LDK378 | GFAP Signal

Non–Small Cell Lung Cancer, Version 5.2017

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

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.

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

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 conflicts 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.

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 first 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 definition, 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

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§ Moffitt 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

Non–Small Cell Lung Cancer, Version 5.2017

CLINICAL PRESENTATION HISTOLOGIC TESTINGa SUBTYPE

• Molecular testing tiEGFR mutation
testing (category 1)
• Adenocarcinoma tiALK testing
• Large Cell (category 1)
TESTING RESULTSa

Sensitizing EGFR See First-Line
mutation positive Therapy (NSCL-18)
ALK positive See First-Line Therapy (NSCL-20)

ROS1 positive See First-Line Therapy (NSCL-22)
PD-L1 positivekk and See First-Line
EGFR, ALK, ROS1 Therapy (NSCL-23) negative or unknown
EGFR, ALK, ROS1, See First-Line
PD-L1 are negative Therapy (NSCL-24) or unknown

Sensitizing EGFR See First-Line
mutation positive Therapy (NSCL-18)

ALK positive See First-Line Therapy (NSCL-20)
ROS1 positive See First-Line Therapy (NSCL-22)
PD-L1 positivekk and See First-Line
EGFR, ALK, ROS1 Therapy (NSCL-23) negative or unknown
EGFR, ALK, ROS1, See First-Line
PD-L1 are negative Therapy (NSCL-25) or unknown

hhIn patients with squamous cell carcinoma, the observed incidence of EGFR mutations is 2.7% with a confidence 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.
iiPaik 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.
jjShaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small cell lung cancer. N Engl J Med 2014;371:1963-1971.
kkPD-L1 expression levels of ≥50% are a positive test result for first-line
• NSCLC not tiROS1 testingjj
• Establish histologic otherwise tiTesting should be
subtypea with specified (NOS) conducted as part
adequate tissue for of broad molecular
molecular testing profiling gg
(consider rebiopsyff • PD-L1 testingkk if appropriate)
Metastatic • Smoking cessation
Disease counseling
• Integrate palliative
carec (See NCCN • Molecular testing
Guidelines for tiConsider EGFR
Palliative Care, mutation and ALK
available at testinghh in never
NCCN.org) smokers or small biopsy specimens,
Squamous cell or mixed histologyii
carcinoma tiConsider ROS1 testingjj
tiTesting should be conducted as part of broad molecular profiling gg
• PD-L1 testingkk

aSee Principles of Pathologic Review (NSCL-A, available online, in these guidelines, at NCCN.org).
cTemel 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.
ffIf repeat biopsy is not feasible, plasma biopsy should be considered. ggThe NCCN NSCLC Panel strongly advises broader molecular profiling
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 profiling 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). pembrolizumab therapy.

NSCL-17

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.

SENSITIZING EGFR MUTATION POSITIVEa

EGFR mutation discovered

FIRST-LINE THERAPY

Erlotinibll (category 1) or
Afatinibll (category 1) or
Gefitinib ll (category 1)

Progression See Subsequent Therapy (NSCL-19)

NSCL-18
prior to first-line chemotherapy

Sensitizing EGFR mutation positive

EGFR mutation discovered

Complete planned chemotherapy, including maintenance therapy, or interrupt, followed by erlotinib or afatinib or gefitinib

aSee Principles of Pathologic Review (NSCL-A, available online, in these guidelines, at NCCN.org).
during first-line chemotherapy

llFor performance status 0-4.

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®.

Non–Small Cell Lung Cancer, Version 5.2017

SENSITIZING EGFR MUTATION POSITIVEa
SUBSEQUENT THERAPY
• Consider local therapy
• Osimertinib (if T790M+)
Asymptomatic (category 1) or
• Continue erlotinib or afatinib or gefitinib pp
• Consider local therapy
• Osimertinib (if T790M+)
T790M (category 1)
Progressionmm testingnn or
Brainoo • Continue erlotinib or

See subsequent
Progression therapy for multiple lesions, noted below

See subsequent
Osimertinib (category 1) therapy for
(if not previously given) multiple lesions,
noted below
See First-line therapy optionsqq Adenocarcinoma (NSCL-24) Squamous cell carcinoma (NSCL-25)

PD-L1 expression positive (≥50%) See First-Line Therapy (NSCL-23)

nnIf tissue biopsy is not feasible, plasma biopsy should be considered. Consider reflex to tissue-based testing, if plasma test is negative for the T790M
afatinib or gefitinib
• See NCCN Guidelines for CNS Cancers, available at NCCN.org
Symptomatic Consider local therapy
• Continue erlotinib or Isolated afatinib or gefitinib
lesion or
• See subsequent therapy for multiple lesions, noted below
Systemic
T790M+

Multiple lesions

T790M- or

aSee Principles of Pathologic Review (NSCL-A, available online, in these guidelines, at NCCN.org).
mmBeware of flare phenomenon in subset of patients who discontinue EGFR TKI. If disease flare occurs, restart mutation.
ooConsider pulse erlotinib for carcinomatosis meningitis.
ppFor rapid radiologic progression or threatened organ function, alternate therapy should be instituted. qqAfatinib + cetuximab may be considered in patients with disease progression on EGFR TKI therapy.

NSCL-19

ALK REARRANGEMENT POSITIVEa

ALK rearrangement discovered

FIRST-LINE THE

Crizotinibll (category1)

RAPY

Progression See Subsequent Therapy (NSCL-21)

aSee Principles of Pathologic Review (NSCL-A, available online, in these guidelines, at NCCN.org).

NSCL-20
prior to first-line chemotherapy

ALK rearrangement positive

ALK rearrangement discovered or Ceritinibll
(category 1)

Complete planned chemotherapy, including maintenance therapy, or interrupt, followed by crizotinib
or ceritinib
during first-line chemotherapy

llFor performance status 0-4.

Non–Small Cell Lung Cancer, Version 5.2017

ALK REARRANGEMENT POSITIVEa
SUBSEQUENT THERAPY

Consider local therapy
• Continue crizotinibpp or
Asymptomatic ceritinibpp or
• Ceritinibss or alectinib

• Consider local therapy and continue crizotinib
Progressionrr or ceritinib
Brain or

See First-line therapy options Adenocarcinoma (NSCL-24)
Squamous cell Progression carcinoma (NSCL-25)
or
PD-L1 expression positive (≥50%)
See First-Line Therapy (NSCL-23)

See First-Line Therapy options for Squamous cell carcinoma (NSCL-25)
• Ceritinibss or alectinib
• See NCCN Guidelines for CNS Cancers, available at NCCN.org

Symptomatic
Isolated • Consider local therapy
lesion • Continue crizotinib or ceritinib

Systemic
Ceritinibss or alectinib
Multiple
lesions Adenocarcinoma (NSCL-24)

aSee Principles of Pathologic Review (NSCL-A, available online, in these guidelines, at NCCN.org). ppFor rapid radiologic progression or threatened organ function, alternate therapy should be instituted. rrPatients who are intolerant to crizotinib may be switched to ceritinib or alectinib.
ssIf not previosuly given.

NSCL-21

ROS1 REARRANGEMENT POSITIVEa

FIRST-LINE THERAPY SUBSEQUENT THERAPY

See First-line therapy options

ROS1 rearrangement positive

Crizotinib

Progression
Adenocarcinoma (NSCL-24) Squamous cell carcinoma (NSCL-25) or
PD-L1 expression positive (≥50%)

See First-Line Therapy (NSCL-23)

aSee Principles of Pathologic Review (NSCL-A, available online, in these guidelines, at NCCN.org).

NSCL-22

Non–Small Cell Lung Cancer, Version 5.2017

PD-L1 EXPRESSION POSITIVEa
FIRST-LINE THERAPY SUBSEQUENT THERAPY

PD-L1

expression positive (≥50%) and EGFR, ALK, ROS1 negative or unknown

Pembrolizumabtt (category 1)

Progression
See First-Line Therapy options for Adenocarcinoma (NSCL-24) or Squamous cell carcinoma (NSCL-25)

aSee Principles of Pathologic Review (NSCL-A, available online, in these guidelines, at NCCN.org).
ttReck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med 2016;375:1823-1833.

NSCL-23

ADENOCARCINOMA, LARGE CELL, NSCLC NOS
FIRST-LINE THERAPY SUBSEQUENT THERAPYuu Systemic immune checkpoint inhibitors (preferred) Nivolumab (category 1)vv or
pembrolizumab (category 1)ss,xx

PS 0-2
or atezolizumab (category 1)vv or
Other systemic therapy:ss Docetaxel or pemetrexed or gemcitabine or
Progressionyy

Progression
ramucirumab + docetaxel

Best supportive care

PS 0-2

Systemic therapyuu
Tumor response evaluationuu
PS 3-4
See NCCN Guidelines for Palliative Care, available at NCCN.org

Progression See Subsequent therapy, above

PS 3-4

Best supportive care See NCCN Guidelines for Palliative Care, available at NCCN.org

Response or stable disease

4–6 cycles (total)

Tumor response evaluationuu

Response or stable disease
Continuation maintenanceuu
•Bevacizumab (category 1)
•Pemetrexed (category 1)
•Bevacizumab + pemetrexedxx
•Gemcitabine (category 2B) or
Switch maintenanceuu (category 2B)
•Pemetrexed or
Close observation

Progression, see Subsequent therapy, above

ssIf not previously given.
uuSee Systemic Therapy for Advanced or Metastatic Disease (NSCL-F, available online, in these guidelines, at NCCN.org). vvIf pembrolizumab not previously given.
wwPembrolizumab is approved for patients with NSCLC tumors with PD-L1 expression levels ≥1%, as determined by an FDA-approved test. xxIf bevacizumab was used with a first-line pemetrexed/platinum chemotherapy regimen.
yyIf 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 care or clinical trial.

