(NSCL-16)
Surveillance
(NSCL-16)
Surveillance
(NSCL-16)
Stage IIIA (T4, N0–1) Definitive concurrent
Unresectable chemoradiationl,s (category 1)
Surveillance
(NSCL-16)
Durvalumabs,t
(category 1)
Stage IIIA (T4, N0–1) Surgical
reevaluation
including
chest CT ±
PET/CT
Table of Contents
Discussion
w Consider RT boost if chemoradiation is given as initial treatment.
NSCL-7
(NCCN®

h Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a clinically (PET
and/or CT) positive mediastinum should undergo subsequent mediastinoscopy prior to surgical resection.
CLINICAL
ASSESSMENT
PRETREATMENT EVALUATION MEDIASTINAL BIOPSY FINDINGS
AND RESECTABILITY
Separate pulmonary
nodule(s)
(Stage IIB, IIIA, IV)
• Bronchoscopy
evaluationh
done)
• Bronchoscopy
evaluationh
done)
N2, N3 nodes negative
N2 nodes positive, M0
N3 nodes positive, M0
Metastatic disease
See Treatment
T1–3, N0–1 (NSCL-9)
See Stage IIIB (NSCL-12)
Separate pulmonary
nodule(s), same lobe
(T3, N0–1) or ipsilateral
non-primary lobe (T4,
N0–1)
Stage IVA (N0, M1a):
Contralateral lung
(solitary nodule)
Extrathoracic
metastatic disease
Stage IIIA (T1–2, N2)
Stage IIIB (T3, N2)
Table of Contents
Discussion
NSCL-8
(NCCN®

p After surgical evaluation, patients likely to receive adjuvant chemotherapy may be treated with induction chemotherapy as an alternative.
MEDIASTINAL BIOPSY
FINDINGS
INITIAL TREATMENT ADJUVANT TREATMENT
T1–3, N0–1
(including T3
with
multiple
nodules in
same lobe)
Resectablek,p
Medically
inoperable
Surgical resectionk
+ mediastinal lymph
node dissection or
systematic lymph
node sampling
See Treatment according
to clinical stage (NSCL-3)
See Adjuvant Treatment (NSCL-4)
T1–2, T3
(other than
invasive),
N2 nodes
positive, M0
chemoradiationl,s (category 1)
or
Induction
chemotherapyq,x ± RTl
No apparent
progression
Progression
Surgeryk ± RTl (if not given)
RTl (if not given) ± chemotherapyq
Local
Systemic
T3
(invasion),
N2 nodes
positive, M0
Surveillance
(NSCL-16)
Surveillance
(NSCL-16)
Durvalumabs,t chemoradiationl,s (category 1)
Durvalumabs,t
(category 1)
Table of Contents
Discussion
x Chest CT with contrast and/or PET/CT to evaluate progression.
NSCL-9
(NCCN®

confirmation.
p After surgical evaluation, patients likely to receive adjuvant chemotherapy may be
treated with induction chemotherapy as an alternative.
u R0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic
residual tumor.
y Lesions with different cell types (eg, squamous cell carcinoma, adenocarcinoma)
may be different primary tumors. This analysis may be limited by small biopsy
samples. However, lesions of the same cell type are not necessarily metastases. z
For guidance regarding the evaluation, workup, and management of subsolid
pulmonary nodules, please see the diagnostic evaluation of a nodule suspicious
CLINICAL PRESENTATION ADJUVANT TREATMENT
Chemotherapyq
Separate pulmonary
nodule(s), same lobe
(T3, N0–1), or
ipsilateral non-
primary
lobe (T4, N0–1)
Contralateral lung
(solitary nodule)
Stage IVA (N0, M1a):
Suspected multiple
lung cancers (based on
the presence of biopsy-
proven synchronous
lesions or history of
lung cancer)y,z
Surgeryk,p
Treat as two primary lung
tumors if both curable
• Chest CT with
contrast
• FDG PET/CT scan
(if not previously
done)j
• Brain MRI with
contrasto
N0–1
N2
Surveillance
(NSCL-16)
Surveillance
(NSCL-16)
Margins negative
(R0)u
Margins
positive
or
Sequential chemotherapyq + RTl
R1u
R2u
Chemoradiationl (sequentialq
or concurrents)
Concurrent
chemoradiationl,s
Surveillance
(NSCL-16)
Surveillance
(NSCL-16)
See Evaluation (NSCL-1)
Disease
outside
of
chest
No disease
outside of
chest
See Systemic Therapy for Metastatic Disease (NSCL-18)
Pathologic
mediastinal
lymph
node
evaluationh N2–3
N0–1
See Systemic Therapy
for Metastatic
Disease (NSCL-18)
See Initial Treatment
(NSCL-11)
Table of Contents
Discussion
o If MRI is not possible, CT of head with contrast. for lung cancer (DIAG-1).
NSCL-10
(NCCN®

for Metastatic
Disease (NSCL-18)
aa Lesions at low risk of becoming symptomatic can be observed (eg, small subsolid nodules with slow growth). However, if the lesion(s) becomes symptomatic or
becomes high risk for producing symptoms (eg, subsolid nodules with accelerating growth or increasing solid component or increasing FDG uptake, even while small),
treatment should be considered.
bb Lung-sparing resection is preferred, but tumor distribution and institutional expertise should guide individual treatment planning. Patients should be evaluated in a
CLINICAL
PRESENTATION
INITIAL TREATMENT
Multiple lung
cancers (N0–1)
Asymptomatic
Symptomatic
Multiple
lesions
Solitary lesion
(metachronous
disease)
Low risk of
becoming
symptomaticaa
High risk of
becoming
symptomaticaa
Observation Surveillance
(NSCL-16)
Definitive
local therapy
possible
Definitive
local therapy
not possible
Parenchymal sparing
resection (preferred)k,bb
or
Radiationl
or
Image-guided thermal
ablation
Palliative
chemotherapy ± local
palliative therapy
or
Observe
Table of Contents
Discussion
multidisciplinary setting (ie, surgery, radiation oncology, medical oncology).
NSCL-11
(NCCN®
Synchronous cancers were defined as those occurring within 6 months of the first
primary cancer, while metachronous cancers were defined as those occurring more
than 6 months later

CLINICAL
ASSESSMENT
PRETREATMENT EVALUATION INITIAL TREATMENT
Stage IIIB
(T1–2, N3)
Stage IIIC
(T3, N3)
• PFTs (if not previously
done)
not previously
done)
• Brain MRI with
contrasto
• Pathologic
confirmation
of N3 disease by:
Mediastinoscopy
Supraclavicular l
y
m
p
h
node biopsy
Thoracoscopy
Needle biopsy
Mediastinotomy
EUS biopsy
EBUS biopsy
N3 negative
N3 positive
Metastatic disease
See Initial treatment for stage I–IIIA (NSCL-
9)
chemoradiationl,s
(category 1)
Surveillance
(NSCL-16)
Durvalumabs,t
(category 1)
Table of Contents
Discussion
NSCL-12
(NCCN®

confirmation.
t Durvalumab is not recommended for patients following definitive surgical
resection.
cc Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a
few patients, however, multiple microscopic examinations of pleural (pericardial)
fluid are negative for tumor, and fluid is non-bloody and not an exudate. If these
elements and clinical judgment dictate that the effusion is not related to the tumor,
CLINICAL
ASSESSMENT
PRETREATMENT EVALUATION INITIAL TREATMENT
Stage IIIB
(T4, N2)
Stage IIIC
(T4, N3)
Stage IVA,
M1a: pleural
or pericardial
effusion
Thoracentesis or
pericardiocentesis
± thoracoscopy if
thoracentesis indeterminate
• FDG PET/CT scanj (if not
previously done)
• Pathologic confirmation
of N2–3 disease by either:
Mediastinoscopy
Supraclavicular l
y
mp
h
node biopsy
Thoracoscopy
Needle biopsy
Mediastinotomy
EUS biopsy
EBUS biopsy
Negativecc
Positivecc
See Treatment according to
TNM stage
Local therapy if necessary (eg,
pleurodesis, ambulatory small catheter
drainage, pericardial window) +
treatment for stage IV disease solitary
site or distant disease (NSCL-18)
Contralateral
mediastinal
node negative
Contralateral
mediastinal
node positive
(T4, N3)
Metastatic disease
Ipsilateral
mediastinal
node negative
(T4, N0–1)
Ipsilateral
mediastinal
node positive
(T4, N2)
See Treatment for Stage IIIA (NSCL-7)
Definitive
concurrent
chemoradiationl,s
(category 1)
chemoradiationl,s
(category 1)
Surveillance
(NSCL-16)
Durvalumabs,t
(category 1)
Durvalumabs,t
category 1
Table of Contents
Discussion
the effusion should be excluded as a staging descriptor.
NSCL-13
(NCCN®

dd Including selected patients with stage M1c and limited number and volume of metastatic lesions amenable to definitive local therapy. Limited number is undefined but
clinical trials have included up to 3 to 5 metastases.
CLINICAL
ASSESSMENT
Stage IVA,
M1bdd
If not previously
done
• Brain MRI with
contrasto
• FDG PET/CT
scanj
• Pathologic
confirmation of
metastatic lesion,
if possible
Limited
metastases
confirmed
Multiple
metastases
See Systemic Therapy for
Metastatic Disease (NSCL-18)
PRETREATMENT EVALUATION INITIAL TREATMENTee
Stereotactic radiosurgery
(SRS) alone
or
Surgical resection,
if symptomatic or
warranted for diagnosis,
followed by SRS or whole
brain RT (WBRT)
See Treatment of
Thoracic Disease
(NSCL-15)
Brainee
Other site
See Treatment of
Thoracic Disease
(NSCL-15)
PS 0–1
PS 2–4
See Systemic Therapy for
Metastatic Disease (NSCL-18)
Table of Contents
Discussion
ee See NCCN Guidelines for Central Nervous System Cancers.
NSCL-14
(NCCN®

