© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 4 | April 2017
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 4 | April 2017
504
Rudy P. Lackner, MD; Michael Lanuti, MD; Ticiana A. Leal, MD;
Leah J. Leisch, MD; Rogerio Lilenbaum, MD; Jules Lin, MD;
Billy W. Loo Jr, MD, PhD; Renato Martins, MD, MPH;
Gregory A. Otterson, MD; Karen Reckamp, MD, MS;
Gregory J. Riely, MD, PhD; Steven E. Schild, MD;
Theresa A. Shapiro, MD, PhD; James Stevenson, MD;
Scott J. Swanson, MD; Kurt Tauer, MD; Stephen C. Yang, MD;
Kristina Gregory, RN, MSN, OCN; and Miranda Hughes, PhD
NCCN
Non–Small Cell
Lung Cancer,
Version 5.2017
Clinical Practice Guidelines in Oncology
David S. Ettinger, MD; Douglas E. Wood, MD, FRCSEd;
Dara L. Aisner, MD, PhD; Wallace Akerley, MD;
Jessica Bauman, MD; Lucian R. Chirieac, MD;
Thomas A. D’Amico, MD; Malcolm M. DeCamp, MD;
Thomas J. Dilling, MD, MS; Michael Dobelbower, MD, PhD;
Robert C. Doebele, MD, PhD; Ramaswamy Govindan, MD;
Matthew A. Gubens, MD, MS; Mark Hennon, MD;
Leora Horn, MD, MSc, FRCPC; Ritsuko Komaki, MD;
Abstract
This selection from the NCCN Guidelines for Non–Small Cell
Lung Cancer (NSCLC) focuses on targeted therapies and im-
munotherapies for metastatic NSCLC, because therapeutic
recommendations are rapidly changing for metastatic disease.
For example, new recommendations were added for atezoli-
zumab, ceritinib, osimertinib, and pembrolizumab for the
2017 updates.
J Natl Compr Canc Netw 2017;15(4):504–535
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there
is uniform NCCN consensus that the intervention is
appropriate.
Category 2A: Based upon lower-level evidence, there
is uniform NCCN consensus that the intervention is
appropriate.
Category 2B: Based upon lower-level evidence, there is
NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there
is major NCCN disagreement that the intervention is
appropriate.
All recommendations are category 2A unless otherwise
noted.
Clinical trials: NCCN believes that the best management for
any cancer patient is in a clinical trial. Participation in clinical
trials is especially encouraged.
Please Note
The NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines
®
) are a statement of consensus of the
authors regarding their views of currently accepted ap-
proaches to treatment. Any clinician seeking to apply or
consult the NCCN Guidelines
®
is expected to use indepen-
dent medical judgment in the context of individual clinical
circumstances to determine any patient’s care or treatment.
The National Comprehensive Cancer Network
®
(NCCN
®
)
makes no representation or warranties of any kind regarding
their content, use, or application and disclaims any respon-
sibility for their applications or use in any way.
© National Comprehensive Cancer Network, Inc.
2017, All rights reserved. The NCCN Guidelines and the
illustrations herein may not be reproduced in any form
without the express written permission of NCCN.
Disclosures for the Non–Small Cell Lung Cancer Panel
At the beginning of each NCCN Guidelines panel meeting, panel
members review all potential conicts of interest. NCCN, in keep-
ing with its commitment to public transparency, publishes these
disclosures for panel members, staff, and NCCN itself.
Individual disclosures for the NCCN Non–Small Cell Lung Cancer
Panel members can be found on page 535. (The most recent
version of these guidelines and accompanying disclosures are
available on the NCCN Web site at NCCN.org.)
These guidelines are also available on the Internet. For the
latest update, visit NCCN.org.
Overview
This selection from the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines) for
Non–Small Cell Lung Cancer (NSCLC) focuses
on targeted therapies and immunotherapies for
metastatic NSCLC, because new recommendations
were added for the 2017 updates. For example, new
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 4 | April 2017
Non–Small Cell Lung Cancer
NCCN
Guidelines
®
505
Journal of the National Comprehensive Cancer Network
Text cont. on page 515.