NSCL-24

Non–Small Cell Lung Cancer, Version 5.2017

SQUAMOUS CELL CARCINOMA
FIRST-LINE THERAPY SUBSEQUENT THERAPYuu

PS 0-2 Systemic immune checkpoint inhibitors (preferred)
• Nivolumab (category 1)vv or pembrolizumab (category 1)ss,ww or atezolizumab (category 1)vv
or
Other systemic therapy:ss
• Docetaxel or gemcitabine or ramucirumab + docetaxel

Progressionzz

See Subsequent therapy, above

Progression, see Subsequent therapy, above

Continuation maintenanceuu
Progression

Best supportive care
Tumor PS 3-4 See NCCN Guidelines for Palliative
PS 0-2 Systemic response Care, available at NCCN.org
therapyuu evaluationuu

Progression

Response 4–6 Tumor
or stable cycles response
disease (total) evaluationuu (category 2B)
Best supportive care • Gemcitabine
PS 3-4 See NCCN Guidelines Response or
for Palliative Care, or stable Switch maintenance
available at NCCN.org disease (category 2B)
• Docetaxel or
Close observation
ssIf not previously given.
uuSee Systemic Therapy for Advanced or Metastatic Disease (NSCL-F, available online, in these guidelines, at NCCN.org). vvIf pembrolizumab not previously given.
wwPembrolizumab is approved for patients with NSCLC tumors with PD-L1 expression levels ≥1%, as determined by an FDA-approved test.
zzIf 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 clinical trial.

NSCL-25

Non–Small Cell Lung Cancer, Version 5.2017
Cont. from page 505.

therapies, and immunotherapies.5–8 Common symp- toms of lung cancer include cough, dyspnea, weight loss, and chest pain; patients with symptoms are more likely to have chronic obstructive pulmonary disease.9
The WHO divides lung cancer into 2 ma- jor classes based on its biology, therapy, and prog- nosis: NSCLC and small cell lung cancer (SCLC) (see the NCCN Guidelines for SCLC, available at NCCN.org).10,11 NSCLC accounts for >80% of all lung cancer cases, and it includes 2 major types: nonsquamous, including adenocarcinoma, large-cell carcinoma, and other cell types; and squamous cell (epidermoid) carcinoma.4 Adenocarcinoma is the most common type of lung cancer seen in the United States and is also the most frequently occurring his- tology in nonsmokers.
Currently, most patients with NSCLC are di- agnosed with advanced cancer, although increas- ing use of lung cancer screening may alter the most typical stage at diagnosis. Symptoms of metastatic cancer include weight loss, bone pain, headaches, anemia, and paraneoplastic syndromes.12 The pre- liminary diagnosis of metastatic disease is based on symptoms, signs, and laboratory tests12; it is aided by imaging (eg, PET/CT scan, brain MRI).13,14 Pa- tients with widespread metastatic disease (stage IV) are usually candidates for systemic therapy (consist- ing of chemotherapy, targeted therapy, or immuno- therapy, depending on performance status [PS] and results from biomarker testing), clinical trials, and/
or palliative treatment.

Predictive and Prognostic Biomarkers Several biomarkers have emerged as predictive and prognostic markers for NSCLC. A predictive bio- marker is indicative of therapeutic efficacy, because there is an interaction between the biomarker and therapy on patient outcome. A prognostic biomarker is indicative of patient survival independent of the treatment received, because the biomarker is an indicator of the innate tumor aggressiveness (see “KRAS Mutations,” page 518).
Predictive biomarkers include the ALK fusion oncogene (fusion between ALK and other genes [eg, echinoderm microtubule-associated protein-like 4]), ROS1 gene rearrangements, and sensitizing EGFR mutations (see “Principles of Pathologic Review” in the complete version of these guidelines, available at
NCCN.org [NSCL-A]). Emerging biomarkers include HER2 (also known as ERBB2) and BRAF V600E mu- tations, RET gene rearrangements, and high-level MET amplifications or MET exon 14 skipping mu- tations (see “Emerging Targeted Agents for Patients with Genetic Alterations” in the complete version of these guidelines, at NCCN.org [NSCL-H]).

EGFR Mutations
In patients with NSCLC, the most commonly found EGFR mutations are deletions in exon 19 (exon 19del [with conserved deletion of the LREA sequence] in 45% of patients with EGFR mutations) and a mu- tation in exon 21 (L858R in 40%). Both mutations result in activation of the tyrosine kinase domain, and both are associated with sensitivity to the small molecule tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib (see “EGFR TKIs,” page 519).15 Thus, these mutations are referred to as sensitizing EGFR mutations. Previously, erlotinib was commonly used in the United States in patients with sensitizing EGFR mutations because of restrictions on the use of gefitinib. However, gefitinib was recent- ly reapproved by the FDA based on a phase IV study and is now available in the United States.16 Afatinib is an oral TKI that inhibits the entire ErbB/HER fam- ily of receptors, including EGFR and HER2.17,18 The FDA has approved afatinib for first-line treatment of patients with metastatic nonsquamous NSCLC who have sensitizing EGFR mutations.19,20
These sensitizing EGFR mutations are found in approximately 10% of Caucasian patients with NSCLC and up to 50% of Asian patients.21 Other drug-sensitive mutations include point mutations at exon 21 (L861Q) and exon 18 (G719X).22 Primary resistance to TKI therapy is associated with KRAS mutations and ALK or ROS1 gene rearrangements. Patients with exon 20 insertion mutations are also resistant to TKIs.23–26 EGFR T790M is a mutation associated with acquired resistance to EGFR TKI therapy and has been reported in approximately 60% of patients with disease progression after initial response to erlotinib, gefitinib, or afatinib.27–34 Most patients with sensitizing EGFR mutations become resistant to erlotinib, gefitinib, or afatinib after ap- proximately 9 to 13 months of EGFR TKI thera- py.29,35–37 However, studies suggest T790M may also occur in patients who have not previously received EGFR TKI therapy, although this is a rare event.38

Osimertinib is recommended (category 1) as second- line and beyond (subsequent) therapy for patients with EGFR T790M whose disease has progressed on sensitizing EGFR TKI therapy, such as, erlotinib, gefitinib, afatinib (see “Osimertinib,” page 520).37,39 Acquired resistance may also be associated with histologic transformation from NSCLC to SCLC and with epithelial to mesenchymal transition (see “Principles of Pathologic Review” in the complete version of these guidelines, at NCCN.org).40–42
DNA mutational analysis is the preferred meth- od to assess for EGFR status.43–45 Various DNA mu- tation detection assays can be used to determine the EGFR mutation status in tumor cells.46 Direct sequencing of DNA corresponding to exons 18 to 21 (or just testing for exons 19 and 21) is a reason- able approach; however, more sensitive methods are available.21,44,47–49 Mutation screening assays us- ing multiplex PCR (eg, Sequenom’s MassARRAY system, SNaPshot Multiplex System) can detect
>50 point mutations, including EGFR.50 Next- generation sequencing (NGS) can also be used to detect EGFR mutations.51
The predictive effects of the drug-sensitive EGFR mutations—exon 19del (LREA deletion) and L858R—are well defined. Patients with these muta- tions have a significantly better response to erlotinib, gefitinib, or afatinib.15 Retrospective studies have shown an objective response rate of approximately 80% with a median progression-free survival (PFS) of 13 months to single-agent EGFR TKI therapy in patients with a bronchioloalveolar variant of adeno- carcinoma and a sensitizing EGFR mutation.52 A pro- spective study has shown that the objective response rate in North American patients with nonsquamous NSCLC and sensitizing EGFR mutations (53% exon 19del [LREA deletion], 26% L858R, and 21% other mutations) is 55%, with a median PFS of 9.2 months.53 EGFR mutation testing is not usually recommended in patients with pure squamous cell carcinoma (SCC) unless they never smoked, if only a small biopsy speci- men (ie, not a surgical resection) was used to assess histology, or if the histology is mixed.54 Data suggest that EGFR mutations can occur in patients with ad- enosquamous carcinoma, which is harder to discrimi- nate from SCC in small specimens.54
Data show that erlotinib, gefitinib, or afatinib (instead of standard first-line chemotherapy) should be used as first-line systemic therapy in patients with
sensitizing EGFR mutations documented before first-line therapy.20,35,55–58 PFS is improved with use of EGFR TKI in patients with sensitizing EGFR muta- tions when compared with standard chemotherapy, although overall survival (OS) is not statistically dif- ferent.20,35,36 Patients receiving erlotinib have fewer treatment-related severe side effects when compared with those receiving chemotherapy.35,59 A phase IV trial showed that gefitinib is safe and effective in patients with sensitizing EGFR mutations.16 Based on these data and the FDA approvals, erlotinib and gefitinib are recommended (category 1) as first-line systemic therapy in patients with sensitizing EGFR mutations.16,35 In a phase III randomized trial, pa- tients receiving afatinib had decreased cough, de- creased dyspnea, and improved health-related qual- ity of life compared with those receiving cisplatin/
pemetrexed.59 Based on these data and the FDA ap- proval, afatinib is also recommended (category 1) as first-line systemic therapy in patients with sensitizing EGFR mutations.20 However, afatinib was potential- ly associated with 4 treatment-related deaths, where- as there were none in the chemotherapy group.20 A combined analysis (LUX 3 and LUX 6) reported a survival advantage in patients with exon 19del who received afatinib compared with chemotherapy.60

ALK Gene Rearrangements
An estimated 2% to 7% of patients with NSCLC have ALK gene rearrangements, approximately 10,000 of whom live in the United States.61 Patients with ALK rearrangements are resistant to EGFR TKIs but have similar clinical characteristics to patients with EGFR mutations (ie, adenocarcinoma histology, nev- er smokers, light smokers) except that they are more likely to be men and may be younger.62 In these se- lected populations, estimates show that approximate- ly 30% of patients will have ALK rearrangements.62,63 ALK rearrangements are not routinely found in pa- tients with SCC. Although rare, patients with ALK gene rearrangements can have mixed squamous cell histology.64 It can be challenging to accurately deter- mine histology in small biopsy specimens; thus, pa- tients may have mixed squamous cell histology (or squamous components) instead of pure squamous cell. The NCCN panel recommends testing for ALK rearrangements if small biopsy specimens were used to assess histology, mixed histology was reported, or patients never smoked. A molecular diagnostic test