T1–3, N0
• Pathologic
mediastinal nodal
evaluationh and
• Surgical resectionk
or SABRl,m
Consider systemic
therapy, if not
already given
(NSCL-18)
Definitive local
therapy for
metastatic site,m,ff
if not already given
x Chest CT with contrast and/or PET/CT to evaluate progression.
TREATMENT OF THORACIC DISEASE
Definitive therapy
for thoracic disease
not feasible
Definitive therapy
for thoracic
disease feasible
for Metastatic
Disease (NSCL-18)
T1–3, N1
T1–3, N2
T4, N0–2
Definitive
chemoradiations
• Pathologic
mediastinal nodal
evaluationh and
• Surgical
resectionk or
Definitive RTl or
Chemoradiations
Consider systemic
therapy (NSCL-
18) and restagingx
to confirm non-
progression
or
Proceed to
definitive
therapy
Table of Contents
Discussion
ff Typically, RT (including SABR) or surgical resection.
NSCL-15
(NCCN®

gg Timing of CT scans within Guidelines parameters is a clinical decision.
hh FDG PET/CT is currently not warranted in the routine surveillance and follow-up of patients with NSCLC. However, many benign conditions (such as atelectasis,
consolidation, and radiation fibrosis) are difficult to differentiate from neoplasm on standard CT imaging, and FDG PET/CT can be used to differentiate true malignancy
in these settings. However, if FDG PET/CT is to be used as a problem-solving tool in patients after radiation therapy, histopathologic confirmation of recurrent disease
No evidence of clinical/radiographic disease
• Stage I–II (primary treatment included surgery
± chemotherapy)
H&P and chest CT ± contrast every 6 m
o
for 2–3 y, then H&P and a low-dose non–
contrast-enhanced chest CT annually
• Stage I–II (primary treatment included RT)
or
stage III or stage IV (oligometastatic with
all
sites treated with definitive intent)
H&P and chest CTgg ± contrast every 3–6 m
o
for 3 y, then H&P and chest CT ± contrast
every 6 mo for 2 y, then H&P and a low-dose
non–contrast-enhanced chest CT annually
Residual or new radiographic
abnormalities may require more frequent
imaging
• Smoking cessation advice, counseling, and
pharmacotherapy
• PET/CThh or brain MRI is not routinely
indicated
• See Cancer Survivorship Care (NSCL-
F)
Locoregional
recurrence
Distant
metastases
See Therapy for Recurrence
and Metastasis (NSCL-17)
See Therapy for Recurrence
and Metastasis (NSCL-17)
SURVEILLANCE AFTER COMPLETION OF DEFINITIVE THERAPY
Recurrence
• PET/CT
• Brain MRI
Table of Contents
Discussion
is needed because areas previously treated with radiation therapy can remain FDG avid for up to 2 years.
NSCL-16
(NCCN®

Locoregional
recurrence or
symptomatic
local
disease
Distant
metastases
THERAPY FOR RECURRENCE AND METASTASIS
Endobronchial
obstruction
Resectable recurrence
Mediastinal lymph
node recurrence
Superior vena cava
(SVC) obstruction
Severe hemoptysis
No prior RT
Prior RT
Any combination of the following:
• Laser/stent/other surgeryk
• External-beam RT or brachytherapyl
• Photodynamic therapy
• Reresection (preferred)k
• External-beam RT or SABRl,m
Systemic therapy (NSCL-18)
• Concurrent chemoradiationl,s
(if not previously given) ± SVC stent
• External-beam RTl ± SVC stent
• SVC stent
Any combination of the following:
• External-beam RT or brachytherapyl
• Laser or photodynamic therapy or
embolization
• Surgery
No evidence
of
disseminated
disease
Evidence of
disseminated
disease
Observation
or
Systemic
therapy
(NSCL-18)
(category
2B)
See Systemic
Therapy for
Metastatic
Disease
(NSCL-18)
Localized symptoms Palliative external-beam RTl
Palliative external-beam RTl,ee
• If risk of fracture, orthopedic stabilization +
palliative external-beam RTl
• Consider bisphosphonate therapy or
denosumab
Diffuse brain metastases
Bone metastasis
Limited metastasis
Disseminated metastases
See pathway for Stage IV, M1b (NSCL-14)
See Systemic Therapy for Metastatic Disease (NSCL-18)
• Chest
CT with
contrast
• Brain
MRI with
contrasto
• PET/CT
See Systemic
Therapy for
Metastatic
Disease
(NSCL-18)
Table of Contents
Discussion
m Image-guided thermal ablation is an option for selected patients. ee See NCCN Guidelines for Central Nervous System Cancers.
NSCL-17
(NCCN®

HISTOLOGIC
TESTINGjj SUBTYPEa
Advanced
or
metastatic
disease
• Establish histologic
subtypea with
adequate tissue for
molecular testing
(consider rebiopsyii
if appropriate)
• Smoking cessation
counseling
• Integrate palliative
carec (See NCCN
Guidelines for Pal
liative
Care)
• Adenocarcinoma
• Large cell
• NSCLC not
otherwise
specified (NOS)
Squamous cell
carcinoma
• Molecular testing
EGFR mutation testing
(category 1)
ALK testing (category 1)
ROS1 testing
BRAF testing
MET exon 14 skipping
testing
RET testing
Testing should be
conducted as part of broad
molecular profilingkk,ll
• PD-L1 testing (category 1)
• Molecular testing
Consider EGFR
mutationmm and
ALK testing in never
smokers or small biopsy
specimens, or mixed
histologynn
Consider ROS1, BRAF,
MET exon 14 skipping,
and RET testing in small
biopsy specimens or
mixed histology
Testing should be
conducted as part of broad
molecular profilingkk,ll
• PD-L1 testing (category 1)
PD-L1 ≥1% and EGFR, ALK, ROS1, BRAF,
MET exon 14 skipping mutation, and RET
negativeii (see NSCL-30)
PD-L1 <1% and EGFR, ALK, ROS1, BRAF,
CLINICAL PRESENTATION
Sensitizing EGFR mutation positive
(see NSCL-19)
ALK positive (see NSCL-22)
ROS1 positive (see NSCL-25)
BRAF V600E positive (see NSCL-
26)
MET exon 14 skipping mutation
positive
(see NSCL-28)
PD-L1 ≥1% and EGFR, ALK, ROS1, BRAF,
PD-L1 <1% and EGFR, ALK, ROS1, BRAF,
TESTING RESULTSjj
Sensitizing EGFR mutation positive
(see NSCL-19)
ALK positive (see NSCL-22)
ROS1 positive (see NSCL-25)
BRAF V600E positive (see NSCL-
26)
MET exon 14 skipping mutation
positive
(see NSCL-28)
RET positive (see NSCL-29)
RET positive (see NSCL-29)
Table of Contents
Discussion
See footnotes on NSCL-18A
NSCL-18
(NCCN®

jj See Principles of Molecular and Biomarker Analysis (NSCL-G).
oo See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-I).
pp For performance status 0–4.
qq If systemic therapy regimen contains an immune checkpoint inhibitor, physicians should be aware of the long half-life of such drugs and data reporting adverse events
when combining checkpoint inhibitors with osimertinib. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential
PD-(L)1 blockade and osimertinib. Ann Oncol 2019;30:839-844; Oshima Y
, Tanimoto T, Yuji K, Tojo A. EGFR-TKI-associated interstitial pneumonitis in nivolumab- treated
patients with non-small cell lung cancer. JAMA Oncol 2018;4:1112-1115; Ahn M-J, Yang J, Yu H, et al. Osimertinib combined with durvalumab in EGFR-mutant non-small
cell lung cancer: Results from the TATTON phase Ib trial. J Thorac Oncol 2016;11:S115.(abstr 1360).
rr Criteria for treatment with bevacizumab: non-squamous NSCLC, and no recent history of hemoptysis.
SENSITIZING EGFR MUTATION POSITIVEjj
FIRST-LINE THERAPYoo
Sensitizing
EGFR
mutation
positive
EGFR mutation
discovered
prior to first-line
systemic
therapy
EGFR mutation
discovered during
first-line systemic
therapy
Preferred
pp
Osimertinib (category 1)
Other Recommended
Erlotinibpp (category 1)
or Afatinibpp (category 1)
or Gefitinibpp (category
1)
or Dacomitinibpp
(category 1)
or Erlotinib +
ramucirumab
Erlotinib + bevacizumabrr,ss
(category 2B)
Complete planned systemic
therapy,qq including
maintenance therapy,
or interrupt, followed by
osimertinib (preferred)
or
erlotinib or afatinib or gefitinib
or dacomitinib or erlotinib +
ramucirumab or erlotinib +
bevacizumabrr,ss (category 2B)
Progression
See Subsequent
Therapy (NSCL-21)
Progression
See Subsequent
Therapy (NSCL-21)
Progression
Progression
See Subsequent
Therapy (NSCL-20)
See Subsequent
Therapy (NSCL-20)
Table of Contents
Discussion
ss An FDA-approved biosimilar is an appropriate substitute for bevacizumab.
NSCL-19
(NCCN®

tt Beware of flare phenomenon in subset of patients who discontinue EGFR TKI. If disease flare occurs, restart EGFR TKI.
uu Consider a biopsy at time of progression to rule out SCLC transformation.
vv Afatinib + cetuximab may be considered in patients with disease progression on EGFR TKI therapy.
SENSITIZING EGFR MUTATION POSITIVEjj SUBSEQUENT THERAPYoo
Progression on
osimertinibtt
Symptomatic
Asymptomatic
Brain
Systemic
Isolated
lesion
Multiple
lesionsuu
• Consider definitive local therapy (eg,
SRS) for limited lesionsm
• Continue osimertinib
• See NCCN Guidelines for CNS Cancers
See Initial systemic therapy optionsvv,ww
Adenocarcinoma (NSCL-32) or
Squamous Cell Carcinoma (NSCL-33)
SABR or surgery) for limited lesionsm
SABR or surgery)m
or
• See subsequent therapy for multiple
lesions, noted below
Progression, see
therapyvv,ww for multiple
lesions, noted below
Table of Contents
Discussion
ww The data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is less effective, irrespective of PD-L1 expression, in EGFR+/ALK+ NSCLC.
NSCL-20
(NCCN®

rr Criteria for treatment with bevacizumab: non-squamous NSCLC, and no recent history of hemoptysis.
tt Beware of flare phenomenon in subset of patients who discontinue EGFR TKI. If disease flare occurs, restart EGFR TKI.
uu Consider a biopsy at time of progression to rule out SCLC transformation.
vv Afatinib + cetuximab may be considered in patients with disease progression on EGFR TKI therapy.
xx Plasma-based testing should be considered at progression on EGFR TKIs for the T790M mutation. If plasma-based testing is negative, tissue-based testing with rebiopsy
material is strongly recommended. Practitioners may want to consider scheduling the biopsy concurrently with plasma testing referral.
yy Consider osimertinib (regardless of T790M status) for progressive leptomeningeal disease. In the Bloom study, osimertinib was used at 160 mg.
SENSITIZING EGFR MUTATION POSITIVEjj
Progression
on erlotinib ±
(ramucirumab
or
bevacizumab),
afatinib,
dacomitinib
gefitinib, or
tt
Symptomatic
Asymptomatic
Brainyy
Multiple
lesionsuu
Systemic
• Consider definitive local therapy (eg, SRS) for limited
lesionsm
• Osimertinibpp (if T790M+) (category 1)
or
Continue erlotinib ± (ramucirumab or bevacizumabrr)
SUBSEQUENT THERAPYoo
• Consider definitive local therapy (eg, SABR or
surgery) for limited lesionsm
• Osimertinibpp (if T790M+) (category 1)
or
rr
Continue erlotinib ± (ramucirumab or bevacizumab )
or afatinib or gefitinib or dacomitinib
testing
T790M
xx
Isolated
lesion
or afatinib or gefitinib or dacomitinibzz
• Consider definitive local therapy (eg, SABR or
surgery)m
• Continue erlotinib ± (ramucirumab or bevacizumabrr)
or afatinib or gefitinib or dacomitinib
or
• See subsequent therapy for multiple lesions below
Osimertinibpp (category 1)
(if not previously given)
T790M+
T790M-
See Initial systemic therapy optionsvv,ww
If progression, see (NSCL-20)
If progression, see
therapyvv,ww for
multiple lesions,
noted below
If progression, see
therapyvv,ww for
multiple lesions,
noted below
Progression, see
therapyvv,ww for
multiple lesions,
noted below
Table of Contents
Discussion
zz In the randomized phase III trial of dacomitinib, patients with brain metastases were not eligible for enrollment. In the setting of brain metastases, consider other options.
NSCL-21
(NCCN®