NCCN Non–Small Cell Lung Cancer Panel
Members
*David S. Ettinger, MD/Chair†
The Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins
*Douglas E. Wood, MD, FRCSEd/Vice Chair¶
Fred Hutchinson Cancer Research Center/
Seattle Cancer Care Alliance
Dara L. Aisner, MD, PhD≠
University of Colorado Cancer Center
Wallace Akerley, MD†
Huntsman Cancer Institute at the University of Utah
Jessica Bauman, MD‡
Fox Chase Cancer Center
Lucian R. Chirieac, MD≠
Dana-Farber/Brigham and Women’s Cancer Center
Thomas A. D’Amico, MD¶
Duke Cancer Institute
Malcolm M. DeCamp, MD¶
Robert H. Lurie Comprehensive Cancer Center of
Northwestern University
Thomas J. Dilling, MD, MS§
Moftt Cancer Center
Michael Dobelbower, MD, PhD§
University of Alabama at Birmingham
Comprehensive Cancer Center
Robert C. Doebele, MD, PhD†
University of Colorado Cancer Center
Ramaswamy Govindan, MD†
Siteman Cancer Center at Barnes-Jewish Hospital and
Washington University School of Medicine
Matthew A. Gubens, MD, MS†
UCSF Helen Diller Family Comprehensive Cancer Center
Mark Hennon, MD¶
Roswell Park Cancer Institute
Leora Horn, MD, MSc, FRCPC†
Vanderbilt-Ingram Cancer Center
Ritsuko Komaki, MD§
The University of Texas MD Anderson Cancer Center
Rudy P. Lackner, MD¶
Fred & Pamela Buffett Cancer Center
Michael Lanuti, MD¶
Massachusetts General Hospital Cancer Center
Ticiana A. Leal, MD†
University of Wisconsin Carbone Cancer Center
Leah J. Leisch, MDÞ
University of Alabama at Birmingham
Comprehensive Cancer Center
Rogerio Lilenbaum, MD†
Yale Cancer Center/Smilow Cancer Hospital
Jules Lin, MD¶
University of Michigan Comprehensive Cancer Center
Billy W. Loo Jr, MD, PhD§
Stanford Cancer Institute
Renato Martins, MD, MPH†
Fred Hutchinson Cancer Research Center/
Seattle Cancer Care Alliance
Gregory A. Otterson, MD†
The Ohio State University Comprehensive Cancer Center –
James Cancer Hospital and Solove Research Institute
Karen Reckamp, MD, MS†‡
City of Hope Comprehensive Cancer Center
Gregory J. Riely, MD, PhD†Þ
Memorial Sloan Kettering Cancer Center
Steven E. Schild, MD§
Mayo Clinic Cancer Center
Theresa A. Shapiro, MD, PhD¥
The Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins
James Stevenson, MD†
Case Comprehensive Cancer Center/
University Hospitals Seidman Cancer Center and
Cleveland Clinic Taussig Cancer Institute
Scott J. Swanson, MD¶
Dana-Farber/Brigham and Women’s Cancer Center
Kurt Tauer, MD†
St. Jude Children’s Research Hospital/
University of Tennessee Health Science Center
Stephen C. Yang, MD¶
The Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins
NCCN Staff: Kristina Gregory, RN, MSN, OCN, and
Miranda Hughes, PhD
KEY:
*Discussion Section Writing Committee
Specialties: †Medical Oncology; ¶Surgery/Surgical Oncology; §Ra-
diation Oncology/Radiotherapy; ≠Pathology; ‡Hematology/Hema-
tology Oncology; фDiagnostic/Interventional Radiology; ¥Patient
Advocate; ÞInternal Medicine
recommendations were added for atezolizumab, ceri-
tinib, osimertinib, and pembrolizumab.
The complete version of the NCCN Guidelines for
NSCLC, available at NCCN.org, addresses all aspects
of management for NSCLC. Additional sections in
the complete version of the NCCN Guidelines include
“Principles of Pathologic Review,” “Principles of Surgical
Therapy,” “Principles of Radiation Therapy,” “Chemo-
therapy Regimens for Neoadjuvant and Adjuvant Thera-
py,” “Systemic Therapy for Advanced or Metastatic Dis-
ease,” “Cancer Survivorship Care,” “Emerging Agents for
Patients with Genetic Alterations,” and “Staging.”