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(using fluorescence in situ hybridization [FISH]) has been approved by the FDA for detecting ALK rear- rangements and is a prerequisite before treatment with crizotinib. Rapid prescreening can be performed with immunohistochemistry (IHC) to assess for ALK rearrangements; if positive, FISH analysis can con- firm ALK positivity.65–74 NGS can also be used to as- sess whether ALK rearrangements are present, if the platform has been appropriately designed and vali- dated to detect ALK rearrangements.75–77
Crizotinib—an inhibitor of ALK, ROS1, and some MET tyrosine kinases (high-level MET am- plification or MET exon 14 skipping mutation)—is FDA-approved for patients with locally advanced or metastatic NSCLC who have ALK gene rearrange- ments (ie, ALK-positive disease) or ROS1 rear- rangements.78–85 Crizotinib yields very high response rates (>60%) when used in patients with advanced NSCLC who have ALK rearrangements, including those with brain metastases.61,81,86–88 Crizotinib has relatively few side effects (eg, eye disorders, edema, transient changes in renal function).87,89,90 However, a few patients have had life-threatening pneumo- nitis; crizotinib should be discontinued in these patients.83 Patients whose disease responds to crizo- tinib may have rapid improvement in symptoms (eg, cough, dyspnea, pain); median time to progression on crizotinib is approximately 7 months to 1 year.91,92
Randomized phase III trials have compared crizotinib with standard second-line (ie, subsequent) chemotherapy (PROFILE 1007) and with standard first-line therapy (PROFILE 1014).7,81,93 First-line therapy with crizotinib improved PFS, response rate (74% vs 45%; P<.001), lung cancer symptoms, and quality of life compared with chemotherapy (peme- trexed with either cisplatin or carboplatin).81 Based on this trial, crizotinib is recommended (category 1) for first-line therapy in patients with ALK-pos- itive NSCLC (see NSCL-20, page 509). Subse- quent therapy with crizotinib improved PFS (7.7 vs 3.0 months; P<.001) and response rate (65% vs 20%; P<.001) compared with single-agent therapy (either docetaxel or pemetrexed) in patients with ALK-positive NSCLC whose disease had progressed after first-line chemotherapy.82 Based on this trial, crizotinib is recommended as subsequent therapy in patients with ALK-positive disease. The term subse- quent therapy was recently substituted for second-line or beyond systemic therapy, because the line of therapy
may vary depending on previous treatment with targeted agents.
For patients whose disease progresses on crizo- tinib, second-generation ALK inhibitors include ceritinib and alectinib; others are in develop- ment.94–104 Ceritinib is an orally active TKI of ALK, which also inhibits the insulin-like growth factor 1 (IGF-1) receptor but not MET. An expanded phase
Itrial showed that ceritinib was very active in 122 patients with locally advanced or metastatic NSCLC who have ALK gene rearrangements.98 The overall response rate to ceritinib was 56% in patients who had previously received crizotinib; the median PFS was 7 months. Based on this study, ceritinib was FDA-approved for patients with ALK-positive meta- static NSCLC that progresses on or who are intoler- ant of crizotinib.105 The NCCN panel recommends ceritinib for patients with ALK-positive metastatic NSCLC that has progressed on crizotinib or who are intolerant to crizotinib based on the data from Shaw et al98 and FDA approval.105 For the 2017 update (Version 5), the panel also recommends (category 1) ceritinib as first-line treatment for ALK-positive metastatic NSCLC based on a recent phase III trial (see “Ceritinib,” page 521).
Alectinib is another oral TKI of ALK, which also inhibits RET but not MET or ROS1. Two phase II trials in patients with ALK rearrangements showed that alectinib was very active in those who had pro- gressed on crizotinib.95,106 In the larger trial (138 patients) by Ou et al,95 patients on alectinib had a response rate of 50% (95% CI, 41%–59%), and me- dian response duration of 11.2 months (95% CI, 9.6 months–not reached). For central nervous system (CNS) disease, the control rate was 83% (95% CI, 74%–91%) and the median response duration was 10.3 months (95% CI, 7.6–11.2 months). Of 84 pa- tients with baseline CNS metastases, 23 (27%) had a complete CNS response to alectinib. Of 23 patients with baseline CNS metastases and no previous brain RT, 10 (43%) had a complete CNS response to alec- tinib. Most adverse events (AEs) were only grade 1 to 2 (constipation, fatigue, and peripheral edema); 4 patients (3%) had grade 3 dyspnea. One death due to intestinal perforation may have been related to alectinib. The other phase II trial in 87 patients with ALK-positive NSCLC that progressed on crizotinib reported that 48% of patients had an objective re- sponse to alectinib.106 Of 16 patients with baseline

CNS metastases, 4 (25%) achieved a complete re- sponse in the CNS; 11 had previously received RT.106 One treatment-related death occurred due to hem- orrhage. Based on these studies, alectinib was FDA- approved for patients with ALK-positive metastatic NSCLC that progresses on or who are intolerant to crizotinib.107 The NCCN panel recommends alec- tinib (category 2A) for patients with ALK-positive metastatic NSCLC that has progressed on crizotinib or who are intolerant to crizotinib based on these 2 trials and FDA approval.95,106,107
ALK or ROS1 rearrangements and sensitiz- ing EGFR mutations are generally mutually exclu- sive.68,108,109 Thus, erlotinib, gefitinib, and afatinib are not recommended as subsequent therapy in patients with ALK or ROS1 rearrangements who experience relapse on crizotinib.62,110 Likewise, crizotinib, ceri- tinib, and alectinib are not recommended for patients with sensitizing EGFR mutations whose disease re- lapses on erlotinib, gefitinib, or afatinib. For patients who experience disease progression on crizotinib, sub- sequent treatment for ALK-positive NSCLC includes ceritinib or alectinib (see “Ceritinib” and “Alectinib,” pages 521 and 522, and NSCL-21, page 510).87,95,111,112 Continuing crizotinib may also be appropriate for pa- tients whose disease progresses on crizotinib.113

ROS1 Rearrangements
Although ROS1 is a distinct receptor tyrosine ki- nase, it is very similar to ALK and members of the insulin receptor family (see “Principles of Pathologic Review” in the complete version of these guidelines, at NCCN.org).114,115 It is estimated that ROS1 gene rearrangements occur in approximately 1% to 2% of patients with NSCLC; they occur more frequently in younger women with adenocarcinoma who are nev- er smokers and in those who are negative for EGFR mutations, KRAS mutations, and ALK gene rear- rangements (also known as triple-negative).115–117 Crizotinib is very effective for patients with ROS1 rearrangements, with response rates of approximate- ly 70%, including complete responses.115 In 50 pa- tients, crizotinib yielded a response rate of 66% (95% CI, 51%–79%); the median duration of response was 18 months.118 The FDA has approved crizotinib for patients with ROS1 rearrangements.118
For the 2017 update (Version 1), the NCCN panel moved the recommendation for ROS1 testing into the main algorithm (and deleted the footnote
recommending ROS1 testing), added a new algo- rithm for ROS1, and added a new section on ROS1 to the molecular diagnostic studies section based on data showing the efficacy of crizotinib for patients with ROS1 rearrangements and on the FDA ap- proval (see NSCL-22, page 511 and “Principles of Pathologic Review” in the complete version of these guidelines, at NCCN.org).80,115,118 Similar to testing for ALK rearrangements, testing for ROS1 is also per- formed using FISH.65,116,119–121 NGS can also be used to assess whether ROS1 rearrangements are present, if the platform has been appropriately designed and validated to detect ROS1 rearrangements.115 Because a companion diagnostic test has not been approved for ROS1, clinicians should use an appropriately validated test to detect ROS1.118 Alectinib and ceri- tinib are not effective in patients with ROS1 rear- rangements whose disease becomes resistant to crizo- tinib.115 Studies are ongoing regarding new agents for patients with ROS1 rearrangements whose disease becomes resistant to crizotinib.122-125

KRAS Mutations
Data suggest that approximately 25% of patients with adenocarcinomas in a North American population have KRAS mutations; KRAS is the most common mutation.52,126–129 KRAS mutation prevalence is asso- ciated with cigarette smoking.130 Patients with KRAS mutations appear to have a shorter survival than those with wild-type KRAS; therefore, KRAS muta- tions are prognostic biomarkers.129,131,132 KRAS muta- tional status is also predictive of lack of therapeutic efficacy with EGFR TKIs; however, it does not appear to affect chemotherapeutic efficacy.52,128,133 KRAS mutations do not generally overlap with EGFR mu- tations, ALK rearrangements, or ROS1 rearrange- ments.68,134,135 Therefore, KRAS testing may identify patients who may not benefit from further molecular testing.133,136 Targeted therapy is not currently avail- able for patients with KRAS mutations, although immune checkpoint inhibitors appear to be effective; MEK inhibitors are in clinical trials.97,127,137,138

Targeted Therapies
Specific targeted therapies are available for the treat- ment of advanced NSCLC.139–141 Erlotinib, gefitinib, and afatinib are small molecule inhibitors of EGFR; osimertinib targets T790M. Crizotinib is a small

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molecule inhibitor that targets ALK, ROS1, and MET (ie, high-level MET amplification, MET exon 14 skipping mutation). Ceritinib is a small mol- ecule inhibitor that targets ALK and IGF-1 receptor. Alectinib is a small molecule inhibitor that targets ALK and RET. Erlotinib, gefitinib, afatinib, crizo- tinib, ceritinib, alectinib, and osimertinib are oral TKIs. Other targeted therapies are being developed (see “Emerging Targeted Agents for Patients With Genetic Alterations” in the complete version of these guidelines, at NCCN.org).

