NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer.
Accreditation Statement NCCN
Physicians: National Comprehensive Cancer Network is accredited by the Accreditation Council for Continuing Medical Education (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™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: National Comprehensive Cancer Network 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.
Pharmacists: National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: 0836-0000-18-007-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the educational content; 2) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/83667; and 3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail firstname.lastname@example.org.
Release date: July 10, 2018; Expiration date: July 10, 2019
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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
Lung cancer is the leading cause of cancer death in the United States.1 In 2018, an estimated 234,030 new cases of lung and bronchial cancer will be diagnosed and 154,050 deaths will occur.2,3 However, quality of life and progression-free survival (PFS) have improved for patients with advanced non–small cell lung cancer (NSCLC) who have specific predictive biomarkers and receive targeted therapy or immunotherapy compared with those receiving chemotherapy.4–9 These NCCN Guidelines Insights focus on recent updates in targeted therapy and immunotherapy for patients with advanced NSCLC. For a list of the 2018 updates, see the complete version of the NCCN Guidelines for NSCLC (available at NCCN.org). The NCCN Guidelines for NSCLC address all aspects of disease management.
A predictive biomarker is correlated with therapeutic efficacy based on the mechanism of action between
Key established predictive biomarkers include ALK rearrangements, ROS1 rearrangements, sensitizing EGFR mutations, BRAF V600E point mutations, and PD-L1 expression levels (see NSCL-G, pages 815–818, and “Established Biomarkers,” following section). The NCCN panel recommends testing for these key established biomarkers in patients with advanced NSCLC before initial treatment, because effective targeted therapy or immunotherapy is available. The panel strongly advises broader molecular profiling to assess for emerging biomarkers (see NSCL-17, page 809, and “Emerging Biomarkers,” page 816).
ALK Rearrangements: Approximately 5% of patients with NSCLC have ALK rearrangements; these patients tend to have adenocarcinoma histology and be never-smokers or light smokers.11,12 The NCCN panel recommends testing for ALK rearrangements (category 1 recommendation) based on the efficacy of alectinib, crizotinib, and ceritinib (see NSCL-17, page 809). Two tests have been FDA-approved for stand-alone testing or rapid prescreening: (1) a fluorescence in situ hybridization (FISH) diagnostic test, and (2) an immunohistochemistry assay.13–22 Next-generation sequencing (NGS) can be used if the platform has been appropriately designed and validated.23–27
Initial ALK-Directed Therapy: Alectinib is an oral tyrosine kinase inhibitor (TKI) that inhibits ALK rearrangements.28 A phase III randomized trial (ALEX) assessed first-line therapy with alectinib versus crizotinib in 303 patients with ALK-positive
A phase III randomized trial (J-ALEX) assessed first-line therapy with alectinib versus crizotinib in 207 Japanese patients with ALK-positive advanced NSCLC, with results similar to the ALEX trial.5 The NCCN panel recommends alectinib as a preferred first-line treatment (category 1) for ALK-positive metastatic NSCLC based on these clinical trials and FDA approval (see NSCL-21, page 810). Two other ALK inhibitors, crizotinib and ceritinib, are also recommended (category 1 for both) by the panel for first-line therapy in patients with ALK-positive NSCLC based on clinical trial data and FDA approvals.6,29,30
Subsequent Therapy: Patients typically experience disease progression after initial therapy with
ROS1 Rearrangements: Although ROS1 is a distinct receptor tyrosine kinase, it is very similar to ALK.45,46 ROS1 rearrangements occur in approximately 1% to 2% of patients with NSCLC, and occur more frequently in younger women (median age, 50 years) with adenocarcinoma who are never-smokers and in those negative for EGFR and KRAS mutations and ALK rearrangements.46–49 The NCCN Guidelines Panel recommends ROS1 testing based on the efficacy of crizotinib and ceritinib (see NSCL-17 and NSCL-24, pages 809 and 813).46,50,51 Testing for ROS1 rearrangements may be performed using FISH (see
First-Line Therapy: Crizotinib inhibits ROS1 rearrangements and is FDA-approved for patients with locally advanced or metastatic ROS1-positive NSCLC.6,29,50,55–59 Crizotinib is very effective for patients with ROS1 rearrangements, yielding response rates of approximately 70% to 80%, including complete responses (CRs).46,50,51 In 50 patients with ROS1-positive advanced NSCLC, crizotinib yielded an objective response rate of 72% (95% CI, 58–84), with 3 CRs and 33 partial responses (PRs).46 The median duration of response was 17.6 months (95% CI, 14.5 months to not reached), and the median PFS was 19.2 months (95% CI, 14.4 months to not reached). Another study assessed crizotinib in 30 patients with ROS1-positive stage IV NSCLC.50 There were 5 CRs (overall response rate [ORR], 80%; disease control rate, 86.7%), and median PFS was 9.1 months. Many patients (n=26) received pemetrexed (either alone or in combination with platinum, and either before or after crizotinib) and had a response rate of 57.7% and a median PFS of 7.2 months. For the 2018 guideline update, the NCCN panel voted that crizotinib is the preferred agent for patients with ROS1-positive NSCLC based on trial data and the FDA approval (see NSCL-24, above).