The NCCN Guidelines for NSCLC were rst pub-
lished in 1996,
1
and are updated at least once a year by
the NCCN panel; there were 5 updates from January
2016 to January 2017. By denition, the NCCN Guide-
lines cannot incorporate all possible clinical variations
and are not intended to replace good clinical
judgment or individualization of treatments. A
brief introduction to NSCLC is provided in the
following paragraphs.
Lung cancer is the leading cause of cancer
death in the United States.
2
In 2017, an estimated
222,500 new cases (116,990 in men and 105,510
in women) of lung and bronchial cancer will be
diagnosed, and 155,870 deaths (84,590 in men
and 71,280 in women) are estimated to occur be-
cause of the disease.
3
Only 17.7% of all patients
with lung cancer are alive ≥5 years after diagnosis.
4
However, much progress has been made recently
for lung cancer such as screening, minimally inva-
sive techniques for diagnosis and treatment, and
advances in radiation therapy (RT), including
stereotactic ablative RT (SABR), targeted
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 4 | April 2017
506
Non–Small Cell Lung Cancer, Version 5.2017
Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All
recommendations are category 2A unless otherwise indicated.
NSCL-18
a
See Principles of Pathologic Review (NSCL-A, available online, in these
guidelines, at NCCN.org).
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.
ff
If repeat biopsy is not feasible, plasma biopsy should be considered.
gg
The NCCN NSCLC Panel strongly advises broader molecular profi ling
with the goal of identifying rare driver mutations for which effective drugs
may already be available, or to appropriately counsel patients regarding the
availability of clinical trials. Broad molecular profi ling is a key component of
the improvement of care of patients with NSCLC. See Emerging Targeted
Agents for Patients With Genetic Alterations (NSCL-H, available online, in
these guidelines, at NCCN.org).
hh
In patients with squamous cell carcinoma, the observed incidence of
EGFR mutations is 2.7% with a confi dence that the true incidence of
mutations is less than 3.6%. This frequency of EGFR mutations does
not justify routine testing of all tumor specimens. Forbes SA, Bharma
G, Bamford S, et al. The catalogue of somatic mutations in cancer
(COSMIS). Curr Protoc Hum Genet 2008;chapter 10:unit 10.11.
ii
Paik PK, Varghese AM, Sima CS, et al. Response to erlotinib in patients
with EGFR mutant advanced non-small cell lung cancers with a squamous
or squamous-like component. Mol Cancer Ther 2012;11:2535-2540.
jj
Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small
cell lung cancer. N Engl J Med 2014;371:1963-1971.
kk
PD-L1 expression levels of ≥50% are a positive test result for fi rst-line
pembrolizumab therapy.
a
See Principles of Pathologic Review (NSCL-A, available online, in these guidelines, at NCCN.org).
ll
For performance status 0-4.
NSCL-17
HISTOLOGIC
SUBTYPE
Metastatic
Disease
• Establish histologic
subtype
a
with
adequate tissue for
molecular testing
(consider rebiopsy
ff
if appropriate)
• Smoking cessation
counseling
• Integrate palliative
care
c
(See NCCN
Guidelines for
Palliative Care,
available at
NCCN.org)
• Adenocarcinoma
• Large Cell
• NSCLC not
otherwise
specifi ed (NOS)
Squamous cell
carcinoma
• Molecular testing
EGFR mutation
testing (category 1)
ALK testing
(category 1)
ROS1 testing
jj
Testing should be
conducted as part
of broad molecular