EGFR TKIs
Erlotinib and Gefitinib: In 2004, erlotinib was ap- proved by the FDA for the treatment of patients with locally advanced or metastatic NSCLC after progres- sion on at least one prior chemotherapy regimen.142 The FDA has also approved the use of erlotinib as first-line therapy in patients with sensitizing EGFR mutations.143 Erlotinib and gefitinib are recommend- ed (category 1) in the NSCLC algorithm as first-line therapy in patients with advanced, recurrent, or metastatic nonsquamous NSCLC who have known active sensitizing EGFR mutations regardless of their PS (see NSCL-18, page 507).36,128,144,145 These recom- mendations are based on a phase III randomized trial (IPASS) in which patients with sensitizing EGFR mutations who received gefitinib had increased PFS (24.9% vs 6.7%), response rate (71.2% vs 47.3%), and quality of life, with fewer side effects (eg, neutro- penia) compared with those receiving chemotherapy (carboplatin/paclitaxel).36 Updated results from the IPASS study showed that OS was similar in patients receiving gefitinib or chemotherapy regardless of sensitizing EGFR mutation status.146 However, these results probably occurred because patients who had been assigned to first-line chemotherapy were able to receive TKIs as subsequent therapy if they were found to have sensitizing EGFR mutations. A phase III randomized trial (EURTAC) in European patients with metastatic NSCLC and sensitizing EGFR mu- tations showed increased PFS and response rate for those receiving erlotinib compared with chemother- apy.35 For erlotinib, the median PFS was 9.7 months compared with 5.2 months for chemotherapy (haz- ard ratio [HR], 0.37; 95% CI, 0.25–0.54; P<.0001). Fewer patients receiving erlotinib had severe AEs or died compared with those receiving chemotherapy.
TKIs are recommended in patients with meta- static NSCLC and sensitizing EGFR mutations, because quality of life is improved when compared with chemotherapy. Previously, erlotinib was com- monly used in the United States in patients with sensitizing EGFR mutations because of restrictions on the use of gefitinib. However, gefitinib was reap- proved by the FDA based on a phase IV study and is now available in the United States.16,147 Erlotinib and gefitinib are orally active TKIs that are very well tolerated by most patients.148,149 An analysis of 5 clinical trials in patients, mainly from the Western hemisphere (n=223), with advanced NSCLC (stage IIIB or IV) found that those with sensitizing EGFR mutations who received TKIs had a 67% response rate and an OS of approximately 24 months.150 The TORCH trial suggested that EGFR mutation test- ing should be performed in patients with advanced nonsquamous NSCLC.151 Survival was increased in patients with wild-type EGFR who received first-line chemotherapy compared with those who received erlotinib first followed by subsequent chemotherapy (11.6 vs 8.7 months). The OPTIMAL trial reported that PFS was increased in patients with sensitizing EGFR mutations who received erlotinib.57,58 ASCO recommends that patients be tested for EGFR muta- tions.152 However, the ESMO Guidelines specify that only patients with nonsquamous NSCLC (eg, ade- nocarcinoma) be assessed for EGFR mutations.136,153 Patients with pure SCC are unlikely to have sensi- tizing EGFR mutations; however, those with adeno- squamous carcinoma may have mutations.54
An updated study (CALGB 30406) compared erlotinib alone versus erlotinib/carboplatin/pacli- taxel in patients (mainly Caucasian) with advanced NSCLC.154 The data showed that erlotinib alone was associated with fewer side effects in patients with sensitizing EGFR mutations when compared with erlotinib/chemotherapy. Thus, it is appropriate to interrupt or complete planned chemotherapy and switch to erlotinib, gefitinib, or afatinib therapy in patients found to have sensitizing EGFR mutations during chemotherapy (see NSCL-18, page 507).155 The NCCN Guidelines do not recommend adding erlotinib, gefitinib, or afatinib to current chemo- therapy based on this CALGB study.154 Erlotinib, gefitinib, or afatinib may be continued in patients who have progressed if patients do not have multiple systemic symptomatic lesions (see “Continuation of

Erlotinib, Gefitinib, or Afatinib After Progression,” page 525).
A phase III trial (WJOG 5108L) assessed gefi- tinib versus erlotinib for patients with advanced lung cancer who had been previously treated with chemo- therapy; most patients (72%) were positive for EGFR mutations.156 The median PFS for gefitinib versus er- lotinib was 8.3 and 10.0 months, respectively, in pa- tients positive for EGFR mutations (HR, 1.093; 95% CI, 0.879–1.358; P=.424). The main grade 3 or 4 toxicities included rash (gefitinib: 2.2% vs erlotinib: 18.1%) and increases in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels (ge- fitinib: 6.1%/13.0% vs erlotinib: 2.2%/3.3%). Afatinib: A randomized phase III trial reported that first-line therapy with afatinib improved PFS com- pared with cisplatin/pemetrexed in patients with metastatic adenocarcinoma who have sensitizing EGFR mutations (11.1 vs 6.9 months; P=.001).20 The FDA approved afatinib for the first-line treatment of patients with metastatic NSCLC who have sensi- tizing EGFR mutations.19,157 Based on this phase III randomized trial and the FDA approval, the NCCN panel recommends afatinib for first-line therapy (cat- egory 1) in patients with metastatic nonsquamous NSCLC who have sensitizing EGFR mutations (see NSCL-18, page 507).17,20,112 Afatinib may also be continued in patients whose disease has progressed if they do not have multiple systemic symptomatic lesions (see “Continuation of Erlotinib, Gefitinib, or Afatinib After Progression,” page 525).15 However, afatinib is not recommended as subsequent therapy based on a phase III randomized trial (see “Second- Line and Beyond (Subsequent) Systemic Therapy,” page 526).158
A phase IIB trial assessed afatinib compared with gefitinib for first-line therapy in patients with metastatic adenocarcinoma and sensitizing EGFR mutations.159 The PFS was essentially the same in patients receiving afatinib compared with those re- ceiving gefitinib (median PFS: 11.0 months [95% CI, 10.6–12.9] with afatinib vs 10.9 months [95% CI, 9.1–11.5] with gefitinib; HR, 0.73; 95% CI, 0.57– 0.95; P=.017). These slight PFS differences are not clinically relevant and the NCCN Guidelines do not state that one EGFR TKI is more efficacious than an- other (see the NCCN Guidelines for NSCLC With Evidence Blocks, available at NCCN.org)156; OS data are not yet available. Patients receiving afatinib had
more serious treatment-related side effects compared with those receiving gefitinib (11% [17/160] for afa- tinib vs 4% [7/159] for gefitinib). One patient receiv- ing gefitinib died from treatment-related hepatic and renal failure; other deaths were not considered to be treatment-related (9% vs 6% [15/160 vs 10/159]). More patients receiving afatinib had diarrhea (13% vs 1%), whereas more patients receiving gefitinib had elevations in liver enzyme levels (0% vs 9%).
For the 2017 update (Version 1), the NCCN panel revised the afatinib evidence block for efficacy to highly effective (ie, the highest rating of 5), so the value is now the same as that for erlotinib and gefi- tinib (see the NCCN Guidelines for NSCLC With Evidence Blocks, available at NCCN.org). However, afatinib is rated as slightly less safe than erlotinib or gefitinib (ie, a rating of 3 for afatinib versus 4 for er- lotinib and gefitinib).
Osimertinib: As previously mentioned, most patients with sensitizing EGFR mutations and metastatic NSCLC typically experience disease progression after approximately 9 to 13 months of erlotinib, gefitinib, or afatinib therapy.29,35–37 EGFR T790M is a muta- tion associated with acquired resistance to EGFR TKI therapy and has been reported in approximately 60% of patients with disease progression after initial re- sponse to sensitizing EGFR TKI therapy.27–34 Osimer- tinib (AZD9291) is an oral TKI that inhibits both EGFR-sensitizing mutations and T790M.
A phase III randomized trial assessed osimer- tinib versus platinum-pemetrexed chemotherapy in patients with EGFR T790M–positive metastatic NSCLC. Data show that osimertinib increased PFS compared with chemotherapy (10.1 vs 4.4 months; HR, 0.30; 95% CI, 0.23–0.41; P<.001).37 PFS was also increased in patients with CNS metastases who received osimertinib (8.5 vs 4.2 months; HR, 0.32; 95% CI, 0.21–0.49). In addition, the objective re- sponse rate was improved with osimertinib (71%; 95% CI, 65%–76%) compared with chemotherapy (31%; 95% CI, 24%–40%) (odds ratio for objec- tive response, 5.39; 95% CI, 3.47–8.48; P<.001). The disease control rate is approximately 93% with osimertinib (95% CI, 90%–96%) and approximately 74% with chemotherapy (95% CI, 66%–81%). Pa- tients receiving osimertinib had fewer grade ≥3 AEs compared with those receiving chemotherapy (23% vs 47% [63/279 vs 64/136]); however, there were 4 fatal events with osimertinib (respiratory failure [2],

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pneumonitis, ischemic stroke) and 1 with chemo- therapy (hypovolemic shock).
Data from a multicenter, single-arm phase II clinical trial indicate that osimertinib is associated with a response rate of approximately 61% (78/127; 95% CI, 52–70), PFS of 9.6 months (95% CI, 8.3– not reached), and disease control rate of approxi- mately 95% (121/127; 95% CI, 90–98) in patients with EGFR T790M whose disease has progressed on sensitizing EGFR TKI therapy; 13% (33/253) of patients had drug-related grade ≥3 AEs with 1 fatal event from pneumonia possibly related to treat- ment.39,160,161 In patients without EGFR T790M, the response rate was 21% (13/61; 95% CI, 12–34) and the PFS was 2.8 months (95% CI, 2.1–4.3).39
The FDA has approved osimertinib for patients with metastatic EGFR T790M–positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy. Based on the data and FDA approval, the NCCN panel recommends osimertinib (category 1) as subsequent therapy for patients with metastatic EGFR T790M– positive NSCLC whose disease has progressed on erlotinib, gefitinib, or afatinib therapy (see “Sec- ond-Line and Beyond (Subsequent) Systemic Ther- apy,” page 526). For the 2017 update (Version 4), the NCCN panel revised the recommendation to category 1 (from category 2A) for osimertinib in patients with EGFR T790M-positive metastatic NSCLC based on the phase 3 randomized trial.37 T790M can be assessed using an FDA-approved test or other validated laboratory test done in a CLIA- approved laboratory. Data suggest that plasma ge- notyping (also known as liquid biopsy or plasma biopsy) may be considered instead of tissue biopsy to detect whether patients have T790M; however, if the plasma biopsy is negative, then tissue biopsy is recommended if feasible.162,163 For the 2017 update (Version 4), the NCCN panel now also recommends osimertinib (category 1) for patients with T790M who have experienced progression with symptom- atic brain metastases based on data showing an improvement.37,164–167