Ceritinib is an oral TKI that inhibits ROS1 rearrangements.60 A phase II trial assessed ceritinib as first-line therapy in patients (n=28 evaluable) with ROS1-positive NSCLC.60 One CR and 19 PRs (ORR, 62%; 95% CI, 45%–77%) were reported. PFS was 19.3 months (95% CI, 1–37 months) for crizotinib-naïve patients and 9.3 months (95% CI, 0–22 months) for all patients; median overall survival
Subsequent Therapy: For patients with ROS1-positive NSCLC who progress on first-line crizotinib or ceritinib, the panel recommends the initial cytotoxic chemotherapy regimens (eg, carboplatin/pemetrexed for nonsquamous NSCLC) used for first-line treatment of NSCLC in patients without genetic alterations or a clinical trial (see NSCL-24, page 813). Alectinib and ceritinib are not recommended in patients with ROS1-positive NSCLC whose disease becomes resistant to crizotinib, because no trial data suggest that these agents would be effective in this setting.46 In patients with biomarkers who have progressed on targeted therapy, immunotherapy appears to be less effective (regardless of PD-L1 expression levels).39–42 Ongoing studies are assessing new agents for patients with ROS1-positive NSCLC whose disease becomes resistant to crizotinib.61–64
BRAF V600E Mutations: BRAF is a serine/threonine kinase that is part of the MAP/ERK signaling pathway. BRAF V600E is the most common of the BRAF point mutations, occurring in 1% to 2% of patients with lung adenocarcinoma who are typically current or former smokers.65–67 BRAF mutations typically do not overlap with EGFR mutations or ALK rearrangements.65,68 The NCCN panel recommends testing for BRAF mutations based on data showing the efficacy of dabrafenib/trametinib (see NSCL-17, page 809).65,68 Real-time PCR, Sanger sequencing, and NGS are the most commonly used methods to assess for BRAF mutations (see NSCL-G, pages 815–818).
Dabrafenib and trametinib inhibit kinases in the RAS/RAF/MEK/ERK pathway.65,68 Dabrafenib inhibits BRAF harboring V600E mutations; trametinib inhibits MEK 1/2, which is downstream of BRAF signaling. A phase II trial assessed first-line
A phase II study assessed subsequent therapy with the dabrafenib/trametinib regimen in 57 patients with advanced NSCLC and BRAF V600E mutations whose disease had progressed on chemotherapy.65,70 The response rate was 63% (n=36) with dabrafenib/trametinib; PFS was 9.7 months (95% CI, 6.9–19.6). Serious AEs occurred in 56% of patients (n=32), including pyrexia, anemia, confusional state, hemoptysis, hypercalcemia, and cutaneous squamous cell carcinoma. Common grade 3 to 4 AEs included neutropenia in 9% (n=5), hyponatremia in 7% (n=4), and anemia in 5% (n=3). Four patients died of retroperitoneal hemorrhage, subarachnoid hemorrhage, respiratory distress, or severe disease progression. Preliminary updated data showed that patients receiving dabrafenib/trametinib had a median OS of 18.2 months (95% CI, 14.3 months to not estimable).71
Based on these trials and the FDA approval, the NCCN Guidelines Panel recommends first-line or subsequent therapy with dabrafenib/trametinib in patients with metastatic NSCLC and BRAF V600E mutations (see NSCL-25, page 814).69,71,72 First-line or subsequent chemotherapy regimens are also recommended options using the same initial cytotoxic regimens recommended for patients without genetic alterations (eg, carboplatin/pemetrexed for nonsquamous disease). Single-agent therapy with dabrafenib or vemurafenib is also an option for patients with BRAF V600E mutations who cannot tolerate combination therapy with dabrafenib/trametinib.68,71,73
The NCCN Guidelines recommend broad-based molecular testing to assess for rare driver mutations for which effective drugs may be available (even if not yet FDA-approved for lung cancer), or to counsel patients regarding the availability of clinical trials in addition to assessing for established biomarkers. Emerging rare driver mutations include HER2 mutations (ie, ERBB2 mutations), RET rearrangements, high-level MET amplification, or MET exon 14 skipping mutations (see “Emerging Targeted Agents for Patients With Genetic Alterations” in the complete version of the NCCN Guidelines [NSCL-H]). Clinical trials are currently in progress for other emerging biomarkers; for example, new targeted agents are being assessed for effectiveness in patients with NTRK fusions.74,75