ALK REARRANGEMENT POSITIVEjj
ALK
rearrangement
positive
ALK rearrangement
discovered prior to
first-line systemic
therapy
ALK rearrangement
discovered during
first-line
systemic
therapy
pp
FIRST-LINE THERAPYoo
Preferred
Alectinibpp (category 1)
Other Recommended
Brigatinibpp (category 1)
or
Ceritinib (category 1)
Useful in Certain
Circumstances
Crizotinibpp (category 1)
Complete planned
systemic therapy,
including maintenance
therapy, or interrupt,
followed by alectinib
(preferred) or brigatinib
or ceritinib
or
crizotinib Progression
Progression
Progression
Progression
See Subsequent
Therapy (NSCL-24)
See Subsequent
Therapy (NSCL-23)
See Subsequent
Therapy (NSCL-24)
See Subsequent
Therapy (NSCL-23)
Table of Contents
Discussion
NSCL-22
(NCCN®

Progression
on alectinib
or brigatinib
or ceritinibaaa
Symptomatic
Asymptomatic
• Consider definitive local therapy (eg, SABR
or surgery) for limited lesionsm
• Continue alectinib or brigatinib or ceritinib
Brain
Systemic
• Consider definitive local therapy (eg, SRS)
for limited lesionsm
Isolated
lesion
Multiple
lesions
SABR or surgery)m
Lorlatinib
or
ww
See Initial systemic therapy options
for Adenocarcinoma (NSCL-32) or
Progression,
Lorlatinib or
See Initial
systemic
therapy optionsww
Adenocarcinoma
(NSCL-32) or
Squamous Cell
Carcinoma (NSCL-33)
Table of Contents
Discussion
aaa Beware of flare phenomenon in subset of patients who discontinue ALK inhibitor. If disease flare occurs, restart ALK inhibitor.
NSCL-23
(NCCN®

Progression on
crizotinibaaa,bbb
Progression,
Lorlatinibeee or See
Initial systemic
therapy optionsww
Adenocarcinoma
(NSCL-32) or
Squamous Cell
Carcinoma (NSCL-33)
SABR or surgery) for limited lesionsm
• Continue crizotinib
or
Alectinibpp,ccc,ddd or brigatinibpp,ccc,ddd or
ceritinibpp,ccc,ddd
Symptomatic
Asymptomatic
Brain
Systemic
SRS) for limited lesionsm
• Alectinibpp,ccc,ddd or brigatinibpp,ccc,ddd
or ceritinibpp,ccc,ddd
Isolated
lesion
Multiple
lesions
SABR or surgery)m
• Continue crizotinib
• Alectinibpp,ccc,ddd or brigatinibpp,ccc,ddd
or ceritinibpp,ccc,ddd
or
• See Initial systemic therapy optionsww
oo See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease
(NSCL-I).
ww The data in the second-line setting suggest that PD-1/PD-L1 inhibitor
monotherapy is less effective, irrespective of PD-L1 expression, in EGFR+/ALK+
aaa Beware of flare phenomenon in subset of patients who discontinue ALK
inhibitor. If disease flare occurs, restart ALK inhibitor.
bbb Patients who are intolerant to crizotinib may be switched to ceritinib, alectinib,
or brigatinib.
ccc If not previously given.
ddd Ceritinib, alectinib, or brigatinib are treatment options for patients with ALK-
positive metastatic NSCLC that has progressed on crizotinib.
eee Lorlatinib is a treatment option after progression on crizotinib and either
Table of Contents
Discussion
NSCLC. alectinib, brigatinib, or ceritinib.
NSCL-24
(NCCN®

ROS1 REARRANGEMENT POSITIVEjj
FIRST-LINE THERAPYoo SUBSEQUENT THERAPYoo
ROS1
rearrangement
positive
Preferred
Crizotinibpp
or
Entrectinibpp
Other Recommended
Ceritinibpp
Progressionfff
Lorlatinib
or
ROS1 rearrangement
discovered prior to
first-line systemic
therapy
ROS1 rearrangement
discovered during
first-line systemic
therapy
Complete planned
systemic therapy,
including maintenance
therapy, or interrupt,
followed by crizotinib
(preferred) or entrectinib
(preferred) or ceritinib
Lorlatinib
or
Progressionfff
Table of Contents
Discussion
fff Beware of flare phenomenon in subset of patients who discontinue TKI. If disease flare occurs, restart TKI inhibitor.
NSCL-25
(NCCN®

BRAF V600E MUTATION POSITIVEjj
BRAF V600E
mutation
positive
Preferred
Dabrafenib + trametinib
Other Recommendedggg
Vemurafenib
or
Dabrafenib
Progression
See Initial systemic therapy
options
Squamous Cell Carcinoma
(NSCL-33)
Progression Dabrafenib + trametinibggg
BRAF V600E
mutation discovered
during first-line
systemic therapy
Complete planned
systemic therapy, including
dabrafenib +
trametinibggg
Progression
options
(NSCL-33)
BRAF V600E
mutation discovered
prior to first-line
systemic therapy
Table of Contents
Discussion
ggg Single-agent vemurafenib or dabrafenib are treatment options if the combination of dabrafenib + trametinib is not tolerated.
NSCL-26
(NCCN®

NTRK GENE FUSION POSITIVEjj
NTRK gene
fusion
positive
Preferred
or
Entrectinibpp
Larotrectinibpp
Progression
options
Adenocarcinoma (NSCL-32)
or Squamous Cell Carcinoma
(NSCL-33)
Progression Larotrectinib
or
Entrectinib
NTRK gene fusion
discovered during
first-line systemic
therapy
Complete planned
larotrectinib or
entrectinib
Progression
options
or Squamous Cell Carcinoma
(NSCL-33)
NTRK gene fusion
discovered prior to
first-line systemic
therapy
Table of Contents
Discussion
NSCL-27
(NCCN®

MET EXON 14 SKIPPING MUTATION
MET exon
14 skipping
mutation
Preferred
Capmatinib
Crizotinib
or
Progression
See Initial systemic
therapy options
(NSCL-33)
Progression
Preferred
Capmatinib
Crizotinib
MET exon 14 skipping
mutation discovered
during first-line
systemic therapy
Complete planned
capmatinib or
crizotinib
Progression
options
(NSCL-33)
MET exon 14 skipping
mutation discovered
prior to first-line
systemic therapy
Progression
Table of Contents
Discussion
NSCL-28
(NCCN®

RET REARRANGEMENT POSITIVE
RET
rearrangement
positive
Preferred
Selpercatinib
Cabozantinib
or
Vandetanib
(category
2B)
Other Recommended
options
(NSCL-33)
Preferred
Selpercatinib
or
Cabozantinib
or
Vandetanib (category 2B)
Progression
RET rearrangement
discovered during
first-line systemic
therapy
Complete planned
selpercatinib, cabozantinib, or
vandetanib (category 2B)
Progression
options
(NSCL-33)
RET rearrangement
discovered prior to
first-line systemic
therapy
Progression
Progression
Table of Contents
Discussion
NSCL-29
(NCCN®

PD-L1 EXPRESSION POSITIVE (≥50%)jj FIRST-LINE THERAPYoo
• Preferred
Pembrolizumab (category 1)
or
(Carboplatin or cisplatin) +
pemetrexed +
pembrolizumab (category 1)
or
Atezolizumab
• Other
Recommende
d
Carboplatin +
paclitaxel +
bevacizumab
ss
+
atezolizumab
(category 1)
or
Carboplatin + albumin-bound paclitaxel +
atezolizumab
or
Nivolumab + ipilimumab + pemetrexed +
(carboplatin or cisplatin)
• Useful in Certain Circumstances
Nivolumab + ipilimumab
• Preferred
Pembrolizumab (category 1)
PD-L1 expression
positive (≥50%)
and EGFR, ALK,
ROS1, BRAF, MET
exon 14 skipping
mutation, and RET
negative and no
contraindications
to PD-1 or PD-L1
inhibitorshhh
PS 0–2
Adenocarcinoma,
large cell,
NSCLC NOS
Squamous cell
carcinoma
or
Carboplatin + (paclitaxel or albumin-bound
paclitaxel) + pembrolizumab (category 1)
or
Atezolizumab
• Other Recommended
Nivolumab + ipilimumab + paclitaxel +
carboplatin
Continuation maintenanceoo
• Pembrolizumab (category 1)iii
• Pembrolizumab + pemetrexed
(category 1)jjj
• Atezolizumab and
bevacizumab (category 1)kkk
• Atezolizumablll
Progression
See Systemic Therapy or
Subsequent Therapy,mmm
• Pembrolizumab
(category 1)iii,nnn
• Atezolizumablll
Response
or stable
disease
Progression
(NSCL-33)
hhh Useful in Certain Circumstances: Contraindications for treatment with PD-1/PD-L1
inhibitors may include active or previously documented autoimmune disease and/or
current use of immunosuppressive agents or presence of an oncogene, which
would predict lack of benefit. If there are contraindications,
iii If pembrolizumab monotherapy given.
jjj If pembrolizumab/carboplatin/pemetrexed or pembrolizumab/cisplatin/pemetrexed given.
kkk If atezolizumab/carboplatin/paclitaxel/bevacizumab given.
lll If atezolizumab/carboplatin/albumin-bound paclitaxel or atezolizumab given.
mmm If patient has not received platinum-doublet chemotherapy, refer to "systemic therapy."
If patient received platinum chemotherapy and anti-PD-1/PD-L1, refer to “subsequent
therapy.”
Response
or stable
disease
See PD-L1 expression
positive (≥1%–49%) NSCL-31
Table of Contents
Discussion
nnn If pembrolizumab/carboplatin/(paclitaxel or albumin-bound paclitaxel) given.
refer to NSCL-32 (adenocarcinoma) or NSCL-33 (squamous cell
carcinoma).
NSCL-30
(NCCN®