ALK/ROS1 Inhibitors
Crizotinib: Crizotinib is approved by the FDA for patients with locally advanced or metastatic NSCLC who are positive for the ALK gene rearrangement.78 The approval is based on a phase II trial that showed
dramatic response rates (>80%) to crizotinib in pa- tients whose disease had previously progressed.83,84 Patients receiving crizotinib reported clinically sig- nificant improvements in pain, dyspnea, and cough. A phase III trial compared first-line crizotinib versus chemotherapy in patients with ALK rearrangements; patients receiving crizotinib had improved PFS, qual- ity of life, and response rates compared with those receiving chemotherapy.81 The NCCN panel recom- mends first-line therapy with crizotinib (category 1) based on the results of this phase III trial and the FDA approval; the panel also feels that crizotinib is appro- priate for patients with PS 0 to 4. Crizotinib may also be continued for patients with ALK rearrangements whose disease has progressed if patients do not have multiple systemic symptomatic lesions.82
Crizotinib is also very effective for patients with ROS1 rearrangements with response rates of approximately 70%, including complete responses (see “ROS1 Rearrangements,” page 518).115,118 For the 2017 update (Version 1), the NCCN Panel moved the recommendation for ROS1 testing into the main algorithm (and deleted the footnote rec- ommending ROS1 testing), added a new algorithm for ROS1, and added a new section on ROS1 to the molecular diagnostic studies section based on data showing the efficacy of crizotinib for patients with ROS1 rearrangements and on the FDA ap- proval (see “Principles of Pathologic Review” in the complete version of these guidelines, at NCCN. org).80,115,118 Alectinib and ceritinib are not effective in patients with ROS1 rearrangements whose dis- ease becomes resistant to crizotinib.
Ceritinib: Ceritinib is approved by the FDA for pa- tients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.105 The approval is based on an expanded phase I study (ASCEND-1) showing overall response rates of 56% to ceritinib in patients (92/163) who had previously received crizotinib; the median duration of response was 8.3 months (range, 6.8–9.7 months).98,168 Com- mon grade 3/4 AEs included increased alanine ami- notransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]).168 Some pa- tients with CNS lesions experienced response to ceri- tinib. Based on the study and the FDA approval, the NCCN panel recommends ceritinib as subsequent therapy for patients with ALK-positive NSCLC that progressed after crizotinib; patients who do not

tolerate crizotinib may be switched to ceritinib or alectinib. A phase II trial (ASCEND-2) assessed ceritinib in patients who had previously received at least ≥2 treatments, had experienced progression on crizotinib, and had brain metastases.169 The overall response rate was 38%; the duration of response was 9.7 months (95% CI, 7.1–11.1 months).169 The in- tracranial overall response rate was 45.0% (95% CI, 23.1%–68.5%).
A recent phase III trial assessed ceritinib versus platinum-based chemotherapy as first-line therapy for patients with ALK-positive metastatic NSCLC.170 The data show that PFS was improved when using ceritinib compared with platinum-based chemo- therapy; the median PFS was 16.6 months (95% CI, 12.6–27.2) for ceritinib and 8.1 months (95% CI, 5.8–11.1) for chemotherapy (HR, 0.55; 95% CI, 0.42–0.73; P<.00001). For ceritinib, common ad- verse events included diarrhea (85% [160/189] of patients), nausea (69% [130/189]), vomiting (66% [125/189), and an increase in alanine aminotrans- ferase (60% [114/189]). For chemotherapy, common adverse events included nausea (55% [97/175] of pa- tients), vomiting (36% [63/175]), and anemia (35% [62/175]). For the 2017 update (Version 5), the NCCN panel now recommends ceritinib as first-line therapy (category 1) for patients with ALK-positive metastatic NSCLC based on this trial.
Alectinib: Alectinib is approved by the FDA for pa- tients with ALK-positive metastatic NSCLC who have experienced progression on or are intolerant to crizotinib.107 The approval is based on 2 phase II trials showing overall response rates of 48% to 50% to alectinib in patients who had previously received crizotinib.95,106 In the larger trial by Ou et al,95 the control rate for CNS disease was 83% (95% CI, 74%–91%), and the median duration of response was 10.3 months (95% CI, 7.6–11.2 months). Of 84 patients with baseline CNS metastases, 23 (27%) had a complete CNS response. Of 23 patients with baseline CNS metastases and without previous brain RT, 10 (43%) had a complete CNS response to alectinib. Based on these trials and the FDA ap- proval, the NCCN panel recommends alectinib as subsequent therapy for patients with ALK-positive NSCLC that has progressed after crizotinib; patients who do not tolerate crizotinib may be switched to alectinib or ceritinib.
Immunotherapeutic Agents
Human immune-checkpoint–inhibitor antibodies inhibit the PD-1 receptor or PD-1 ligand (PD-L1), which improves antitumor immunity; PD-1 recep- tors are expressed on activated cytotoxic T-cells.171–173 The NCCN panel recommends immune checkpoint inhibitors as preferred agents for subsequent therapy based on improved OS rates, longer duration of re- sponse, and fewer AEs when compared with cyto- toxic chemotherapy.171,174–176 Immune checkpoint inhibitors are associated with a delay in benefit compared with targeted therapy or cytotoxic che- motherapy. Pseudoprogression has been reported; therefore, traditional RECIST criteria may not be applicable.177 Current or former smoking status cor- related with the response rate to immune checkpoint inhibitors.171,178–180 Data suggest that mismatch repair deficiency is associated with response to immune checkpoint inhibitors.181 Immune-related AEs, such as pneumonitis, may occur with immune checkpoint inhibitors.173,178,182–189 Intravenous high-dose cortico- steroids should be administered based on the severity of the reaction for patients with immune-mediated AEs. Immune checkpoint inhibitors should be dis- continued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated AEs when indicated (see prescribing information).
Nivolumab: The NCCN panel recommends nivolumab (category 1) as subsequent therapy for pa- tients with metastatic nonsquamous NSCLC that has progressed on or after first-line chemotherapy based on data from a phase III randomized trial (Check- Mate-057) and FDA approval (see NSCL-24, page 513).171,190 Nivolumab inhibits PD-1 receptors.175 The category 1 recommendation for nivolumab is based on the published data from CheckMate-057 and FDA ap- proval of nivolumab for patients with metastatic non- squamous NSCLC. For patients receiving nivolum- ab, median OS was 12.2 months compared with 9.4 months for docetaxel (HR, 0.73; 95% CI, 0.59–0.89; P=.002).171 The median duration of response was 17.2 months with nivolumab compared with 5.6 months for docetaxel. At 18 months, the OS rate was 39% (95% CI, 34%–45%) with nivolumab compared with 23% (95% CI, 19%–28%) with docetaxel. Fewer grade 3 to 5 AEs were reported for nivolumab (10%) compared with docetaxel (54%) in the CheckMate-057 trial.

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Although many patients with metastatic non- squamous NSCLC benefit from nivolumab, those whose tumors have PD-L1 staining of 1% to ≥10% have an OS of 17 to 19 months compared with 8 to 9 months for docetaxel. For patients who did not have PD-L1 expression, there was no difference in OS for nivolumab versus docetaxel; however, nivolumab was associated with a longer duration of response and fewer side effects. To help clinicians determine which patients with nonsquamous NSCLC may ben- efit most from treatment with nivolumab, the FDA approved a complementary diagnostic biomarker test to assess for PD-L1 protein expression.191 Testing for PD-L1 is not required for prescribing nivolumab but may provide useful information.192
The NCCN panel also recommends (category 1) nivolumab as subsequent therapy for patients with metastatic squamous cell NSCLC that has progressed on or after first-line chemotherapy based on data from a phase III randomized trial (CheckMate-017), FDA approval, and results of a phase II trial (see NSCL- 25, page 514).175,186 In the CheckMate-017 trial, the median OS was 9.2 months with nivolumab com- pared with 6.0 months for docetaxel.175 Patients had a response rate of 20% with nivolumab compared with 9% for docetaxel (P=.008). PD-L1 expression was not associated with response to nivolumab in pa- tients with squamous cell NSCLC. There were fewer grade 3/4 AEs with nivolumab (7%) compared with docetaxel (55%). No patients died in the nivolumab arm versus 3 deaths in the docetaxel arm. Pembrolizumab: For the 2017 updates (Versions 1
and 2), the NCCN panel recommends pembrolizum- ab (category 1) as first-line therapy for patients with PD-L1 expression levels of ≥50% and with negative or unknown tests results for EGFR mutations, ALK rearrangements, and ROS1 rearrangements based on a phase III randomized trial (Keynote-024) com- paring pembrolizumab versus platinum-based che- motherapy; the FDA approved pembrolizumab for first-line therapy based on this trial (see NSCL-23, page 512).193 At 6 months, the OS rate was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (HR for death, 0.60; 95% CI, 0.41–0.89; P=.005). Reponses were higher in the pembrolizumab group than in the chemotherapy group (44.8% vs 27.8%).193 There were fewer se- vere treatment-related AEs (grades 3–5) in patients
receiving pembrolizumab compared with those receiving chemotherapy (26.6% vs 53.3%).
For the 2017 update (Version 1), the NCCN pan- el recommends (category 2A) IHC testing for PD-L1 expression before first-line treatment in patients with metastatic NSCLC with negative or unknown tests results for EGFR mutations, ALK rearrangements, and ROS1 rearrangements.194 Although it is not an optimal biomarker, PD-L1 expression is currently the best available biomarker to assess whether patients are candidates for pembrolizumab.195,196 PD-L1 expression is continuously variable and dynamic; thus, a cutoff value for a positive result is artificial. Patients with PD-L1 expression levels just below and just above 50% will probably have similar responses.195 Unique anti–PD-L1 IHC assays are being developed for each one of the different immune checkpoint inhibitors currently in clinical trials.192,195 The definition of a positive PD-L1 test result varies depending on which biomarker assay is used.192
Ideally, PD-L1 expression levels are assessed in patients with negative or unknown test results for EGFR mutations, ALK rearrangements, or ROS1 rearrangements. Every effort needs to be made to es- tablish the genetic alteration status. However, if the risk of biopsy is high and genetic alteration testing is not feasible and therefore technically unknown, then it is appropriate to test for PD-L1 expression levels. There are blood assays to evaluate for EGFR mutations and ALK rearrangements, although they are less sensitive than tissue assays.
The NCCN panel also recommends pembro- lizumab (category 1) as subsequent therapy for pa- tients with metastatic nonsquamous or squamous NSCLC and PD-L1 expression based on the random- ized phase II/III trial (KEYNOTE-010), the phase I KEYNOTE-001 trial, and FDA approval (see NSCL- 24, page 513 and NSCL-25, page 514).176,179,197 Pem- brolizumab inhibits the PD-1 receptor.193
A randomized phase II/III trial (KEYNOTE-010) assessed pembrolizumab in patients with previous- ly treated advanced nonsquamous and squamous NSCLC who were PD-L1 positive (≥1%); most patients were current or former smokers.176 There were 3 arms in this trial: pembrolizumab at 2 mg/
kg, pembrolizumab at 10 mg/kg, and docetaxel at 75 mg/m² every 3 weeks. The median OS was 10.4 months for the lower dose of pembrolizumab, 12.7 months for the higher dose, and 8.5 months for

