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National Comprehensive Cancer Network

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NCCN Flash Updates: NCCN Guidelines®, NCCN Compendium®, and NCCN Templates® for Non-Small Cell Lung Cancer and NCCN Guidelines with NCCN Evidence Blocks for Occult Primary

NCCN has published updates to the following NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) with NCCN Evidence Blocks:

  • Occult Primary (Cancer of Unknown Primary [CUP]), Version 1.2020

NCCN has published updates to the NCCN Guidelines® and the NCCN Drugs and Biologics Compendium (NCCN Compendium®) for Non-Small Cell Lung Cancer (NSCLC). These NCCN Guidelines are currently available as Version 1.2020.

  • Preference Stratification applied throughout the Guidelines for systemic therapy recommendations.
  • Diagnostic Follow-up of Incidental Findings (DIAG-2, DIAG-3)
    • Footnote j:
      • Previous version: Patients with a suspicion of lung cancer after PET/CT require histologic confirmation before any nonsurgical therapy. When a biopsy is not possible, a multidisciplinary evaluation should be done including radiation oncology, surgery, and interventional pulmonology.
      • Updated version: Patients require tissue confirmation of lung cancer before any nonsurgical therapy. Multidisciplinary evaluation that at least includes interventional radiology, thoracic surgery, and interventional pulmonology is recommended to determine the safest and most efficient approach, or to provide consensus that a biopsy is too risky or difficult and that the patient can proceed with therapy without tissue confirmation. (IJsseldijk MA, Shoni M, Siegert C, et al. Survival after stereotactic body radiation therapy for clinically diagnosed or biopsy-proven early-stage NSCLC: A systematic review and meta-analysis. J Thorac Oncol 2019;14:583-595.) (same footnote added as footnote n on NSCL-2, NSCL-3)
  • Initial Evaluation (NSCL-1)
    • Last bullet added: For tools to aid in the optimal assessment and management of older adults, see the NCCN Guidelines for Older Adult Oncology.
  • Treatment with Ablative Therapy (NSCL-2, NSCL-17)
    • Footnote m modified: Interventional radiology ablation Image-guided thermal ablation is an option for selected patients.
      • Footnote added to NSCL-15, NSCL-20, NSCL-21, NSCL-23, NSCL-24
  • Stage IB (peripheral T2a, N0); Stage I (central T1abc–T2a, N0); Stage II (T1abc–2ab, N1; T2b, N0); Stage IIB (T3, N0); Stage IIIA (T3, N1) (NSCL-3)
    • Medically inoperable, N0
      • Consider adjuvant chemotherapy changed from a category 2B recommendation to a category 2A recommendation.
    • Medically inoperable, N1
      • Footnote t added: Durvalumab is not recommended for patients following definitive surgical resection. (also applies to NSCL-6, NSCL-7, NSCL-9, NSCL-12, and NSCL-13)
  • Chest wall, proximal airway, or mediastinum (T3 invasion, N0-1; resectable T4 extension, N0-1) and Stage IIIA (T4, N0-1) (NSCL-7)
    • Surgical reevaluation including chest CT ± PET/CT added after concurrent chemoradiation or chemotherapy.
  • Mediastinal Biopsy Findings: T1-2, T3 (other than invasive), N2 nodes positive, M0 (NSCL-9)
    • Induction chemotherapy ± RT; No apparent progression
      • Chemotherapy removed as an option with surgery ± RT.
  • Multiple Lung Cancers (N0-1) (NSCL-11)
    • Ablation clarified as image-guided thermal ablation.
  • Surveillance (NSCL-16)
    • Recurrence followed by PET/CT and Brain MRI added.
  • Advanced or Metastatic Disease (NSCL-18)
    • Footnote ii:
      • Previous version: If repeat biopsy is not feasible, plasma testing should be considered.
      • Updated version: If there is insufficient tissue to allow testing for all of EGFR, ALK, ROS1, and BRAF, repeat biopsy and/or plasma testing should be done. If these are not feasible, treatment is guided by available results and, if unknown, these patients are treated as though they do not have driver oncogenes.
    • Testing Results
      • The following modifications were made:
        • PD-L1 ≥1% and EGFR, ALK, ROS1, BRAF, negative or unknown
        • EGFR, ALK, ROS1, BRAF negative or unknown, PD-L1 <1% or unknown
  • Advanced or Metastatic Disease
    • Sensitizing EGFR Mutation Positive (NSCL-19)