PD-L1 EXPRESSION POSITIVE (≥1%–49%)jj FIRST-LINE THERAPYoo
• Preferred
(Carboplatin or cisplatin) + pemetrexed
+ pembrolizumab
(category 1)
Carboplatin + paclitaxel +
bevacizumabss + atezolizumab
(category 1)
or
Carboplatin + albumin-bound
paclitaxel
+ atezolizumab
or
Nivolumab +
ipilimumab +
pemetrexed
+ (carboplatin
or cisplatin)
or
Pembrolizumab (category 2B)ooo
PD-L1 expression
positive (≥1%–49%)
and EGFR, ALK,
ROS1, BRAF, MET
exon 14 skipping
mutation, and RET
negative and no
contraindications
to PD-1 or PD-L1
inhibitorshhh
Adenocarcinoma,
large cell,
NSCLC NOS
Squamous cell
carcinoma
• Preferred
Carboplatin + (paclitaxel or albumin-
bound paclitaxel) + pembrolizumab
(category 1)
Nivolumab + ipilimumab + paclitaxel
+ carboplatin
or
Pembrolizumab (category 2B)ooo
PS 0–2
• Pembrolizumab (category 1)iii
(category 1)jjj
bevacizumab (category 1)kkk
• Atezolizumablll
Progression
• Pembrolizumabiii,nnn
Response
or stable
disease
Progression
(NSCL-33)
jj See Principles of Molecular and Biomarker Analysis (NSCL-
G).
hhh Useful in Certain Circumstances: Contraindications for treatment with PD-1/PD-L1
inhibitors may include active or previously documented autoimmune disease and/or
current use of immunosuppressive agents or presence of an oncogene, which
would predict lack of benefit. If there are contraindications,
refer to NSCL-32 (adenocarcinoma) or NSCL-33 (squamous cell carcinoma).
jjj If pembrolizumab/carboplatin/pemetrexed or pembrolizumab/cisplatin/pemetrexed given.
lll If atezolizumab/carboplatin/albumin-bound paclitaxel given.
mmm If patient has not received platinum-doublet chemotherapy, refer to "systemic therapy."
If patient received platinum chemotherapy and anti-PD-1/PD-L1, refer to “subsequent
therapy.”
nnn If pembrolizumab/carboplatin/(paclitaxel or albumin-bound paclitaxel) given.
ooo Pembrolizumab monotherapy can be considered in PD-L1 1%–49%, in patients with
Response
or stable
disease
See PD-L1 expression
positive (≥50%) NSCL-30
Table of Contents
Discussion
iii If pembrolizumab monotherapy given. poor PS or other contraindications to combination
chemotherapy.
NSCL-31
(NCCN®

c Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with
metastatic non-small cell lung cancer. N Engl J Med 2010;363:733-742.
NSCLC.
jjj If pembrolizumab/carboplatin/pemetrexed or pembrolizumab/cisplatin/
pemetrexed given.
lll If atezolizumab/carboplatin/albumin-bound paclitaxel given.
ppp See Systemic Therapy for Advanced or Metastatic Disease (NSCL-J).
qqq In general, four cycles of initial systemic therapy (ie, with carboplatin or
cisplatin) are administered prior to maintenance therapy. However, if patient is
tolerating therapy well, consideration can be given to continue to 6 cycles.
rrr If progression on PD-1/PD-LI inhibitor, switching to another PD-1/PD-L1
inhibitor
is not recommended.
sss Pembrolizumab is approved for patients with NSCLC tumors with PD-L1
ttt If bevacizumab was used with a first-line pemetrexed/platinum chemotherapy
regimen.
uuu If not already given, options for PS 0–2 include (nivolumab, pembrolizumab, or
atezolizumab), docetaxel (category 2B), pemetrexed (category 2B), gemcitabine
(category 2B), or ramucirumab + docetaxel (category 2B); options for PS 3–4
include best supportive care. Options for further progression are best supportive
ADENOCARCINOMA, LARGE CELL, NSCLC NOS
INITIAL SYSTEMIC THERAPY
PS 0–2
Systemic
therapyppp
Tumor
evaluation
response
ppp
Progression
Response
or stable
disease
PS 0–2
PS 3–4
4–6
cycles
(total)qqq
Response
or stable
disease
Progression See Subsequent Therapy, above
Progressionrrr,uuu
SUBSEQUENT THERAPY
Preferred (no previous IO):
Systemic immune checkpoint
inhibitorsc,ww,rrr
Nivolumab (category 1)
or pembrolizumab (category
1)sss
or atezolizumab (category 1)
Other Recommended (no previous IO or
previous IO):ccc
Docetaxel or pemetrexed or gemcitabine
or ramucirumab + docetaxel
Best supportive care
See NCCN Guidelines for Palliative Care
Continuation maintenanceppp
• Bevacizumab (category 1)
• Pemetrexed (category 1)
• Bevacizumab + pemetrexedttt
(category 1)jjj
kkk
or
ppp
bevacizumab (category 1)
• Atezolizumablll
• Gemcitabine (category 2B)
Switch maintenance
• Pemetrexed
Progression,
see
Subsequent
Therapy,
above
PS 3–4
See NCCN
Guidelines
for Palliative Care
Tumor
response
evaluationppp
Table of Contents
Discussion
expression levels ≥1%, as determined by an FDA-approved test. care or clinical trial.
NSCL-32
(NCCN®

SQUAMOUS CELL CARCINOMA
INITIAL SYSTEMIC THERAPY
Other Recommended (no previous
IO or previous IO):ccc
• Docetaxel or gemcitabine or
ramucirumab + docetaxel
SUBSEQUENT THERAPY
Preferred (no previous IO):
Systemic immune checkpoint
inhibitorsc,ww,rrr
• Nivolumab (category 1)
or pembrolizumab (category 1)sss
or atezolizumab (category 1)
Continuation maintenanceppp
• Pembrolizumabjjj
•Gemcitabine (category 2B)
or
Switch maintenanceppp
(category 2B)
• Docetaxel
c Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with
metastatic non-small cell lung cancer. N Engl J Med 2010;363:733-742.
NSCLC.
jjj If pembrolizumab/carboplatin/(paclitaxel or albumin-bound paclitaxel) given.
ppp See Systemic Therapy for Advanced or Metastatic Disease (NSCL-J).
qqq In general, four cycles of initial systemic therapy (ie, with carboplatin or
cisplatin) are administered prior to maintenance therapy. However, if patient is
rrr If progression on PD-1/PD-LI inhibitor, switching to another PD-1/PD-L1 inhibitor
is not recommended.
sss Pembrolizumab is approved for patients with NSCLC tumors with PD-L1
expression levels ≥1%, as determined by an FDA-approved test.
vvv If not already given, options for PS 0-2 include (nivolumab, pembrolizumab,
or atezolizumab), docetaxel (category 2B), gemcitabine (category 2B), or
ramucirumab + docetaxel (category 2B); options for PS 3-4 include best
supportive care. Options for further progression are best supportive care or
PS 0–2
Progression
Response
or stable
disease
See Subsequent Therapy, above
Progression,
see
Subsequent
Therapy,
above
PS 3–4
See NCCN
Guidelines
for Palliative Care
PS 0–2
Systemic
therapyppp
Tumor
evaluation
response
ppp
Progression
PS 3–4
See NCCN Guidelines for Palliative Care
Progressionrrr,vvv
Response
or stable
disease
4–6
cycles
(total)qqq
Tumor
response
evaluationppp
Table of Contents
Discussion
tolerating therapy well, consideration can be given to continue to 6 cycles. clinical trial.
NSCL-33
(NCCN®