docetaxel. OS was significantly longer for both doses of pembrolizumab compared with docetaxel (pem- brolizumab, 2 mg/kg: HR, 0.71; 95% CI, 0.58–0.88; P=.0008) (pembrolizumab, 10 mg/kg: HR, 0.61; CI, 0.49–0.75; P<.0001). For patients with at least 50% PD-L1 expression in tumor cells, OS was also sig- nificantly longer at either dose of pembrolizumab compared with docetaxel (pembrolizumab, 2 mg/kg: 14.9 vs 8.2 months; HR, 0.54; 95% CI, 0.38–0.77; P=.0002 and pembrolizumab, 10 mg/kg: 17.3 vs 8.2 months; HR, 0.50; CI, 0.36–0.70; P<.0001). When compared with docetaxel, there were fewer grade 3 to 5 treatment-related AEs at either dose of pembro- lizumab (pembrolizumab, 2 mg/kg: 13% of patients [43/339]; pembrolizumab, 10 mg/kg: 16% [55/343]; and docetaxel: 35% [109/309]). A total of 6 treat- ment-related deaths occurred in patients receiving pembrolizumab (3 at each dose) and 5 treatment- related deaths occurred in the docetaxel arm.
A phase I trial (KEYNOTE-001) assessed the safety and efficacy of pembrolizumab for patients with metastatic NSCLC.179 Among all patients, the response rate was 19%, the median duration of re- sponse was 12.5 months, PFS was 3.7 months, and median OS was 12.0 months. Patients with a PD- L1 expression score of at least 50% had a response rate of 45%, a PFS of 6.3 months, and OS was not reached. Less than 10% of patients had serious toxicity of grade ≥3.
The FDA approved pembrolizumab as subse- quent therapy for patients with metastatic NSCLC whose disease has progressed after platinum-based chemotherapy if their tumors express PD-L1.197 The FDA has approved a companion diagnostic biomark- er test for assessing PD-L1 expression and determin- ing which patients are eligible for pembrolizumab therapy. Other immunotherapeutic agents are being investigated.174,198–200
Atezolizumab: For the 2017 update (Version 4), the NCCN panel revised the recommendation to cat- egory 1 for atezolizumab as subsequent therapy for pa- tients with metastatic nonsquamous or squamous cell NSCLC based on a recent phase III trial178; previously this was a category 2A recommendation based on pre- liminary data from a phase III randomized trial, data from a phase II trial, and recent FDA approval (see
201
Testing for PD-L1 expression levels is not required for
prescribing atezolizumab but may provide useful infor- mation. Atezolizumab inhibits PD-L1.200
A phase III randomized trial (OAK) assessed at- ezolizumab versus docetaxel alone in patients with metastatic NSCLC that had progressed during or af- ter systemic therapy.178,201 Most patients were current or former smokers and had received platinum-based chemotherapy; few patients (10%) had EGFR mu- tations, and ALK rearrangements were not report- ed.178,201 Data show that patients with nonsquamous NSCLC who received atezolizumab had improved OS compared with those receiving docetaxel (15.6 vs 11.2 months; HR, 0.73 [0.6–0.89]; P=.0015). OS was only slightly improved in patients with squamous cell NSCLC receiving atezolizumab versus docetaxel (8.9 vs 7.7 months; HR, 0.73 [0.54–0.98]; P=.038); howev- er, there were fewer patients in the squamous NSCLC group compared with the nonsquamous group (222 vs 628). There were fewer treatment-related severe AEs (grades 3/4) for atezolizumab versus docetaxel (15% vs 43% [90/609 vs 247/578]). For the 2017 update (Ver- sion 4), the NCCN panel revised the atezolizumab evidence block for efficacy to a rating of 4 (very effec- tive) from the previous rating of 3 (moderately effec- tive) (see the NCCN Guidelines for NSCLC With Evidence Blocks, available at NCCN.org).

Treatment of Recurrences and Distant Metastases
For patients with recurrent and metastatic disease, the NCCN Guidelines recommend that histologic subtype should be determined before therapy so that the best treatment can be selected (see NSCL-17, page 506).202 In addition, testing for genetic altera- tions (ie, driver events) is recommended in patients with NSCLC, because targeted therapy has been shown to decrease tumor burden, decrease symp- toms, and dramatically improve the quality of life for patients with specific genetic alterations. The num- ber of available targeted agents is increasing. Several targeted agents, such as erlotinib, gefitinib, afatinib, and crizotinib, have category 1 recommendations for first-line therapy based on larger trials.155
EGFR mutation testing (category 1) is recom- mended in patients with nonsquamous NSCLC (ie, adenocarcinoma, large cell carcinoma) or NSCLC not otherwise specified (NOS), because erlotinib, gefitinib, and afatinib (category 1 for all) are recom-

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mended for patients who are positive for sensitiz- ing EGFR mutations (see NSCL-17, page 506 and NSCL-18, page 507).15,36,56,128,203 Testing for ALK re- arrangements (category 1) is also recommended in patients with nonsquamous NSCLC, because crizo- tinib is recommended (category 1) for patients who are positive for ALK rearrangements.70,204 Crizotinib is also recommended for patients who are positive for ROS1 rearrangements and MET amplifica- tion.115,116,205,206 For the 2017 update (Version 1), the NCCN panel added a recommendation for testing for ROS1 rearrangements (category 2A). Testing for ROS1 has typically been performed using FISH; however, a validated NGS platform that can detect this gene fusion may also be used.120 The NCCN panel recommends that EGFR mutation testing be performed as part of broad molecular profiling (eg, multiplex mutation screening assays or NGS). Test- ing for ALK gene rearrangements can be performed with FISH or with NGS if the platform is validated and can identify gene fusions.51,126,207 For the 2017 up- date (Version 1), the NCCN panel also added a rec- ommendation for upfront PD-L1 expression testing before first-line therapy in patients with metastatic NSCLC to assess whether patients are candidates for immune checkpoint inhibitors (see “Pembroli- zumab,” page 523).
As previously mentioned, recommendations from an international panel suggest that general his- tologic categories be avoided (eg, NSCLC), because more effective treatment can be selected when the histology is known.208 Patients with pure squamous cell carcinoma do not seem to have ALK rearrange- ments, ROS1 rearrangements, or sensitizing EGFR mutations; therefore, routine testing is not recom- mended in these patients.54,209–211 However, testing for ALK rearrangements, ROS1 rearrangements, or EGFR mutations can be considered in patients with squamous cell carcinomas who never smoked and those whose histology was determined using small biopsy specimens or mixed histology specimens.54 Treatment recommendations and eligibility criteria for patients with nonsquamous NSCLC (or NSCLC NOS) who are negative or unknown for ALK or ROS1 rearrangements, sensitizing EGFR mutations, or PD-L1 expression are described in the complete version of the NCCN Guidelines. Treatment recom- mendations and eligibility criteria for patients with
squamous cell carcinoma are also described in the complete version of the NCCN Guidelines.

