Non–Small Cell Lung Cancer, Version 6.2015

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

Abstract

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

NCCN: Continuing Education

Accreditation Statement

This activity is designated to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

NCCN designates this educational activity for a maximum of 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-000015-006-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/65998; and 4) view/print certificate.

Release date: May 13, 2015; Expiration date: May 13, 2016

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to the NCCN Guidelines for Non–Small Cell Lung Cancer

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Non–Small Cell Lung Cancer

F1NCCN Guidelines Insights: Non–Small Cell Lung Cancer, Version 6.2015

Version 6.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 5; 10.6004/jnccn.2015.0071

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

In 2015, an estimated 221,200 new cases (115,610 in men and 105,590 in women) of lung and bronchial cancer will be diagnosed, and 158,040 deaths (86,380 in men and 71,660 in women) are estimated to occur in the United States.1 Currently, most lung cancer is diagnosed clinically when patients present with symptoms such as persistent cough, pain, and weight loss. Unfortunately, most patients are diagnosed when they already have advanced-stage disease. Even for earlier-stage disease, the relapse rate after radical therapy is significant. Taking into account all stages at diagnosis, the 5-year survival rate for lung cancer is only 16.8%.2,3 The 5-year survival rate for those with stage IV disease at diagnosis is much lower (≈2%). However, for select patients with advanced lung cancer, the advent of targeted therapies has had a profound effect on the ability to control the disease, palliate symptoms, and potentially prolong life

F2NCCN Guidelines Insights: Non–Small Cell Lung Cancer, Version 6.2015

Version 6.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 5; 10.6004/jnccn.2015.0071

for patients with the specific molecular aberrations in their tumors that make them sensitive to these therapies.419 Therefore, it is important to perform molecular testing on tumor tissue from patients with advanced non–small cell lung cancer (NSCLC) to determine whether they have genetic alterations and thus are candidates for targeted therapy. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have 2 of the most common actionable genetic alterations: anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations. The complete version of the NCCN Guidelines addresses all aspects of management for NSCLC, including screening, diagnosis, evaluation, staging, treatment, surveillance, and therapy for recurrence and metastasis. The NCCN Guidelines for NSCLC are updated at least once a year by the NCCN Panel; the 2015 updated version marks 20 years of their publication.20

Genetic Alterations

Targeted therapy is potentially very effective in select patients with advanced NSCLC harboring genetic alterations. The 2 best characterized examples to date represent patients with either ALK gene rearrangements or sensitizing EGFR mutations in their tumors.46,812 Patients whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations are usually highly sensitive to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy.6,11,12 Patients whose tumors have ALK gene rearrangements are usually highly sensitive to ALK inhibitors.4,5,810 Other actionable molecular abnormalities continue to be discovered and explored, including BRAF mutations and ROS1 and RET rearrangements.7,2125

Sensitizing EGFR mutations are found in approximately 10% of Caucasian patients with NSCLC and up to 50% of Asian patients26; they include (in addition to the L858R and exon 19 deletions) other, rarer, drug-sensitive EGFR mutations, such as those

F3NCCN Guidelines Insights: Non–Small Cell Lung Cancer, Version 6.2015

Version 6.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 5; 10.6004/jnccn.2015.0071

at exon 21 (L861Q) and exon 18 (G719X).27 Clinical characteristics associated with the presence of an EGFR mutation include adenocarcinoma, little or no smoking history, female sex, and East Asian ancestry.6,11,28 Some EGFR mutations are activating, but resistant to standard EGFR TKIs, most notably exon 20 insertion mutations (with the exception of the rare FQEA exon 20 insertion, which is TKI-sensitive).2933 Most patients treated with the first- or second-generation EGFR TKIs (eg, erlotinib, gefitinib, afatinib) will develop disease progression approximately 1 year after initiating therapy. These patients have developed acquired resistance, associated with the selection of additional biological changes within the tumor. The most common of these changes is the T790M mutation, occurring in 50% to 60% of patients with EGFR mutations, because of the development of an exon 20 point mutation in cis with the original sensitizing mutation in the EGFR.3439 The presence of the T790M mutation in the TKI-naïve state has also been described in 2 separate contexts. First, highly sensitive sequencing techniques may be able to detect low-level clones harboring T790M that are later selected out by EGFR-TKI therapy. Because these clones may be present in only a small fraction of cells, the patient may still derive clinical benefit from the initial TKI therapy, although the progression-free survival may be shorter.40 Second, families with germline T790M have been rarely described, wherein the development of lung cancer seems to depend on the development of a second, more classical L858R or exon 19 deletion.41,42 In these families, because T790M is, by definition, present in all cells in the cancer (and in the host), first- or second-generation TKIs have little efficacy.3440,43