PRINCIPLES OF MOLECULAR AND BIOMARKER ANALYSIS
• Molecular Targets for Analysis
In general, the mutations/alterations described below are seen in a non-overlapping fashion, although between 1%–3% of NSCLC may
harbor concurrent alterations.
EGFR (Epidermal Growth Factor Receptor) Gene Mutations: EGFR is a receptor tyrosine kinase normally found on the surface of epithelial
cells and is often overexpressed in a variety of human malignancies.
The most commonly described mutations in EGFR (exon 19 deletions, p.L858R point mutation in exon 21) are associated with
responsiveness to EGFR tyrosine kinase inhibitor (TKI) therapy; most recent data indicate that tumors that do not harbor a sensitizing
EGFR mutation should not be treated with EGFR TKI in any line of therapy.
Many of the less commonly observed alterations in EGFR, which cumulatively account for ~10% of EGFR-mutated NSCLC (ie, exon
19 insertions, p.L861Q, p.G719X, p.S768I) are also associated with responsiveness to EGFR TKI therapy, although the number of
studied patients is lower.
Some mutations in EGFR are associated with lack of responsiveness to EGFR TKI therapy, including most EGFR exon 20 insertions,
and
p.T790M.
– Most EGFR exon 20 insertion mutations predict resistance to clinically achievable levels of TKIs. The exception is a rare EGFR exon
20 insertion variant, p.A763_Y764insFQEA, which is associated with responsiveness to EGFR TKI therapy. Therefore, knowledge of an
EGFR exon 20 insertion must be included in the specific sequence alteration.
– The finding of p.T790M is most commonly associated with relapse following initial therapy with EGFR TKI, which is a known
mechanism of resistance. If identified prior to TKI exposure, genetic counseling should be considered, because germline p.T790M is
associated with familial lung cancer predisposition and additional testing is warranted.
As use of NGS testing increases, additional EGFR variants are increasingly identified; however, the clinical implications of individual
alterations are unlikely to be well established.
Some clinicopathologic features—such as smoking status, ethnicity, and histology—are associated with the presence of an EGFR
mutation; however, these features should not be utilized in selecting patients for testing.
Testing Methodologies: Real-time PCR, Sanger sequencing (ideally paired with tumor enrichment), and NGS are the most commonly
deployed methodologies for examining EGFR mutation status.
ALK (Anaplastic Lymphoma Kinase) Gene Rearrangements: ALK is a receptor tyrosine kinase that can be rearranged in NSCLC, resulting
in dysregulation and inappropriate signaling through the ALK kinase domain.
The most common fusion partner seen with ALK is echinoderm microtubule-associated protein-like 4 (EML4), although a variety of
other
fusion partners have been identified.
The presence of an ALK rearrangement is associated with responsiveness to ALK TKIs, with recent studies demonstrating improved
efficacy of alectinib over crizotinib in the first-line setting.
Some clinicopathologic features—such as smoking status and histology—have been associated with the presence of an ALK
rearrangement; however, these features should not be utilized in selecting patients for testing.
Testing Methodologies: FISH break-apart probe methodology was the first methodology deployed widely. IHC can be deployed as an
effective screening strategy. FDA-approved IHC (ALK [D5F3] CDx Assay) can be utilized as a stand-alone test, not requiring confirmation
by FISH. Numerous NGS methodologies can detect ALK fusions. Targeted real-time PCR assays are used in some settings, although it is
unlikely to detect fusions with novel partners.
Table of Contents
Discussion
Continued
NSCL-G
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 ROS1 (ROS proto-oncogene 1) Gene Rearrangements: ROS1 is a receptor tyrosine kinase that can be rearranged in NSCLC, resulting i
n
dysregulation and inappropriate signaling through the ROS1 kinase domain.
Numerous fusion partners are seen with ROS1, and common fusion partners include: CD74, SLC34A2, CCDC6, and FIG.
The presence of a ROS1 rearrangement is associated with responsiveness to oral ROS1 TKIs.
Some clinicopathologic features—such as smoking status and histology—have been associated with the presence of a ROS1
rearrangement;
however, these features should not be utilized in selecting patients for testing.
Testing Methodologies: FISH break-apart probe methodology can be deployed; however, it may under-detect the FIG-ROS1 variant. IHC
approaches can be deployed; however, IHC for ROS1 fusions has low specificity, and follow-up confirmatory testing is a necessary component
of utilizing ROS1 IHC as a screening modality. Numerous NGS methodologies can detect ROS1 fusions, although DNA-based NGS may under-
detect ROS1 fusions. Targeted real-time PCR assays are utilized in some settings, although they are unlikely to detect fusions with novel
partners.
BRAF (B-Raf proto-oncogene) point mutations: BRAF is a serine/threonine kinase that is part of the canonical MAP/ERK signaling pathway.
Activating mutations in BRAF result in unregulated signaling through the MAP/ERK pathway.
Mutations in BRAF can be seen in NSCLC. The presence of a specific mutation resulting in a change in amino acid position 600 (p.V600E) has
been associated with responsiveness to combined therapy with oral inhibitors of BRAF and MEK.
Note that other mutations in BRAF are observed in NSCLC, and the impact of those mutations on therapy selection is not well understood at
this time.
Testing Methodologies: Real-time PCR, Sanger sequencing (ideally paired with tumor enrichment), and NGS are the most commonly deployed
methodologies for examining BRAF mutation status. While an anti-BRAF p.V600E-specific monoclonal antibody is commercially available, and
some studies have examined utilizing this approach, it should only be deployed after extensive validation.
 KRAS (KRAS proto-oncogene) point mutations: KRAS is a G-protein with intrinsic GTPase activity, and activating mutations result in unregulated
signaling through the MAP/ERK pathway.
Mutations in KRAS are most commonly seen at codon 12, although other mutations can be seen in NSCLC.
The presence of a KRAS mutation is prognostic of poor survival when compared to patients with tumors without KRAS mutation.
Mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy.
Owing to the low probability of overlapping targetable alterations, the presence of a known activating mutation in KRAS identifies patients who
are unlikely to benefit from further molecular testing.
NTRK (neurotrophic tyrosine receptor kinase) gene fusions
NTRK 1/2/3 are tyrosine receptor kinases that are rarely rearranged in NSCLC as well as in other tumor types, resulting in dysregulation and
inappropriate signaling.
Numerous fusion partners have been identified.
To date, no specific clinicopathologic features, other than absence of other driver alterations, have been identified in association with these
fusions.
Testing Methodologies: Various methodologies can be used to detect NTRK gene fusions, including: FISH, IHC, PCR, and NGS; false negatives
may occur. IHC methods are complicated by baseline expression in some tissues. FISH testing may require at least 3 probe sets for full
analysis. NGS testing can detect a broad range of alterations. DNA-based NGS may under-detect NTRK1 and NTRK3 fusions.
Table of Contents
Discussion
Continued
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• Testing in the Setting of Progression on Targeted Therapy:
For many of the above listed analytes, there is growing recognition of the molecular mechanisms of resistance to therapy. Re-testing of a
sample from a tumor that is actively progressing while exposed to targeted therapy can shed light on appropriate next therapeutic steps:
For patients with an underlying EGFR sensitizing mutation who have been treated with EGFR TKI, minimum appropriate testing
includes high-sensitivity evaluation for p.T790M; when there is no evidence of p.T790M, testing for alternate mechanisms of resistance
(MET amplification, ERBB2 amplification) may be used to direct patients for additional therapies. The presence of p.T790M can direct
patients to third-generation EGFR TKI therapy.
– Assays for the detection of EGFR p.T790M should be designed to have an analytic sensitivity of a minimum of 5% allelic fraction. The
original sensitizing mutation can be utilized as an internal control in many assays to determine whether a p.T790M is within the
range of detection if present as a sub-clonal event.
For patients with underlying ALK rearrangement who have been treated with ALK TKI, it is unclear whether identification of specific
tyrosine kinase domain mutation can identify appropriate next steps in therapy, although some preliminary data suggest that specific
kinase domain mutations can impact next line of therapy.
• PD-L1 (Programmed Death Ligand 1): PD-L1 is a co-regulatory molecule that can be expressed on tumor cells and inhibit T-cell–mediated
cell death. T-cells express PD-1, a negative regulator, which binds to ligands including PD-L1 (CD274) or PD-L2 (CD273). In the presence of
PD-L1, T-cell activity is suppressed.
Checkpoint inhibitor antibodies block the PD-1 and PD-L1 interaction, thereby improving the antitumor effects of endogenous T cells.
IHC for PD-L1 can be utilized to identify disease most likely to respond to first-line anti PD-1/PD-L1.
Various antibody clones have been developed for IHC analysis of PD-L1 expression, and while several show relative equivalence,
some
do not.
Interpretation of PD-L1 IHC in NSCLC is typically focused on the proportion of tumor cells expressing membranous staining at any
level and therefore is a linear variable, scoring systems may be different in other tumor types.
The FDA-approved companion diagnostic for PD-L1 guides utilization of pembrolizumab in patients with NSCLC and is based on
the tumor proportion score (TPS). TPS is the percentage of viable tumor cells showing partial or complete membrane staining at
any intensity.
The definition of positive and negative testing is dependent on the individual antibody and platform deployed, which may be unique to
each checkpoint inhibitor therapy. The potential for multiple different assays for PD-L1 has raised concern among both pathologists and
oncologists.
Although PD-L1 expression can be elevated in patients with an oncogenic driver, targeted therapy for the oncogenic driver should take
precedence over treatment with an immune checkpoint inhibitor.
Table of Contents
Discussion
Continued
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• Plasma Cell-Free/Circulating Tumor DNA Testing:
Cell-free/circulating tumor DNA testing should not be used in lieu of a histologic tissue diagnosis.
Some laboratories offer testing for molecular alterations examining nucleic acids in peripheral circulation, most commonly in processed
plasma (sometimes referred to as "liquid biopsy").
Studies have demonstrated cell-free tumor DNA testing to generally have very high specificity, but significantly compromised sensitivity,
with up to 30% false-negative rate.
Standards for analytical performance characteristics of cell-free tumor DNA have not been established, and in contrast to tissue-based
testing, no guidelines exist regarding the recommended performance characteristics of this type of testing.
Cell-free tumor DNA testing can identify alterations that are unrelated to a lesion of interest, for example, clonal hematopoiesis o
f
indeterminate potential (CHIP).
The use of cell-free/circulating tumor DNA testing can be considered in specific clinical circumstances, most notably:
If a patient is medically unfit for invasive tissue sampling
In the initial diagnostic setting, if following pathologic confirmation of a NSCLC diagnosis there is insufficient material for molecular
analysis, cell-free/circulating tumor DNA should be used only if follow-up tissue-based analysis is planned for all patients in which an
oncogenic driver is not identified
Table of Contents
Discussion
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1Ou SH, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small
cell lung cancer patient with de novo MET amplification. J Thorac Oncol 2011;6:942-946.
2Camidge RD, Ou S-HI, Shapiro G, et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer. J Clin Oncol 2014;32(Suppl 5): Abstract
8001.
3Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: Results from a phase II basket trial. J Clin Oncol 2018;36:2532-2537.
4Hellmann MD, Ciuleanu TE, Pluzanski A et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018; 378:2093-2104.
5Carbone DP
, Reck M, Paz-Ares L et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376:2415-2426.
EMERGING BIOMARKERS TO IDENTIFY NOVEL THERAPIES FOR PATIENTS WITH METASTATIC NSCLC
Genetic Alteration (ie, Driver event) Available Targeted Agents with
Activity Against Driver Event in Lung
Cancer
High-level MET amplification Crizotinib1-2
ERBB2 (HER2) mutations Ado-trastuzumab emtansine3
Tumor mutational burden (TMB)* Nivolumab +
ipilimumab4
Nivolumab5
*TMB is an evolving biomarker that may be helpful in selecting patients for immunotherapy.
There is no consensus on how to measure TMB.
Table of Contents
Discussion
NSCL-H
(NCCN®