Continuation of Erlotinib, Gefitinib, or Afatinib After Progression
Previously, erlotinib was commonly used in the United States in patients with sensitizing EGFR mu- tations because of restrictions on the use of gefitinib. However, gefitinib was reapproved by the FDA based on a phase IV study and is now available in the Unit- ed States.16 Patients may continue to derive benefit from erlotinib, gefitinib, or afatinib after disease progression; discontinuation of these TKIs leads to more rapid progression of disease (symptoms, tumor size, and FDG-avidity on PET scan).212 This strategy mirrors the experience in other oncogene-addicted cancers, particularly HER2-amplified breast can- cer. In women with HER2-amplified breast cancer who have had disease progression on trastuzumab, improved radiographic response rate, time to pro- gression, and OS are observed when conventional chemotherapy is added to trastuzumab.213
After development of acquired resistance in patients with lung adenocarcinoma and sensitizing EGFR mutations, erlotinib, gefitinib, or afatinib may be continued, but osimertinib is also an option for se- lect patients; local therapy should be considered (eg, stereotactic radiosurgery to brain metastases or other sites, SABR for thoracic disease).214–217 The NCCN panel recommends continuing erlotinib, gefitinib, or afatinib and considering local therapy in patients with asymptomatic progression; however, treatment varies for patients with symptomatic progression (see NSCL-19, page 508).218–220 For the 2017 updates (Versions 1 and 4), the NCCN panel revised the rec- ommendations for patients with sensitizing EGFR mutations whose disease has progressed on erlotinib, gefitinib, or afatinib. Osimertinib is now recom- mended (category 1) for patients with symptomatic brain metastases.37 Another option is to continue use of erlotinib, gefitinib, or afatinib for these patients; however, additional therapy may be added or sub- stituted (eg, local therapy, systemic therapy). First- line systemic therapy options are recommended for patients with multiple symptomatic lesions who are negative for T790M; osimertinib is recommended (category 1) for patients positive for T790M.
Accumulating data suggest how cancers become resistant to EGFR inhibitors.221 The most common

known mechanism is the acquisition of T790M (which is a secondary mutation in EGFR), which renders the kinase resistant to erlotinib, gefitinib, or afatinib.222,223 Therefore, if patients are T790M- positive, osimertinib is recommended (category 1) and erlotinib, gefitinib, or afatinib are discontinued. Am- plification of the MET oncogene is another validated resistance mechanism. To overcome resistance, EGFR must still be inhibited. In the case of MET amplifica- tion, new inhibitors must be added to the EGFR in- hibitor; however, EGFR inhibition is still required to induce remission. Furthermore, data by Riely et al212 show that when cancers start to progress, which were once sensitive to EGFR inhibitors, discontinuation of the EGFR TKI can lead to a much more accelerated progression of the cancer.224 Thus, continuing EGFR TKIs is beneficial in many patients even after they develop resistance to EGFR TKIs.217

Second-Line and Beyond (Subsequent) Systemic Therapy
The phrase subsequent therapy was substituted for the terms second-line, third-line, and beyond systemic ther- apy, because the line of therapy may vary depending on previous treatment with targeted agents. Subse- quent systemic therapy regimens for patients who have disease progression during or after first-line therapy are described in the NSCLC algorithm and depend on the specific genetic alteration, the histo- logic subtype, and whether the patient has symptoms (see the complete version of these guidelines, avail- able at NCCN.org).225–234 For the 2017 update (Ver- sion 1), the NCCN panel now recommends response assessment of known sites of disease with CT (with contrast) every 6 to 12 weeks in patients receiving subsequent therapy. Note that traditional RECIST 1.1 criteria are used to assess response for most types of systemic therapy, but different response crite- ria may be useful for assessing response in patients receiving immunotherapy.235–237
The NCCN panel recommends immune check- point inhibitors as preferred agents for subsequent therapy in patients with metastatic NSCLC based on improved survival rates, longer duration of re- sponse, and fewer AEs compared with cytotoxic che- motherapy (see “Nivolumab,” “Pembrolizumab,” and “Atezolizumab,” pages 522, 523, and 524, respec- tively).171,175,201 Human immune-checkpoint–inhibi- tor antibodies inhibit the PD-1 receptor or PD-L1,
which improves antitumor immunity; PD-1 recep- tors are expressed on activated cytotoxic T cells.171–173 The NCCN panel recommends nivolumab (catego- ry 1) as subsequent therapy for patients with meta- static nonsquamous or squamous NSCLC based on a phase III randomized trial (CheckMate-057) and FDA approval.171 The NCCN panel recommends pembrolizumab (category 1) as subsequent therapy for patients with metastatic nonsquamous or squa- mous NSCLC and PD-L1 expression based on a phase II/III randomized trial (KEYNOTE-010) trial, KEYNOTE-001 trial, and FDA approval.176,179 The NCCN panel also recommends atezolizumab (cate- gory 1) as subsequent therapy for patients with meta- static nonsquamous or squamous NSCLC based on a phase III randomized trial (OAK), data from a phase
IItrial (POPLAR), and FDA approval.178,200,201
The NCCN panel recommends osimertinib (category 1) as subsequent therapy for patients with metastatic EGFR T790M–positive NSCLC that has progressed on erlotinib, gefitinib, or afatinib thera- py based on data and FDA approval (see “Osimer- tinib,” page 520).37,39 Osimertinib (AZD9291) is an oral TKI that inhibits both EGFR-sensitizing muta- tions and T790M. Data from a phase III trial report that osimertinib is associated with a response rate of approximately 71% and disease control rate of ap- proximately 93% (95% CI, 90%–96%) in patients whose disease has progressed on sensitizing EGFR TKI therapy; 23% of patients had drug-related grade ≥3 AEs with 4 fatal events.37,39,160,161 The FDA has approved osimertinib for patients with metastatic EGFR T790M–positive NSCLC, as detected by an FDA-approved test, that has progressed on or after EGFR TKI therapy. Most patients with sensitizing EGFR mutations and metastatic NSCLC typically experience disease progression after approximately 9 to 13 months of erlotinib or gefitinib therapy.35–37 EGFR T790M is associated with acquired resistance to TKI therapy and has been reported in approxi- mately 60% of patients with disease progression after initial response to sensitizing EGFR TKI therapy.27–34 T790M can be assessed using an FDA-approved test or other validated laboratory test performed in a CLIA-approved laboratory.
For patients with sensitizing EGFR mutations who progress during or after first-line targeted ther- apy, recommended therapy depends on whether the progression is asymptomatic or symptomatic and

Non–Small Cell Lung Cancer, Version 5.2017

includes continuing erlotinib, afatinib, or gefitinib with (or without) local therapy; osimertinib; or a first-line systemic therapy regimen for either non- squamous or squamous cell NSCLC (such as cis- platin/pemetrexed or cisplatin/gemcitabine, respec- tively). For the 2017 update (Version 4), the NCCN panel now also recommends osimertinib (category 1) for patients with T790M who have brain metasta- ses.37,164–166 Data suggest that an afatinib/cetuximab regimen may be useful for patients whose disease has progressed after receiving EGFR TKI therapy and chemotherapy.238 Patients with T790M-positive and T790M-negative tumors had a similar response rate to an afatinib/cetuximab regimen (32% vs 25%; P=.341). The NCCN panel recommends (category 2A) considering an afatinib/cetuximab regimen for patients whose disease has progressed after receiving EGFR TKIs and chemotherapy based on these data.
Among patients with sensitizing EFGR muta- tions, no improvement in OS has been noted in the phase III trials assessing pembrolizumab, nivolumab, or atezolizumab compared with docetaxel, but there were not enough patients with these mutations to determine whether there were statistically significant differences (see next paragraph).171,176,201,239 Immuno- therapy was not worse than chemotherapy and was better tolerated. In the phase III trials for pembroli- zumab, nivolumab, or atezolizumab versus docetaxel as subsequent therapy for patients with metastatic NSCLC, subset analyses were performed in patients with EGFR mutations to determine the best subse- quent therapy.171,176,201 The HRs for OS do not favor docetaxel over nivolumab (HR, 1.18; CI, 0.69–2.0), pembrolizumab (HR, 0.88; CI, 0.45–1.7), or atezoli- zumab (HR, 1.24; CI, 0.7–2.2); the CIs for the HRs are wide probably because there were so few patients with EGFR mutations. The HRs for PFS do favor docetaxel for patients with EGFR mutations com- pared with either pembrolizumab (HR, 1.79; CI, 0.94–3.42) or nivolumab (HR, 1.46; CI, 0.90–2.37). But again, the CIs are wide. The evidence is weak for recommending docetaxel, pembrolizumab, nivolum- ab, or atezolizumab as subsequent therapy for patients with EGFR mutations. Data suggest that patients with EGFR mutations or ALK rearrangements have a low response rate to PD-1 or PD-L1 inhibitors when com- pared with patients without these genetic alterations (response rate, 3.6% vs 23%, respectively).239
For patients with ALK rearrangements whose disease progresses during or after first-line targeted therapy, recommended therapy also depends on whether the progression is asymptomatic or symp- tomatic and includes continuing crizotinib with (or without) local therapy; ceritinib; alectinib; or a first-line systemic therapy regimen for either non- squamous or squamous cell NSCLC. After further progression on subsequent targeted therapy, first-line combination chemotherapy options for nonsqua- mous NSCLC or squamous cell carcinoma are rec- ommended for patients with PS of 0 to 1, such as cisplatin/pemetrexed or cisplatin/gemcitabine (both are category 1), respectively.139,240 Other chemother- apy options are also recommended for patients with PS 2, such as docetaxel (see “Systemic Therapy for Advanced or Metastatic Disease” in the complete version of these guidelines, at NCCN.org).
Most patients with NSCLC do not have ALK rearrangements, ROS1 rearrangements, or sensitiz- ing EGFR mutations. For patients with all histologic subtypes and PS of 0 to 2 but without these genetic alterations who have disease progression during or after first-line therapy, recommended subsequent systemic therapy options include nivolumab (cat- egory 1), pembrolizumab (category 1), atezolizumab (category 1), docetaxel with (or without) ramucirumab, or gemcitabine if not already given; pemetrexed is recommended for patients with non- squamous NSCLC. For the 2017 update (Version 4), the NCCN panel revised the recommendation for atezolizumab to category 1 (from category 2A) as subsequent therapy. The NCCN panel recommends immune checkpoint inhibitors—nivolumab, pem- brolizumab, and atezolizumab—as preferred options for subsequent therapy for all histologic subtypes based on improved survival rates, longer duration of response, and fewer AEs compared with cytotoxic chemotherapy (see “Nivolumab,” “Pembrolizumab,” and “Atezolizumab,” pages 522, 523, and 524).171,175,201
For the 2017 update (Version 2.2017), the NCCN panel deleted the recommendation for er- lotinib as subsequent therapy (and as switch main- tenance therapy) for patients with nonsquamous NSCLC and PS 0 to 2 but without EGFR mutations based on results from a phase III randomized trial (IUNO) and revised indication by the FDA. The data showed that OS and PFS were not improved in patients receiving erlotinib compared with