profi ling
gg
• PD-L1 testing
kk
• Molecular testing
Consider EGFR
mutation and ALK
testing
hh
in never
smokers or small
biopsy specimens,
or mixed histology
ii
Consider ROS1
testing
jj
Testing should be
conducted as part
of broad molecular
profi ling
gg
• PD-L1 testing
kk
Sensitizing EGFR
mutation positive
PD-L1 positive
kk
and
EGFR, ALK, ROS1
negative or unknown
EGFR, ALK, ROS1,
PD-L1 are negative
or unknown
See First-Line
Therapy (NSCL-18)
See First-Line
Therapy (NSCL-23)
See First-Line
Therapy (NSCL-24)
See First-Line
Therapy (NSCL-25)
Sensitizing EGFR
mutation positive
TESTING RESULTS
a
TESTING
a
ALK positive
See First-Line
Therapy (NSCL-20)
ALK positive
ROS1 positive
ROS1 positive
See First-Line
Therapy (NSCL-22)
PD-L1 positive
kk
and
EGFR, ALK, ROS1
negative or unknown
EGFR, ALK, ROS1,
PD-L1 are negative
or unknown
See First-Line
Therapy (NSCL-18)
See First-Line
Therapy (NSCL-23)
See First-Line
Therapy (NSCL-20)
See First-Line
Therapy (NSCL-22)
CLINICAL PRESENTATION
SENSITIZING EGFR MUTATION POSITIVE
a
FIRST-LINE THERAPY
Sensitizing
EGFR
mutation
positive
EGFR mutation
discovered
prior to fi rst-line
chemotherapy
EGFR mutation
discovered
during fi rst-line
chemotherapy
Erlotinib
ll
(category 1)
or
Afatinib
ll
(category 1)
or
Gefi tinib
ll
(category 1)
Complete planned
chemotherapy,
including maintenance
therapy, or interrupt,
followed by erlotinib or
afatinib or gefi tinib
Progression
See Subsequent
Therapy (NSCL-19)
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 4 | April 2017
507
Non–Small Cell Lung Cancer, Version 5.2017
Version 5.2017, 03-16-17 ©2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines
®
and this illustration may not be
reproduced in any form without the express written permission of NCCN
®
.
NCCN Clinical Practice Guidelines in Oncology
NSCL-18
a
See Principles of Pathologic Review (NSCL-A, available online, in these
guidelines, at NCCN.org).
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.
ff
If repeat biopsy is not feasible, plasma biopsy should be considered.
gg
The NCCN NSCLC Panel strongly advises broader molecular profi ling
with the goal of identifying rare driver mutations for which effective drugs
may already be available, or to appropriately counsel patients regarding the
availability of clinical trials. Broad molecular profi ling is a key component of
the improvement of care of patients with NSCLC. See Emerging Targeted
Agents for Patients With Genetic Alterations (NSCL-H, available online, in
these guidelines, at NCCN.org).
hh
In patients with squamous cell carcinoma, the observed incidence of
EGFR mutations is 2.7% with a confi dence that the true incidence of
mutations is less than 3.6%. This frequency of EGFR mutations does
not justify routine testing of all tumor specimens. Forbes SA, Bharma
G, Bamford S, et al. The catalogue of somatic mutations in cancer
(COSMIS). Curr Protoc Hum Genet 2008;chapter 10:unit 10.11.
ii
Paik PK, Varghese AM, Sima CS, et al. Response to erlotinib in patients
with EGFR mutant advanced non-small cell lung cancers with a squamous
or squamous-like component. Mol Cancer Ther 2012;11:2535-2540.
jj
Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small
cell lung cancer. N Engl J Med 2014;371:1963-1971.
kk
PD-L1 expression levels of ≥50% are a positive test result for fi rst-line
pembrolizumab therapy.
a
See Principles of Pathologic Review (NSCL-A, available online, in these guidelines, at NCCN.org).
ll
For performance status 0-4.