TARGETED THERAPY OR IMMUNOTHERAPY FOR ADVANCED OR METASTATIC DISEASE
Monitoring During Initial Therapy
•Response assessment after 2 cycles, then every 2–4 cycles with CT of known sites of disease with or without contrast or when clinically
indicated. Monitoring During Subsequent Therapy
• Response assessment with CT of known sites of disease with or without contrast every 6–12 weeks. Timing of CT scans within
Guidelines parameters is a clinical decision.
Sensitizing EGFR Mutation Positive
• First-line therapy
Afatinib1
Erlotinib2
Dacomitinib3
Gefitinib4,5
Osimertinib6
Erlotinib + ramucirumab7
Erlotinib + bevacizumab (nonsquamous)8
• Subsequent therapy
Osimertinib9
ALK Rearrangement Positive
Alectinib10,11
Brigatinib12
Ceritinib13
Crizotinib10,14
Alectinib15,16
Brigatinib17
Ceritinib18
Lorlatinib19
ROS1 Rearrangement Positive
Ceritinib20
Crizotinib21
Entrectinib22
BRAF V600E Mutation Positive
Dabrafenib/trametinib23
Dabrafenib/trametinib24,25
NTRK Gene Fusion Positive
• First-line/Subsequent therapy
Larotrectinib26
Entrectinib27
MET Exon 14 Skipping Mutation
• First-line therapy/Subsequent therapy
Capmatinib28
Crizotinib29
RET Rearrangement Positive
• First-line therapy/Subsequent therapy
Selpercatinib30
Cabozantinib31,32
Vandetanib33
PD-L1 ≥1%
• First-line therapy*
Pembrolizumab34-36
(Carboplatin or cisplatin)/pemetrexed/
pembrolizumab (nonsquamous)37
Carboplatin/paclitaxel/bevacizumab**/
atezolizumab (nonsquamous)38
Carboplatin/(paclitaxel or albumin-bound
paclitaxel)/pembrolizumab (squamous)39
Carboplatin/albumin-bound paclitaxel/
atezolizumab (nonsquamous)40
Nivolumab/ipilimumab41
Nivolumab + ipilimumab + pemetrexed +
(carboplatin or cisplatin) (nonsquamous)42
Nivolumab + ipilimumab + paclitaxel +
carboplatin (squamous)42
PD-L1 ≥50%
Atezolizumab43
References
*Continuation maintenance refers to the use of at least one of the agents given in first line, beyond 4–6 cycles, in the absence of disease progression.
**An FDA-approved biosimilar is an appropriate substitute for bevacizumab.
Table of Contents
Discussion
NSCL-I
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(NCCN®

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE
Monitoring During Initial Therapy
• Response assessment after 2 cycles, then every 2–4 cycles with CT of known sites of disease with or without contrast or when clinically
indicated.
Maintenance Therapy
• Continuation maintenance refers to the use of at least one of the agents given in first line, beyond 4–6 cycles, in the absence of disease
progression. Switch maintenance refers to the initiation of a different agent, not included as part of the first-line regimen, in the absence of
disease progression, after 4–6 cycles of initial therapy.
• Patients should receive maintenance therapy for 2 years if they received front-line immunotherapy.
•Patients should receive maintenance therapy until progression if they received second-line immunotherapy.
Monitoring During Subsequent Therapy
• Response assessment with CT of known sites of disease with or without contrast every 6–12 weeks. Timing of CT scans within Guidelines
parameters is a clinical decision.
See Initial Systemic Therapy Options for Adenocarcinoma,
Large Cell, NSCLC NOS on NSCL-J (2 of 4)
See Initial Systemic Therapy Options for
Squamous Cell Carcinoma on NSCL-J (3 of 4)
Continued
Table of Contents
Discussion
NSCL-J
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(NCCN®

e 3,d,f,g,h
ADENOCARCINOMA, LARGE CELL, NSCLC NOS (PS 0–1)
No contraindications to PD-1 or PD-L1 inhibitorsc
Preferred
• Pembrolizumab/carboplatin/pemetrexed (category 1)1,2,d
• Pembrolizumab/cisplatin/pemetrexed (category 1)2,d
Other Recommended
• Atezolizumab/carboplatin/paclitaxel/bevacizumab (category 1)
• Atezolizumab/carboplatin/albumin-bound paclitaxel4,d
• Nivolumab + ipilimumab5,d
• Nivolumab + ipilimumab + pemetrexed + (carboplatin or cisplatin)6,d
Contraindications to PD-1 or PD-L1 inhibitorsc
• Bevacizumabe/carboplatin/paclitaxel (category 1)7,f,g,h
• Bevacizumabe/carboplatin/pemetrexed7,8,f,g,h
• Bevacizumabe/cisplatin/pemetrexed9,f,g,h
• Carboplatin/albumin-bound paclitaxel (category 1)10
• Carboplatin/docetaxel (category 1)11
• Carboplatin/etoposide (category 1)12,13
• Carboplatin/gemcitabine (category 1)14
• Carboplatin/paclitaxel (category 1)15
• Carboplatin/pemetrexed (category 1)16
• Cisplatin/docetaxel (category 1)11
• Cisplatin/etoposide (category 1)17
• Cisplatin/gemcitabine (category 1)15,18
• Cisplatin/paclitaxel (category 1)19
• Cisplatin/pemetrexed (category 1)18
• Gemcitabine/docetaxel (category 1)20
• Gemcitabine/vinorelbine (category 1)21
a Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in
patients who have experienced hypersensitivity reactions after receiving paclitaxel or
docetaxel despite premedication, or for patients where the standard premedications (ie,
dexamethasone, H2 blockers, H1 blockers) are contraindicated.
b Carboplatin-based regimens are often used for patients with comorbidities or those who
cannot tolerate cisplatin.
c Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously
documented autoimmune disease and/or current use of immunosuppressive agents or
presence of an oncogene, which would predict lack of benefit.
ADENOCARCINOMA, LARGE CELL, NSCLC NOS (PS 2)
Preferred
• Carboplatin/pemetrexed16
Other Recommended
• Carboplatin/albumin-bound paclitaxel23,24
• Carboplatin/docetaxel11
• Carboplatin/etoposide12,13
• Carboplatin/gemcitabine14
• Carboplatin/paclitaxel15
• Albumin-bound paclitaxel22
• Docetaxel25,26
• Gemcitabine27-29
• Gemcitabine/docetaxel20
• Gemcitabine/vinorelbine21
• Paclitaxel30-32
• Pemetrexed33
d If progression on PD-1/PD-L1 inhibitor, switching to another PD-1/PD-L1 inhibitor is not
recommended.
e An FDA-approved biosimilar is an appropriate substitute for bevacizumab.
f Bevacizumab should be given until progression.
g Any regimen with a high risk of thrombocytopenia and the potential risk of bleeding should
be used with caution in combination with bevacizumab.
h Criteria for treatment with bevacizumab: non-squamous NSCLC, and no recent history of
hemoptysis. Bevacizumab should not be given as a single agent, unless as maintenance if
initially used with chemotherapy.
SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE -- INITIAL SYSTEMIC THERAPY OPTIONSa,b
References
Table of Contents
Discussion
NSCL-J
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SQUAMOUS CELL CARCINOMA (PS 0–1)
No contraindications to PD-1 or PD-L1 inhibitorsc
Preferred
• Pembrolizumab/carboplatin/paclitaxel34,d (category 1)
• Pembrolizumab/carboplatin/albumin-bound paclitaxel34,d
(category 1)
Other recommended
• Nivolumab + ipilimumab5,d
• Nivolumab + ipilimumab + paclitaxel + carboplatin6,d
Contraindications to PD-1 or PD-L1 inhibitorsc
• Carboplatin/albumin-bound paclitaxel (category 1)9
• Carboplatin/docetaxel (category 1)11
• Carboplatin/gemcitabine (category 1)14
• Carboplatin/paclitaxel (category 1)15
• Cisplatin/docetaxel (category 1)11
• Cisplatin/etoposide (category 1)17
• Cisplatin/gemcitabine (category 1)15,18
• Cisplatin/paclitaxel (category 1)19
• Gemcitabine/docetaxel (category 1)20
• Gemcitabine/vinorelbine (category 1)21
SQUAMOUS CELL CARCINOMA (PS 2)
Preferred
• Carboplatin/albumin-bound paclitaxel23,24
• Carboplatin/gemcitabine14
• Carboplatin/paclitaxel15
Other Recommended
• Carboplatin/docetaxel11
• Carboplatin/etoposide12,13
• Albumin-bound paclitaxel22
• Docetaxel25,26
• Gemcitabine27-29
• Gemcitabine/docetaxel20
• Gemcitabine/vinorelbine21
• Paclitaxel30-32
SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE -- INITIAL SYSTEMIC THERAPY OPTIONSa,b,i
References
a Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in patients who have experienced hypersensitivity reactions after receiving paclitaxel or
docetaxel despite premedication, or for patients where the standard premedications (ie, dexamethasone, H2 blockers, H1 blockers) are contraindicated.
b Carboplatin-based regimens are often used for patients with comorbidities or those who cannot tolerate cisplatin.
c Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of
immunosuppressive agents or presence of an oncogene, which would predict lack of benefit.
d If progression on PD-1/PD-L1 inhibitor, switching to another PD-1/PD-L1 inhibitor is not recommended.
i Cisplatin/gemcitabine/necitumumab in the first-line setting and afatinib in the second-line setting are not used at NCCN Member Institutions for these
indications related
to the efficacy and safety of these agents compared to the efficacy and safety of other available agents.
Table of Contents
Discussion
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Prinsip Terapi Bedah
Determination of resectability, surgical staging, and pulmonary
resection should be performed by thoracic surgeons who perform
lung cancer surgery as a prominent part of their practice.
• CT and PET/CT used for staging should be within 60 days before
proceeding with surgical evaluation.

Staging and
risk
assessment
Treatment recommendations for patients
with locoregional NSCLC, based on
imaging, invasive LN staging tests and
multidisciplinary assessment
*Category description according to CTimagingas in
ACCP staging document (Silvestri GAet al. Chest
2013;143(5
Suppl):e211S–50S)
**Refer to slide ‘Treatment: Locally advanced
NSCLC (stage III) – Resectable’

Brunelli Aet al. Eur Respir J 2009;34:17–
41.
Reprinted with permission from the
European Respiratory Society.
Staging and
risk
assessment
Preoperative respiratory
evaluation

Y
acoub WNet al. Semin Thorac
Cardiovasc Surg 2010;22:38–43.
Reprinted with permission from Elsevier.
Staging and
risk
assessment
Patients with clinical stage I lung cancer and
limited pulmonary function due to emphysema

Points
Weighted factors
Ischaemic heart disease* 1.5
History of cerebrovascular disease† 1.5
Serum creatinine > 2 mg/dL 1
Pneumonectomy planned 1.5
Class groupings
A 0
B 1–1.5
C 2–2.5
D > 2.5
Recalibrated thoracic revised cardiac
risk index
*Ischaemic heart disease: history of myocardial
infarction, history of positive exercise test,
current complaint of chest pain (myocardial
ischaemia),
nitrate therapy, ECG with pathological Q waves
†Cerebrovascular disease: transient ischaemic
attack, stroke
Adapted from Brunelli Aet al. Ann Thorac
Surg 2010;90:199–203
Staging and
risk
assessment

*Original RCRIweighted factors:high-risk surgery
(including lobectomy or pneumonectomy); ischaemic
heart disease (prior myocardial infarction, angina
pectoris); heart
failure; insulin-dependent diabetes; previous stroke or
TIA; creatinine > 2 mg/dL
Brunelli Aet al. Eur Respir J 2009;34:17–41.Reprinted
with permission from the European Respiratory
Society.
Staging and
risk
assessment
Preoperative cardiac evaluation

Pathology Anatomy
Pathologic evaluation is performed to determine the histologic
classification of lung tumors and relevant staging parameters.
• The World Health Organization (WHO) tumor classification system
provides the foundation for the classification of lung tumors, including
histologic subtype, staging factors, clinical featu res, molecular
characteristics, genetics, and epidemiology.1-3
• SCLC is a poorly differentiated neuroendocrine carcinoma.
Distinguishing SCLC from other neuroendocrine tumors, particularly
typical and atypical carcinoids, is important due to significant
differences in epidemiology, genetics, treatment, and prognosis.