      • Footnote qq added: If systemic therapy regimen contains an immune checkpoint inhibitor, physicians should be aware of the long half-life of such drugs and data reporting adverse events when combining checkpoint inhibitors with osimertinib. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol 2019;30:839-844; Oshima Y, Tanimoto T, Yuji K, Tojo A. EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. JAMA Oncol 2018;4:1112-1115; Ahn M-J, Yang J, Yu H, et al. Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: Results from the TATTON phase Ib trial. J Thorac Oncol 2016;11:S115.(abstr 1360).
    • Sensitizing EGFR Mutation Positive (NSCL-20, NSCL-21)
      • Progression on osimertinib or Progression on erlotinib, afatinib, gefitinib, or dacomitinib
        • Multiple lesions
          • Footnote ss added: Consider a biopsy at time of progression to rule out SCLC transformation.
    • Sensitizing EGFR Mutation Positive (NSCL-21)
      • Symptomatic brain metastases
        • Footnote ww modified: Consider osimertinib (regardless of T790M status) or pulse erlotinib for progressive leptomeningeal disease. In the Bloom study, osimertinib was used at 160 mg.
    • ROS1 Rearrangement Positive (NSCL-25)
      • Progression
        • Footnote ddd added: Beware of flare phenomenon in subset of patients who discontinue TKI. If disease flare occurs, restart TKI inhibitor.
    • PD-L1 Expression ≥1% (NSCL-28, NSCL-29)
      • First-line therapy
        • Squamous cell carcinoma
          • Cisplatin combination with (paclitaxel or albumin-bound paclitaxel) + pembrolizumab removed.
      • Continuation maintenance
        • Close observation removed
        • Adenocarcinoma, large cell, NSCLC NOS: atezolizumab and/or bevacizumab
    • Adenocarcinoma, Large Cell, NSCLC NOS and EGFR, ALK, ROS1, and BRAF negative, PD-L1 <1% (NSCL-30)
      • Footnote ooo added: In general, four cycles of initial systemic therapy (ie, with carboplatin or cisplatin) are administered prior to maintenance therapy. However, if patient is tolerating therapy well, consideration can be given to continue to 6 cycles. (also applies to NSCL-31)
      • Footnote ppp modified: If progression on PD-1/PD-LI inhibitor, switching to another PD-1/PD-L1 inhibitor is not routinely recommended. (also applies to NSCL-31)
      • Continuation maintenance
        • Close observation removed (also applies to NSCL-31)
        • Atezolizumab and/or bevacizumab
  • Principles of Radiation Therapy
    • Conventionally Fractionated RT for Locally Advanced NSCLC (NSCL-C 4 of 10)
      • Bullet 2, Sub-bullet 1, Sentence 3 modified
        • While optimal RT dose intensification remains a valid question, a higher doses of 74 Gy are is not currently recommended for routine use.
      • Table 5. Normal Tissue Dose-Volume Constraints for Conventionally Fractionated RT with Concurrent Chemotherapy (NSCL-C 8 of 10)
        • References added
      • References 81 and 96 added (NSCL-C 10 of 10)
  • Chemotherapy Regimens used with Radiation Therapy (NSCL-E)
    • Regimen removed: Cisplatin 100 mg/m2 days 1 and 29; vinblastine 5 mg/m2/weekly x 5; concurrent thoracic RT
    • Footnote § added: If using durvalumab, an additional 2 cycles of chemotherapy is not recommended, if patients have not received full-dose chemotherapy concurrently with RT.
  • Principles of Molecular and Biomarker Analysis
    • Testing Methodologies (NSCL-G 1 of 5)
      • New sub-bullet 2
        • It is recommended at this time that when feasible, testing be performed via a broad, panel-based approach, most typically performed by next generation sequencing (NGS). For patients who, in broad panel testing don’t have identifiable driver oncogenes (especially in never smokers), consider RNA-based NGS if not already performed, to maximize detection of fusion events.
    • ALK Gene Rearrangements (NSCL-G 2 of 5)
      • Sub-bullet 4; sentence modified
        • FDA-approved IHC (ALK [D5F3] CDx Assay) can be utilized as a stand-alone test, not requiring confirmation by FISH, although secondary confirmation is encouraged. Numerous NGS methodologies can detect ALK fusions. Targeted real-time PCR assays are used in some settings, although they are it is unlikely to detect fusions with novel partners.
    • ROS1 Gene Rearrangements (NSCL-G 3 of 5)
      • Testing Methodologies section modified
        • Numerous NGS methodologies can detect ROS1 fusions, although DNA-based NGS may under-detect ROS1 fusions. Targeted real-time PCR assays are utilized in some settings, although they are unlikely to detect fusions with novel partners (which may lead to under-detection of ROS1 fusion events).