The NCCN panel recommends first-line pembrolizumab/carboplatin (or cisplatin)/pemetrexed (category 1) for patients with advanced nonsquamous NSCLC (ie, adenocarcinoma, large cell carcinoma) or NSCLC not otherwise specified based on data from phase II and III trials and on the FDA approval (pembrolizumab/carboplatin/pemetrexed).76,77 Pembrolizumab/chemotherapy is recommended for patients without (or unknown) genetic alterations whose PD-L1 levels are <50% or unknown. Most patients received pembrolizumab/carboplatin/pemetrexed (72%; n=445), but some received pembrolizumab/cisplatin/pemetrexed (28%; n=171); patients did not have EGFR mutations or ALK rearrangements. The estimated OS rate at 1 year was 69.2% (95% CI, 64.1–73.8) for pembrolizumab/chemotherapy versus 49.4% (95% CI, 42.1–56.2) for chemotherapy alone (HR for death, 0.49; 95% CI, 0.38–0.64; P<.001) after a median follow-up of 10.5 months. OS was improved regardless of PD-L1 expression levels, although most patients (63%) had levels of ≥1%. Median PFS was 8.8 months (95% CI, 7.6–9.2 months) for pembrolizumab/chemotherapy
For the 2018 update, the NCCN panel added a recommendation for atezolizumab/carboplatin/paclitaxel/bevacizumab (category 1) as first-line therapy for patients with metastatic nonsquamous NSCLC based on results of a recent phase III randomized trial (IMpower150).78 This regimen is recommended for patients whose PD-L1 levels are <50% or unknown. Maintenance therapy with atezolizumab, bevacizumab, or both is also recommended (category 1). Patients with EGFR mutations or ALK rearrangements who had experienced disease progression on (or were intolerant of) prior TKI were enrolled in this trial. Median OS was 19.2 months (95% CI, 17.0–23.8) in the atezolizumab arm compared with 14.7 months (95% CI, 13.3–16.9) in the control arm of carboplatin/paclitaxel/bevacizumab; the HR for death was 0.78 (95% CI, 0.64–0.96; P=.02). PFS was increased in the atezolizumab arm versus chemotherapy/bevacizumab (8.3 vs 6.8 months; HR, 0.62; 95% CI, 0.52–0.74; P<.001).
The NCCN panel also added a first-line therapy recommendation (category 2A) for carboplatin/paclitaxel (or nab-paclitaxel)/pembrolizumab for patients with metastatic squamous cell NSCLC based on preliminary data from the phase III KEYNOTE-407 trial.79 This pembrolizumab/chemotherapy regimen is recommended for patients whose PD-L1 levels are <50% or unknown. Maintenance therapy with pembrolizumab is also a recommended option (category 2A). Patients receiving pembrolizumab/chemotherapy had an overall response rate of 58.4% compared with 35.0% in those receiving chemotherapy alone (P=.0004).
The NCCN Guidelines for NSCLC address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to targeted therapy for patients with advanced NSCLC who have ALK or ROS1 rearrangements or BRAF V600E mutations. For the 2018 guideline update, the panel recommends crizotinib as a preferred agent for patients with ROS1 rearrangements. The panel also recommends ceritinib (category 2A) for patients with ROS1-positive advanced NSCLC. A new section was added that describes key established biomarkers and appropriate testing to identify patients with these biomarkers. The NCCN panel also revised the recommendation for pembrolizumab/carboplatin (or cisplatin)/pemetrexed to category 1 (from category 2A) based on recent trial data.78,79 In addition, the following regimens are now recommended: (1) atezolizumab/carboplatin/paclitaxel/bevacizumab (category 1) as first-line therapy for patients with metastatic nonsquamous NSCLC; and (2) pembrolizumab/carboplatin/paclitaxel (or nab-paclitaxel) (category 2A) as first-line therapy for patients with metastatic squamous cell carcinoma.
For a list of all 2018 updates, see the complete NCCN Guidelines for NSCLC (available at NCCN.org).
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BrahmerJRRodriguez-AbreuDRobinsonAG. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol2017;18:1600–1609.
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WallanderMLGeiersbachKBTrippSRLayfieldLJ. Comparison of reverse transcription-polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization methodologies for detection of echinoderm microtubule-associated proteinlike 4-anaplastic lymphoma kinase fusion-positive non-small cell lung carcinoma: implications for optimal clinical testing. Arch Pathol Lab Med2012;136:796–803.
PlanchardDGroenHJMKimTM. Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol2015;33(Suppl 15):Abstract 8006.
PlanchardDBesseBKimTM. Updated survival of patients (pts) with previously treated BRAF V600E–mutant advanced non-small cell lung cancer (NSCLC) who received dabrafenib (D) or D + trametinib (T) in the phase II BRF113928 study [abstract]. J Clin Oncol2017;35(Suppl 15):Abstract 9075.