Approximately 2% to 7% of patients with NSCLC have ALK gene rearrangements.4,4446 EML4 is the most common fusion partner with ALK, leading to at least 13 different variants, but other fusion partners with ALK have been reported.46 Patients with ALK rearrangements usually have adenocarcinoma histology and little or no smoking history.47 Most driver oncogenes tend to be mutually exclusive with other driver oncogenes. For example, ALK rearrangements tend to be mutually exclusive with other common driver mutations, such as EGFR or KRAS mutations, and vice versa.48,49 Consequently, clinical enrichment (eg, only assessing patients with adenocarcinomas who are never/light smokers and/or those known to be wild-type for other common oncogenes) can be used to significantly increase the frequency of detecting either ALK rearrangements or sensitizing EGFR mutations in the tested population. However, because many exceptions to the classical phenotype exist, clinical enrichment may miss patients with ALK rearrangements or EGFR mutations who do not meet the classical phenotype.48,5053 Currently, crizotinib is the only ALK TKI approved for the treatment of patients with ALK-positive NSCLC who are ALK TKI-naïve. Similar to those treated with an EGFR TKI, patients treated with an ALK TKI will develop acquired resistance to therapy. However, the different mechanisms of acquired resistance to ALK TKIs seem to be more complex than the EGFR story. Ceritinib is a second-generation ALK inhibitor that is approved in the post-crizotinib setting and shows activity in approximately 60% of cases.7

Molecular Testing

The NCCN Guidelines for NSCLC recommend molecular testing for ALK gene rearrangements and EGFR mutations (category 1) in patients with advanced adenocarcinoma so that these patients can receive effective first-line treatment with targeted agents, such as crizotinib for ALK-positive disease or erlotinib or afatinib for sensitizing EGFR mutation–positive disease (see NSCL-16, NSCL-17, and NSCL-18, pages 517–519).46,5456 In patients with squamous cell carcinoma, in which these abnormalities are rarer, molecular testing for ALK gene rearrangements and sensitizing EGFR mutations can be considered, especially when the biopsy specimen is small and a mixed histology tumor cannot be ruled out, and/or in a patient with other significant risk factors such as minimal smoking history. Both erlotinib and afatinib are FDA-approved for first-line use in patients with proven sensitizing EGFR mutations; gefitinib and icotinib are also EGFR TKIs that are licensed in other countries.57 EGFR, KRAS, and ALK genetic alterations do not usually overlap49; KRAS mutations are the most common mutation in lung adenocarcinomas. Although KRAS mutations are not currently considered directly actionable, upfront KRAS testing has been proposed as a sequential approach to determine which patients (ie, those positive for KRAS mutations) may not require additional molecular diagnostic testing.46,55,58 However, sequential testing has also been criticized because it slows down the determination of actionable abnormalities and therefore decreases the ability of patients to be treated in the first-line setting. Moreover, sequential testing may deplete samples, necessitating additional biopsies to provide tissue for molecular testing in patients with lung cancer whose tumors are not easily accessible and therefore only small specimens are available.

DNA mutational analysis to detect EGFR mutations is the preferred method for determining whether patients are eligible for EGFR-TKI therapy46,5961; immunohistochemistry (IHC) and EGFR copy number analysis are not recommended as a means of determining who should receive EGFR-TKI therapy.46 Various DNA mutation 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 of the EGFR gene is a reasonable approach; however, more-sensitive methods are available.60,6265 The joint College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/ASCO guidelines suggest that the methodology should detect all actionable mutations occurring with a frequency of 1% or more among EGFR mutations.46 Mutation-specific screening assays for detecting multiple biomarkers simultaneously, such as the Sequenom MassARRAY system and SNaPshot Multiplex System, have been developed that can detect more than 50 point mutations, including a range of different sensitizing and resistant EGFR mutations.66,67 ALK gene rearrangements can be detected using the dual probe “break-apart” fluorescence in situ hybridization (FISH) assay, which has been approved by the FDA for detecting ALK rearrangements and is a prerequisite before treatment with crizotinib.46,68 However, several other assays can be used, including IHC for ALK or reverse transcriptase–polymerase chain reaction (RT-PCR) for specific fusion transcripts.45,68 Multiple studies have explored IHC for ALK; however, the antibody used, antigen retrieval technique, staining technique, scoring system, and cutpoint for determining positivity are not yet standardized. Some studies suggest that IHC can be used to screen for ALK rearrangements, either alone or as part of a sequential screen, reserving FISH analysis to confirm or deny some or all IHC-positive cases. However, until a specific widespread IHC methodology is validated, it is not yet possible to recommend IHC (not otherwise specified) for ALK screening.4446,6976