Pathology Anatomy
SCLC is characterized by small blue cells with scant cytoplasm, high nuclear-to-
cytoplasmic ratio, granular chromatin, and absent or inconspicuous nucleoli.
SCLC cells are round, oval, or spindle-shaped with molding and high mitotic
counts.
The most useful characteristics for distinguishing SCLC from large-cell
neuroendocrine carcinoma (LCNEC) are the high nuclear-tocytoplasmic
ratio and paucity of nucleoli in SCLC.
• Careful counting of mitoses is essential, because it is the most important
histologic criterion for distinguishing SCLC from typical and atypical
carcinoids.
SCLC (>10 mitoses/2 mm2 field)
atypical carcinoid (2–10 mitoses/2 mm2 field)
typical carcinoid (0–1 mitoses/2 mm2 field)
Mitoses should be counted in the areas of highest activity and per 2 mm2 field,
rather than per 10 high-power fields.

Immunohistochemistry can be very helpful in diagnosing SCLC in
limited samples.
• Nearly all SCLCs are positive for cytokeratin antibody mixtures with
broad reactivity, such as AE1/AE3 and CAM5.2.
• The majority of SCLCs are reactive to markers of neuroendocrine
differentiation, including CD56/NCAM, synaptophysin, and
chromogranin A. Fewer than 10% of SCLCs are negative for all
neuroendocrine markers.
• Thyroid transcription factor-1 (TTF-1) is positive in 85% to 90% of
SCLCs.
• Ki-67 immunostaining can be very helpful in distinguishing SCLC
from carcinoid tumors, especially in small biopsy samples with
crushed or necrotic tumor cells in which counting mitotic figures is
difficult. The Ki-67 proliferative index in SCLC is typically 50% to 100%.

Biologi Molekular Lung Ca
• Lung Ca  85% NSCLC & 15% SCLC.
• NSCLC  Adenocarcinoma, Squamous Cell Carcinoma
• Lung Adenocarcinoma
• mutasi oncogenes terbanyak KRAS (Kristen Rat Sarcoma) dan EGFR (Epidermal Growth Factor)
• Mutasi tumor supresor gene : TP53, KEAP1, LKB1, NF1.
• TP53 jg hadir pada lbh dari 90% di LUSC
• CDKN2A (tumor supresor yg meregulasi siklus sel  inaktivasi pada 70% LUSC)
• MUTASI EGFR dan/atau translokasi ALK dan ROS1 tinggi pada yang bukan perokok. Sedangkan pada
perokok, mutasi KRAS dan TP53 lebih umum dijumpai.
• SCLC
• high grade neuroendocrine (NE) tumor. 75% SCLC mengekspresikan ASCL1 dan 15% mengekspresikan NEUROD1, di
mana kedunya meregulasikan diferensiasi neuronal dan NE.
• 90% pada SCLC kehilangan fungsi dari TP53 dan RB1
• Mutasi pada gene kinase pada SCLC adalah sedang, dan mutasi EGFR atau KRAS sangat jarang  FDA tidak
mengapproved target therapi pada SCLC.

Tumor Microenvironment (TME)
• Tdd dr : ekstraselular matrix, vaskular, jaringan limfatik, cancer associated
fibroblast, infiltrating host immune cell  perubahan genomic intrinsik
dimana premalignant atau sel neoplastik dapat memprogram ulang
kandungan dari TME u/ memfasilitasi carsinogenesis.
• Host immune cell  komponen kritikal dari TME, studi menyebutkan sel
imun trdpt di TME pada hampir lesi paru premalignan dan neoplastik .
• Inflamasi airway kronis brkontribusi pd perubahan patologis dari TME 
memfasilitasi inisiasi dan progersi kanker.
• Trjd DNA damage melalui ROS, memproduksi sitokin dan growth factor 
mengaktifkan jalur multiple tumorigenesis sprt NF-KB dan COX-2.

Perkembangan terapi lung cancer

Tatalaksana Locally advanced or metastatic
NSCLC : Targeted Therapy

EGFR
• 115.815 pasien dgn NSCLC  32.3% ditemukan mutasi EGFR dgn mayoritas trdpt deletion exon 19 (squence
LREA) atau mutasi exon 21 (40% L858R)  mengaktifkan domain TKI  sensitif terhadap small molecule
EGFR TKIs (Erlotinib, gefitinib, afatinib, osimertinib, dacomitinib).
• Rekomendasi ASCO dan ESMO  pasien NSCLC (adenocarcinoma) harus dinilai mutasi EGFR nya.
• Ktika ditemukan pasien dgn mutasi EGFR  terapi prtama menggunakan sensitizing EGFR TKI monoterapi.
(data menunjukan progression free survival lebih panjang) dibandingkan dengan penggunaan sitotoksik
sitemik terapi.
• Tidak responnya terapi EGFR TKI dihubungkan dengan mutasi KRAS dan BRAF dan fusi gene ALK atau ROS1.
pasien dgn mutasi insersi exon 20 juga biasanya resistant trhdp EGFR TKI
• EGFR T790M adalah mutasi yg dihubungkan dengan resisten dari terapi EGFR TKI dan dilaporkan trjd pd 60%
pasien dengan progresi penyakit stlh respon awal dari erlotinib, gefitinib atau afatinib.
• Resistensi dari EGFR TKI yg didapat juga dihubungkan dgn transforamsi dari NSCLC menjadi SCLC dan dengan
transisi epitelial menjadi mesencimal.
• IHK tdk direkomendasikan u/ menilai mutasi EGFR, namun mealui RT-PCR, sanger squencing dan NGS.
• Osimertinib first line EGFR TKI (category 1).

ALK (anaplastic lymphoma kinase)
• Fusi dari EML4 dan ALK melalui inversi kromosom 2p  teridentifikasi
pertama kali di ALK pada NSCLC. Saat ini variasi aktivasi fusi ALK tlh bnyk
dtmukan dimana mengarah pada aktivasi dari ALK kinase domain dan jalur
subsequent downstream (PI3K-AKT, JAK-STAT3, ERK/MAPK). Insidensi
bervariasi 3%-13%.
• Pasien dgn fusi ALK resistant trhdp EGFR TKIs.
• Pada pasien metastatic squamous cell NSCLC  testing fusi ALK
direkomendasikan oleh NCCN, menggunakan FISH test atau rapid
prescrening dgn IHK.
• Alectinib (generasi kedua ALK TKIs)  diinvestigasi lebih baik dibandingkan
crizotinib pd tatalaksana ALK rearranged NSCLC.

ROS1
• ROS1 adalah reseptor TK yg berbeda, namun sgt mirip dgn ALK dan
merupakan bagian dari keluarga reseptor insulin.
• ROS1 gene rearrangement trjd pd 1-2% dari pasien NSCLC, dan trlihat lbh
sring pada pasien dgn mutasi EGFR, KRAS dan fusi gen ALK yg negatif.
• Test ROS1 (categori 2A) dpt diprtimbangkan pd pasien metastasis NSCLC
squamous cell jika spesimen biopsi digunakan u/ menilai histologi atau
mixed histologi.  menggunakan FISH dan NGS.
• Crizotinib sgt efektif (70-80%) dgn respon komplit.
• Jika progresi trjd stlh terapi dgn crizotinib  rekomendasi lorlatinib
(generasi ke 3 TKI) atau inisial sistemik terapi (carboplatin/paclitaxel)

BRAF V600E Mutations
• BRAF adalah TK bagian dari MAP/ERK pada signaling pathway.
• Mutasi BRAF V600E umum dtemukan pada mutasi BRAF pd hampir seluruh jenis
tumor. Trjd 1-2% pada lung adenoca.
• Pasien dgn mutasi BRAF v600E biasanya perokok atau mantan perokok (brbeda
dgn mutasi EGFR atau fusi ALK yg biasanya non perokok).
• Test dianjurkan pd metastatic squamous cell NSCLC dgn menggunakan RT-PCR,
Sanger sequencing dan NGS.
• First line terapi  dabrafenib + trametinib. Jika kombinasi tdk dpt ditoleransi 
single agent menggunakan dabrafenib atau vemurafenib.
• Penggunaan regimen kemo jg dpt digunakan pada awal terapi sistemik
(carboplatin/pemetrexed)

NTRK gene Fusion
• Fusi gen NTRK mengkode protein fusi tropomyosin reseptor kinase
(TRK)  sbg driver oncogenik u/ solid tumor (lung, salivary gland,
thyroid, sarcoma).
• Fusi gen NTRK trjd pd 0.2% pasien dgn NSCLC.
• Metode u/ cek  FISH, IHK, NGS, PCR.
• First line  larotrectinib dan entrectinib.
• Fusi gen NTRK dpt diprtimbangkan u/ diperiksa jika driver utama
oncogenic negatif (EGFR, ALK, ROS1, BRAF)

MET Axon 14 skipping Mutations
• C-MET, reseptor HGF adalah TKR yg mrupakan bagian dari survival dan
proliferasi sel. Driver onkogenik perubahan genomik pada MET trmasuk
METex14 skiping mutations, MET gene copy number gain or amplification
dan MET protein overexpression.
• Trjd pd 3-4% pada pasien adenoca NSCLC dan 1-2% pd pasien dgn histologi
NSCLC lain.
• Bbrp tipe brbeda dari METex14 skipping mutasi dpt trjd, sprt mutasi,
substitusi base, dan deletions  sulit u/ ditest u/ mutasinya.
• NGS dan RT-PCR dpt dgunakan u/ mendeteksi METex14 skipping mutations.
• First line  capmatinib.