NSCL-17
HISTOLOGIC
SUBTYPE
Metastatic
Disease
• Establish histologic
subtype
a
with
adequate tissue for
molecular testing
(consider rebiopsy
ff
if appropriate)
• Smoking cessation
counseling
• Integrate palliative
care
c
(See NCCN
Guidelines for
Palliative Care,
available at
NCCN.org)
• Adenocarcinoma
• Large Cell
• NSCLC not
otherwise
specifi ed (NOS)
Squamous cell
carcinoma
• Molecular testing
EGFR mutation
testing (category 1)
ALK testing
(category 1)
ROS1 testing
jj
Testing should be
conducted as part
of broad molecular
profi ling
gg
• PD-L1 testing
kk
• Molecular testing
Consider EGFR
mutation and ALK
testing
hh
in never
smokers or small
biopsy specimens,
or mixed histology
ii
Consider ROS1
testing
jj
Testing should be
conducted as part
of broad molecular
profi ling
gg
• PD-L1 testing
kk
Sensitizing EGFR
mutation positive
PD-L1 positive
kk
and
EGFR, ALK, ROS1
negative or unknown
EGFR, ALK, ROS1,
PD-L1 are negative
or unknown
See First-Line
Therapy (NSCL-18)
See First-Line
Therapy (NSCL-23)
See First-Line
Therapy (NSCL-24)
See First-Line
Therapy (NSCL-25)
Sensitizing EGFR
mutation positive
TESTING RESULTS
a
TESTING
a
ALK positive
See First-Line
Therapy (NSCL-20)
ALK positive
ROS1 positive
ROS1 positive
See First-Line
Therapy (NSCL-22)
PD-L1 positive
kk
and
EGFR, ALK, ROS1
negative or unknown
EGFR, ALK, ROS1,
PD-L1 are negative
or unknown
See First-Line
Therapy (NSCL-18)
See First-Line
Therapy (NSCL-23)
See First-Line
Therapy (NSCL-20)
See First-Line
Therapy (NSCL-22)
CLINICAL PRESENTATION
SENSITIZING EGFR MUTATION POSITIVE
a
FIRST-LINE THERAPY
Sensitizing
EGFR
mutation
positive
EGFR mutation
discovered
prior to fi rst-line
chemotherapy
EGFR mutation
discovered
during fi rst-line
chemotherapy
Erlotinib
ll
(category 1)
or
Afatinib
ll
(category 1)
or
Gefi tinib
ll
(category 1)
Complete planned
chemotherapy,
including maintenance
therapy, or interrupt,
followed by erlotinib or
afatinib or gefi tinib
Progression
See Subsequent
Therapy (NSCL-19)
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 4 | April 2017
508
Non–Small Cell Lung Cancer, Version 5.2017
Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All
recommendations are category 2A unless otherwise indicated.
NSCL-20
a
See Principles of Pathologic Review (NSCL-A, available online, in these guidelines, at NCCN.org).
mm
Beware of fl are phenomenon in subset of patients who discontinue EGFR TKI. If disease fl are occurs, restart EGFR TKI.
nn
If tissue biopsy is not feasible, plasma biopsy should be considered. Consider refl ex to tissue-based testing, if plasma test is negative for the T790M
mutation.
oo
Consider pulse erlotinib for carcinomatosis meningitis.
pp
For rapid radiologic progression or threatened organ function, alternate therapy should be instituted.
qq
Afatinib + cetuximab may be considered in patients with disease progression on EGFR TKI therapy.
NSCL-19
a
See Principles of Pathologic Review (NSCL-A, available online, in these guidelines, at NCCN.org).
ll
For performance status 0-4.
SENSITIZING EGFR MUTATION POSITIVE
a
SUBSEQUENT THERAPY
Progression
mm
Symptomatic
Asymptomatic
Brain
oo
Systemic
Isolated
lesion
Multiple
lesions
• Consider local therapy
• Osimertinib (if T790M+)
(category 1)
or
• Continue erlotinib or
afatinib or gefi tinib
• See NCCN Guidelines
for CNS Cancers,
available at NCCN.org
See First-line therapy options
qq
Adenocarcinoma (NSCL-24)
Squamous cell carcinoma (NSCL-25)
or
PD-L1 expression positive (≥50%)
See First-Line Therapy (NSCL-23)
• Consider local therapy
• Osimertinib (if T790M+)
(category 1)
or
• Continue erlotinib or
afatinib or gefi tinib
pp
Progression
T790M
testing
nn
See subsequent
therapy for
multiple lesions,
noted below
Consider local therapy
• Continue erlotinib or
afatinib or gefi tinib
or
• See subsequent therapy
for multiple lesions,
noted below
Osimertinib (category 1)
(if not previously given)
T790M+
T790M-
See subsequent
therapy for
multiple lesions,
noted below
FIRST-LINE THERAPY
ALK
rearrangement
positive
ALK rearrangement
discovered
prior to fi rst-line
chemotherapy
ALK rearrangement
discovered
during fi rst-line
chemotherapy
Crizotinib
ll
(category1)
or
Ceritinib
ll
(category 1)
Complete planned
chemotherapy,
including
maintenance
therapy, or
interrupt, followed
by crizotinib
or ceritinib
Progression
See Subsequent
Therapy (NSCL-21)
ALK REARRANGEMENT POSITIVE
a