Serial testing of genes, such as KRAS, EGFR, and ALK, is likely to miss other potentially actionable targets and to deplete the scant tissue material. Next-generation sequencing (NGS; ie, massive parallel sequencing) can identify a very large number of genetic abnormalities at the same time. Comprehensive analysis of the whole genome, whole exome, and/or transcriptome sequencing using NGS technology has significantly advanced the understanding of the molecular pathogenesis of cancer. However, conducting these assays in the clinic routinely poses several challenges, including the complexity of bioinformatics, high cost, and a long turnaround time. Instead, targeted NGS using a panel of cancer-related genes allows unbiased variant detection using a single platform. It is now feasible to conduct these assays using formalin-fixed paraffin-embedded specimens. However, it is important to recognize that NGS requires quality control as much as any other diagnostic technique; because NGS is primer-dependent, the panel of genes and abnormalities detected with NGS will vary depending on the makeup of the NGS panel. For example, some panels can detect both mutations and gene rearrangements, and copy number variation, but they are not uniformly present in all NGS assays being conducted either commercially or in institutional laboratories.7780 The NCCN Guidelines Panel strongly endorses broader molecular profiling using either multiplex mutational analyses and FISH or appropriate NGS panels to minimize delay and tissue requirements (and thus increase both efficiency and cost-effectiveness when compared with doing multiple separate analyses) and to identify other actionable driver abnormalities beyond ALK and EGFR to ensure that patients receive the most appropriate treatment.55 Patients found to have novel oncogenes with molecular profiling may be eligible for clinical trials of targeted agents that are being explored for their activity in these subtypes of disease.

Summary

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for NSCLC. Targeted therapy is very effective in select patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue for these genetic alterations in patients with advanced NSCLC to determine whether they are candidates for targeted therapy. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most common actionable abnormalities, notably ALK gene rearrangements and sensitizing EGFR mutations.

The NCCN Guidelines for NSCLC recommend molecular testing for ALK gene rearrangements and EGFR mutations (category 1) in patients with advanced adenocarcinoma so that these patients can receive effective first-line treatment with targeted agents, such as erlotinib or afatinib for EGFR-sensitizing mutations, or crizotinib for ALK-rearranged disease (see NSCL-16, NSCL-17, and NSCL-18, pages 517–519).46,5456 In patients with squamous cell carcinoma, in which these abnormalities are much rarer, molecular testing for ALK gene rearrangements and sensitizing EGFR mutations can be considered, especially in patients with a small biopsy specimen in which a mixed histology component may be missed or in those who have other risk factors, such as minimal smoking history. DNA mutational analysis for sensitizing EGFR mutations is the preferred method to determine eligibility for EGFR-TKI therapy.46,5961 Direct sequencing of DNA corresponding to exons 18 to 21 of the EGFR gene is a reasonable approach; however, more-sensitive mutation-specific methods are available.60,6265 ALK gene rearrangements can be detected using dual-probe “break-apart” FISH assay.46 Studies suggest that other assays, such as RT-PCR or IHC, can also be used to screen for ALK rearrangements. However, because multiple different techniques exist for IHC, until a specific widespread ALK IHC technique is validated, it is not yet possible to recommend IHC for ALK screening. Multiplex molecular testing may be possible for actionable mutations and for gene rearrangements, depending on the techniques and platforms used. Multiplex molecular testing offers potential advantages by minimizing delays and tissue requirements, potentially increasing both efficiency and cost-effectiveness, and identifying rarer but still potentially actionable abnormalities in other driver oncogenes that would make patients candidates for enrollment onto clinical trials.

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    Version 6.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    Version 6.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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