NCCN: Continuing Education
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
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
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.
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
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.4–6,8–12 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.4,5,8–10 Other actionable molecular abnormalities continue to be discovered and explored, including BRAF mutations and ROS1 and RET rearrangements.7,21–25
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
Approximately 2% to 7% of patients with NSCLC have ALK gene rearrangements.4,44–46 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.48,50–53 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
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).46,54–56 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 therapy46,59–61; 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.60,62–65 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.44–46,69–76
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.77–80 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.
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).46,54–56 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.46,59–61 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.60,62–65 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.
HowladerNNooneAMKrapchoM. SEER Cancer Statistics Review 1975-2011 based on November 2013 SEER data submission posted to the SEER web site April 2014.Bethesda, MD: National Cancer Institute; 2014. Available at: http://seer.cancer.gov/csr/1975_2011/. Accessed April 21 2015.
RosellRCarcerenyEGervaisR. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol2012;13:239–246.
FukuokaMWuYLThongprasertS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol2011;29:2866–2874.
AliGProiettiAPelliccioniS. ALK rearrangement in a large series of consecutive non-small cell lung cancers: comparison between a new immunohistochemical approach and fluorescence in situ hybridization for the screening of patients eligible for crizotinib treatment. Arch Pathol Lab Med2014;138:1449–1458.
LindemanNICaglePTBeasleyMB. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol2013;8:823–859.
LeighlNBRekhtmanNBiermannWA. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: american society of clinical oncology endorsement of the college of american pathologists/international association for the study of lung cancer/association for molecular pathology guideline. J Clin Oncol2014;32:3673–3679.
EberhardDAGiacconeGJohnsonBENon-Small-Cell Lung Cancer Working Group. Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. J Clin Oncol2008;26:983–994.