RET rearrangments
• RET adalah TKR yg mempengaruhi proliferasi dan diferensiasi sel. Fusi dpt
trjd pada NSCL antar gen RET dan domain lain, khususnya famili kinesin
5B (KIF5B) dan CCDC6  overekspresi protein RET.
• Trjd pd 1-2% pd pasien dgn NSCLC, dan lbh srg pd px dgn histologi
adenoca.
• Terjadi pada perokok dan non perokok.
• RET rearrangements dpt overlap dgn mutasi EGFR dan KRAS.
• Pasien dgn RET rearrangments memiliki minimal respon trhdp
imunoterapi.
• First line  selpercatinib.

Immunotherapy
• Terapi antibodi menargetkan T-cell receptor programmed cell death-1 (PD-1) dan
ligannya (PDL1)  di approved sbg monoterapi dan kombinasi dgn kemoterapi u/
advanced NSCLC.
• Mekanisme aksi : evasi dari sistem imun adaptif melalui disungsi sel T yg diinduksi
oleh reseptor inhibitor walaupun tumor mikroenvironment jg memainkan peran.
• Aktivasi Tcell membutuhkan APC oleh MHC kpd reseptor sel T dan trjd signal
kedua yg diperantarai oleh interaksi antara reseptor kostimulatory CD28 dan
CD80/CD8 pada APC.
• Cytotoxic T-lymphocyte antigen 4 (CTLA-4) adalah reseptor inhibitor yg ditemukan
pada efektor dan t sel regulator dimana akan berkompetisi dgn CD28 pada sel T
saat awal mula aktivasi imun.

PD-1/PDL-1
• Adalah reseptor inhibitor yg meupregulasi pada sel T setelah
eksposure antigen. Ikatan antara PD-1 dan ligannya PD-L1 
menurunkan fungsi efektor sel T.
• Ekspresi PD-1 didapati pada sel T dan B, makrofag, sel endotel, sel
ganas.
• Ekspresi PD-L1 diupregulasi oleh beberapa sitokin proinflamasi (INF-Y)
dan dpt mengunduksi sel tumor melalui aktivasi onkogene atau
penghambatan jalur supresi tumor.
• PD-1 dan PD-L1 blocking antibodi digunakan u/ tatalaksana NSCLC.

PDL-1 expression level
• Antibodi Human ICI (imuno-oncology) menhambat reseptor PD-1 atau
PD-L1 dimana memperbaiki imunitas antitumor. Reseptor PD-1
diekspresikan pada citotoksik sel T yang teraktifasi.
• Nivolumab dan pembrolizumab menghambat reseptor PD-1.
atezolizumab dan durvalumab menghambat PD-L1.
• Rekomendasi NCCN  IHK test u/ ekspresi PD-L1 dikerjakan sblm
treatment first line pd seluruh pasien dgn metastasis NSCLC.
• Diagnostik test u/ ekspresi PD-L1 brdasar tumor proportion score
(TPS). TPS adalah persentase dari sel tumor yg trlihat yg menunjukan
staining membran sebagian atau seluruhnya pada intensitas apapun.

BIOMARKER
• Suatu biomolekul yang timbul akibat suatu proses
fisiologis maupun patologis
• Biomarker yang ideal  suatu biomarker yang
tidak dapat dideteksi atau nilainya rendah dalam
keadaan non inflamasi & akan meningkat dalam
keadaan inflamasi yang selanjutnya akan
mengalami penurunan saat proses inflamasi
mereda
• Biomarker kanker  jaringan tumor/serum dan
mencakup luas berbagai molekul, termasuk DNA,
mRNA, enzim, metabolit, faktor transkripsi &
reseptor permukaan sel

KLASIFIKASI
BIOMARKER
Biomarker diagnostik  CYFRA 21-1 (Cytokeratin),
EPCAM (Molekul Adhesi Sel Epitel), ProGRP (Pro Gastrin
Releasing Peptide), CEA (Carcinoembryonic Antigen)
Biomarker Prognostik  microRNA (miRNA), CEA
(Carcinoembryonic antigen)
Biomarker Prediktif  EGFR, KRAS, BRAF, PDGFRA, KIT,
HER2, BCR-ABL, dan EML4-ALK
Biomarker terapeutik  protein yang dapat digunakan
sebagai target terapi  inhibitor tirosin kinase (TKIs)
dan antibodi monoklonal

KLASIFIKASI
BIOMARKER
Berdasarkan
aplikasi
klinis
Biomarker serologi  metode ELISA
(enzyme-linked immunosorbent assay)
dengan bahan darah (serum) pasien
Biomarker molekuler  menganalisis DNA,
semua molekul RNA, perubahan interaksi
protein dan respon imunologis
Biomarker pencitraan  Xray, Computed
Tomography (CT), PET, Single Photo Emission
Computed Tomography (SPECT) dan MRI

PROSES KARSINOGENESIS SEBAGAI ASAL BIOMARKER

Pezzuto Federica, Fortarezza, Lunardi Francesca et al. Are There Any Theranostic Biomarkers In Small Cell Lung Carcinoma?. 2019;1(11): S102–S112.6

Cicek Y, Kosar PA, Ozturk O. Molecular Genetics Of Lung Cancer. Eurasian J Pulmonol 2018; 20:111-7

BIOMARKER
SMALL CELL
LUNG
CANCER
(SCLC)
• Biomarker Molekuler SCLC
• DLL3 (Delta Like Canonical Notch Ligand 3)
• ProGRP (Pro Gastrin Releasing Peptide)
• Nilai normal Pro GRP  35 pgmL− 1
dan
pasien dengan tumor jinak  45-103
pgmL−1
• Biomarker Serologi SCLC
• NSE (Neuron Specific Enolase)  (nilai Normal
≤15 ng/ml. )
• CTCs (Circulating Tumors Cells)
• CEA

• Protein DLL3 baru-baru ini telah dipelajari sebagai biomarker potensial yang dapat
ditargetkan untuk SCLC
• Saunders et al (2015)  menunjukkan pengaturan dan ekspresi menyimpang dari DLL3
di SCLC  pengobatan anti DLL3 menghasilkan efek dalam memberantas sel-sel pemicu
tumor
• ProGRP ditemukan dalam plasma darah pasien SCLC dan kanker tiroid noduler
• NSE hanya spesifik untuk SCLC
• Hou et al  CTCs merupakan faktor prognostik yang independen untuk SCLC.
• Wang et al  hubungan antara kadar CTCs dan NSE serum tetapi tidak dengan respons
terapi

BIOMARKER
UNTUK
NSCLC
• The Epidermal Growth Factor Receptor (EFGR) dan Mutasi
T790M
• Limfoma Kinase Anaplastik (ALK)
• ROS1
• RET Proto-onkogen
• MET Proto-onkogen
• The discoidin domain receptor tyrosine kinase 2 gene (DDR2)
• The Fibroblast Growth Factor Receptor (FGFR)
• The Human Epidermal Growth Factor Receptor 2 Gene (HER)
• The B-RAF proto-oncogene, serine/threonine kinase (BRAF)
• Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit
alpha (PIK3CA)
Biomarker Molekuler NSCLC
• CEA
• CYFRA 21-1
Biomarker Serologi NSCLC

BIOMARKER
SPESIFIK
KARSINOMA
SEL
SKUAMOUS
• FGFR (Fibroblast Growth Factor
Receptor)
• Discoidin Domain Reseptor 2 (DDR2)
‐
MOLEKULAR
• CK-19 (sitokeratin-19)
• CYFRA 21-1 (sitokeratin fragmen-19)
• SCCA (Serum Squamosa Cell
Carcinoma Antigen)
SEROLOGI

• FGFR  Berfungsi sebagai reseptor permukaan sel untuk faktor pertumbuhan fibroblast,
memainkan peran penting dalam perkembangan embrionik, proliferasi sel, diferensiasi,
dan sebagai kontrol migrasi
• FGFR-1, FGFR-2, FGFR-3 dan FGFR-4.
• mutasi DDR2 terlihat pada 3%-4% dari karsinoma sel skuamosa
• Lee et al  biomarker CYFRA 21-1 meningkat pada karsinoma sel skuamosa.
• Lai et al  sensitivitas CYFRA 21-1 untuk karsinoma sel skuamosa, adenokarsinoma dan
karsinoma large cell masing-masing adalah 62%, 39%, dan 36%
• SCCA (Serum Squamosa Cell Carcinoma Antigen)  protein 48-kDa yang ditemukan pada
kanker paru skuamosa

BIOMARKER SPESIFIK
ADENOCARCINOMA
Molekular
• EGFR
• ERCC (Extracellular RNA Communication Programe)
• BRAF (B-Raf Proto Onkogene)
• RRM 1 (Ribonucleoside Difosfat Reduktase)
• KRAS (KRAS Proto Onkogen)
• RET (Proto-oncogene tyrosine-protein kinase receptor Ret)
• TS (Thymidylate Synthetase)
• ROS-1 (Reactive oxygen species-1)
• EML4-ALK (Echinoderm Microtubule Associated Protein-Like 4)
• Mikro RNA (miRNA)
SEROLOGI
• CEA NILAI NORMAL ≤5,2 ng/ml
• CYFRA 21-1 NILAI normal ≤ 3,3 ng/ml

Mikro RNA (miRNA)  molekul RNA kecil yang dikodekan oleh gen
microRNA.
• miR205 spesifik untuk karsinoma sel skuamos
• miR-124a spesifik untuk adenokarsinoma
penelitian metaanalisis terbaru  ekspresi miR-21 yang tinggi
dikaitkan dengan kelangsungan hidup yang rendah pada NSCLC
CEA secara signifikan lebih tinggi pada pasien dengan adenokarsinoma
dibandingkan dengan pasien dengan karsinoma sel skuamosa
Lee et al  CEA terutama meningkat pada adenokarsinoma sedangkan
CYFRA 21-1 meningkat pada karsinoma sel skuamosa.

BIOMARKER
SPESIFIK
LARGE CELL
CARCINOM
A
• LARGE CELL CARCINOMA adalah tumor epitel
ganas yang terdiri dari sel-sel poligon besar yang
tidak berdiferensiasi serta polimorfik secara
histologi
• Data tentang biomarker spesifik jenis kanker ini
belum ditemukan

BIOMARKER SPESIFIK
LARGE CELL
NEUROENDOCRINE
CARCINOMA
BIOMARKER yang umum diketahui
TOPSST (Topoisomerasis
Somatostatin Precursor)
ERCC1 (Excision Repair 1,
Endonuclease Non-Catalytic
Subunit)
Thyroid transcription factor-1
(TTF-1) dapat menjadi
penanda untuk membedakan
LCNEC dan bukan LCNEC
Sangat jarang dan sulit
terdiagnosis, sering menyerupai
NSCLC

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