placebo.241 Ramucirumab/docetaxel is an option for subsequent therapy for all histologic subtypes based on a phase III randomized trial.242 The me- dian OS was slightly increased with ramucirumab/
docetaxel versus docetaxel alone (10.5 vs 9.1 months, respectively). Contraindications for ramu- cirumab/docetaxel therapy include risk for severe hemorrhage, grade 3 to 4 gastrointestinal bleeding, gastrointestinal perforation or fistula, and poorly controlled hypertension.
Docetaxel has been proven superior to best sup- portive care, vinorelbine, or ifosfamide with im- proved survival and quality of life.231,232 Compared with docetaxel, pemetrexed has similar median survival but less toxicity.233,243 Pemetrexed is recom- mended in patients with nonsquamous NSCLC.244 Docetaxel is recommended for patients with wild- type EGFR tumors based on 2 randomized trials comparing erlotinib versus docetaxel.245,246 In pa- tients with PS of 3 to 4, best supportive care is rec- ommended (see NSCL-24, page 513 and NSCL-25, page 514).9,247,248 Patients often have a limited re- sponse to subsequent chemotherapy other than im- mune checkpoint inhibitors, although it may serve a useful palliative role.249
The NCCN panel deleted erlotinib as an option for subsequent therapy for patients with squamous cell NSCLC based on a study comparing afatinib with erlotinib; this study was statistically significant but not clinically significant. 158 OS was slightly bet- ter in the afatinib group than in the erlotinib group (median OS, 7.9 months [95% CI, 7.2–8.7] vs 6.8 months [95% CI, 5.9–7.8]; HR, 0.81 [95% CI, 0.69– 0.95]; P=.0077); however, almost 60% of patients in each arm had grade ≥3 AEs. In contrast, the median OS was 9.2 months with nivolumab compared with
6.0 months for docetaxel for patients with squamous cell NSCLC.175 In addition, only 7% of patients re- ceiving nivolumab had grade ≥3 AEs. Erlotinib and afatinib are not recommended as second-line ther- apy for squamous cell carcinoma based on a phase
IIIrandomized trial showing low response rates and because they are less efficacious and safe compared with other available options.158
If patients with either ALK fusions or sensi- tizing EGFR mutations progress with symptom- atic systemic multiple lesions after therapy with crizotinib, erlotinib, gefitinib, or afatinib and/or af- ter ceritinib, alectinib, or osimertinib, then first-line doublet chemotherapy options are recommended for either nonsquamous NSCLC or squamous cell carcinoma.250 Erlotinib, gefitinib, or afatinib may be continued in patients with sensitizing EGFR mu- tations whose disease has progressed after first-line therapy.15,218–220 Osimertinib is recommended for pa- tients with T790M whose disease becomes resistant to erlotinib, afatinib, or gefitinib. 39 Afatinib/cetux- imab may be considered for patients with sensitizing EGFR mutations whose disease has progressed after EGFR TKI therapy and chemotherapy.238 Ceritinib or alectinib is recommended in patients with ALK- positive NSCLC whose disease has progressed after first-line therapy with crizotinib or who are intoler- ant to crizotinib.95,98 Nivolumab, pembrolizumab, at- ezolizumab, docetaxel with or without ramucirumab (category 2B for both), gemcitabine (category 2B), or pemetrexed (nonsquamous only) (category 2B) are recommended for subsequent therapy after sec- ond disease progression in patients with advanced NSCLC and PS 0 to 2 if these agents have not already been given.226,246,251,252

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Individual Disclosures for the Non–Small Cell Lung Cancer Panel
Promotional Advisory Boards,
Clinical Research Support/Data Scientific Advisory Boards, Consultant, or Date
Panel Member Safety Monitoring Board Consultant, or Expert Witness Speakers Bureau Completed
Dara L. Aisner, MD, PhD None None AstraZeneca 2/3/17 Pharmaceuticals LP; and
Invitae Corporation
Wallace Akerley, MD Bristol-Myers Squibb Company; Flat Iron AstraZeneca Pharmaceuticals LP None 3/9/17
Healthcare; Genentech, Inc.; Mirati Therapeutics, Inc.; and Novartis Pharmaceuticals Corporation
Jessica Bauman, MD None None None 12/28/16
Lucian R. Chirieac, MD None Medical Science Afiliates; Shook, None 10/17/16
Hardy & Bacon; and Wilcox and Savage
Thomas A. D’Amico, MD None Scanlan None 3/19/17
Malcolm M. DeCamp, MD PulmonX Auris Surgical Robotics Inc.; Holaira Inc; None 2/15/17
Intuitive Surgical, Inc.; and Soffio Medical Inc.
Thomas J. Dilling, MD, MS None None None 3/2/17
Michael Dobelbower, MD, PhD Robert C. Doebele, MD, PhDa Covidien AG; and Varian Medical Systems, Inc. None None 3/22/17
ARIAD Pharmaceuticals, Inc.; AstraZeneca None ARIAD Pharmaceuticals, 10/28/16
Pharmaceuticals LP; Bristol-Myers Squibb Inc.; AstraZeneca
Company; GlaxoSmithKline; OncoMed Pharmaceuticals LP;
Pharmaceuticals; Corvus; CytRx; Ignyta; Trovagene; and Pfizer
Loxo Oncology; Strategia; and Inc. Threshold Pharmaceuticals
David S. Ettinger, MD Golden Biotechnology Corp ARIAD Pharmaceuticals, Inc.; None 2/23/17
BeyondSpring Pharmaceuticals; Boehringer Ingelheim GmbH; Bristol- Myers Squibb Company; Eli Lilly and Company; EMD Serono; Genentech, Inc.; Helsinn Therapeutics (US), Inc.; Heron Therapeutics; McGivney Global Consultant; and Trovagene, Inc.
Ramaswamy Govindan, MD Abbott Laboratories; Abraxis Oncology; ARIAD Abbott Laboratories; Bayer HealthCare; None 2/13/17
Pharmaceuticals, Inc.; AstraZeneca Pharmaceuticals Celgene Corporation; Clovis; Helsinn
LP; Bayer HealthCare; Boehringer Ingelheim Healthcare; and Roche Laboratories, Inc. GmbH; Bristol-Myers Squibb Company; Genentech,
Inc.; and GlaxoSmithKline
Matthew A. Gubens, MD, MS Celgene Corporation; Merck & Co., Inc.; AbbVie; ARIAD Pharmaceuticals, Inc.; None 2/10/17
Novartis Pharmaceuticals Corporation; AstraZeneca Pharmaceuticals LP; Bristol-
OncoMed Pharmaceuticals; and Roche Myers Squibb Company; Genentech, Inc.;
Laboratories, Inc. and Pfizer Inc.
Mark Hennon, MD None None None 3/15/17
Leora Horn, MD, MSc, FRCPC AstraZeneca Pharmaceuticals LP; Bayer Bayer HealthCare; Bristol-Myers Squibb Abbvie 10/10/16
HealthCare; Bristol-Myers Squibb Company; Company; Eli Lilly and Company;
Celgene Corporation; Eli Lilly and Company; EMD Serono; Genentech, Inc.;
Genentech, Inc.; Merck & Co., Inc.; Merrimack; Merck & Co., Inc.; and Xcovery Novartis Pharmaceuticals Corporation;
OSI Pharmaceuticals, Inc.; and Xcovery
Ritsuko Komaki, MD ACRIN None None 2/2/17
Rudy P. Lackner, MD None None None 2/24/17
Michael Lanuti, MD NCI None None 1/25/17
Ticiana A. Leal, MD None ARIAD Pharmaceuticals, Inc.; and None 2/1/17
Genentech, Inc.
Leah J. Leisch, MD None None None 1/23/17
Rogerio Lilenbaum, MD None Genentech, Inc. AstraZeneca 3/20/17 Pharmaceuticals LP
Jules Lin, MD None None Intuitive Surgical, Inc. 1/23/17
Billy W. Loo Jr, MD, PhDa None None None 10/13/16
Renato Martins, MD, MPH AstraZeneca Pharmaceuticals LP; Bristol-Myers None None 2/21/17
Squibb Company; Celgene Corporation; Eisai Inc.; Eli Lilly and Company; Genentech, Inc.; GlaxoSmithKline; Merck & Co., Inc.; Millennium
Pharmaceuticals, Inc.; Mirati Therapeutics; Novartis Pharmaceuticals Corporation; and Pfizer Inc.
Gregory A. Otterson, MD Boehringer Ingelheim GmbH; Boston Biomedical; Boehringer Ingelheim GmbH; None 3/19/17
Bristol-Myers Squibb Company; Celgene Genentech, Inc.; and Novartis
Corporation; Clovis; Genentech, Inc.; Pharmaceuticals Corporation Merck & Co., Inc.; and Pfizer Inc.
Karen Reckamp, MD, MS Abbott Laboratories; Adaptimmune; ARIAD Amgen Inc.; ARIAD Pharmaceuticals, Inc.; None 1/21/17
Pharmaceuticals, Inc.; Boehringer Ingelheim Astellas; and Celgene Corporation GmbH; Bristol-Myers Squibb Company; Clovis;
Eisai Inc.; Genentech, Inc.; Pfizer Inc.; and Xcovery
Gregory J. Riely, MD, PhD ARIAD Pharmaceuticals, Inc.; GlaxoSmithKline; Genentech, Inc. None 10/13/16
Infinity Pharmaceuticals; Millennium Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; and Roche Laboratories, Inc.
Steven E. Schild, MD None None None 3/7/17
Theresa A. Shapiro, MD, PhD None None None 3/8/17
James Stevenson, MD Bayer HealthCare; Bristol-Myers Squibb Company; None None 3/3/17
and Merck & Co., Inc.
Scott J. Swanson, MD None Covidien AG; and Ethicon, Inc. None 2/2/17
Kurt Tauer, MD None None None 3/20/17
Douglas E. Wood, MD, FRCSEd Spiration GRAIL, Inc.; Lung Cancer Alliance; None 1/6/17
and Spiration, Inc.
Stephen C. Yang, MD None None None 3/26/17
The NCCN Guidelines Staff have no conflicts to disclose.
aThe following individuals have disclosed that they have an Employment/ Governing Board, Patent, Equity, or Royalty conflict:
Robert C. Doebele, MD, PhD: Abbott Molecular
Billy W. Loo Jr, MD, PhD: Stanford University, and TibaRay, Inc.LDK378