    • KRAS Point Mutations (NSCL-G 3 of 5)
      • Sub-bullet 4 modified
        • Owing to the low probability of overlapping targetable alterations, the presence of a known activating mutation in KRAS may identifies patients who will not are unlikely to benefit from further molecular testing.
    • New section added: NTRK (neurotrophin tyrosine receptor kinase) gene fusions
      • NTRK 1/2/3 are tyrosine receptor kinases that are rarely rearranged in NSCLC as well as in other tumor types, resulting in dysregulation and inappropriate signaling.
      • Numerous fusion partners have been identified.
      • To date, no specific clinicopathologic features, other than absence of other driver alterations, have been identified in association with these fusions.
      • Testing Methodologies: Various methodologies can be used to detect NTRK gene fusions, including: FISH, IHC, PCR, and NGS; false negatives may occur. IHC methods are complicated by baseline expression in some tissues. FISH testing may require at least 3 probe sets for full analysis. NGS testing can detect a broad range of alterations. DNA-based NGS may under-detect NTRK1 and NTRK3 fusions.
    • PD-L1 (NSCL-G 4 of 5)
      • Sub-bullet 2; Entry 2 modified
        • Interpretation of PD-L1 IHC in NSCLC is typically focused on the proportion of tumor cells expressing membranous staining at any level and therefore is a linear variable, scoring systems may be different in other tumor types.
      • Sub-bullet 2; Entry 3 modified
        • The FDA-approved IHC assay for PD-L1 utilizes a cutoff of ≥1% tumor proportion score for first-line and 1% tumor proportion score for second-line therapy with pembrolizumab. The FDA-approved companion diagnostic for PD-L1 guides utilization of pembrolizumab in patients with NSCLC and is based on the tumor proportion score (TPS). TPS is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity.
      • Sub-bullet 2; Entry 5 is new
        • Although PD-L1 expression can be elevated in patients with an oncogenic driver, targeted therapy for the oncogenic driver should take precedence over treatment with an immune checkpoint inhibitor.
    • Content removed: IHC for Biomarker Selection in NSCLC: (NSCL-G 5 of 5)
      • ALK fusions: IHC assays for ALK can serve as a screening modality for further ALK testing, and can alternatively be used as a stand-alone test to determine eligibility for ALK TKI. An FDA-approved IHC assay for ALK is available.
      • ROS1 fusions: IHC assays for ROS1 should only be deployed as a screening modality for further ROS1 testing, because the specificity of a positive result is low. Positive ROS1 IHC should not be utilized to select patients for TKI therapy without additional confirmatory testing. Currently there is not an FDA-approved IHC assay for ROS1.
      • BRAF p.V600E mutations: An antibody specific to the p.V600E mutation is available. Some studies have examined utilization of this antibody in cases of NSCLC; however, optimization of this antibody may be tumor-specific and care should be exercised when using this approach.
    • Plasma Cell-Free/Circulating Tumor DNA Testing (NSCL-G 5 of 5)
      • Sub-bullet 1 modified
        • Cell-free/circulating tumor DNA testing should not be used in lieu of a tissue diagnosis histologic tissue diagnosis.
  • Systemic Therapy for Advanced or Metastatic Disease
    • Maintenance Therapy (NSCL-J 1 of 4)
      • Bullets added:
        • Patients should receive maintenance therapy for 2 years if they received front-line immunotherapy.
        • Patients should receive maintenance therapy until progression if they received second-line immunotherapy.
      • Initial Systemic Therapy Options (NSCL-J 3 of 4)
        • Squamous Cell Carcinoma (PS 0-1)
          • The following regimens were removed:
            • Pembrolizumab/cisplatin/paclitaxel
            • Pembrolizumab/cisplatin/albumin-bound paclitaxel

NCCN has published updates to the NCCN Chemotherapy Order Templates (NCCN Templates®) for Non-small Cell Lung Cancer (NSCLC) to reflect the NCCN Guidelines for Non-small Cell Lung Cancer v1.2020

  • The following NCCN Templates have been removed:
    • NSC7: CISplatin/VinBLAStine with Concurrent Radiation
    • NSC90: PACLitaxel/CISplatin + Pembrolizumab followed by Pembrolizumab Maintenance
    • NSC91: Albumin-bound PACLitaxel/CISplatin + Pembrolizumab followed by Pembrolizumab Maintenance

For the complete updated versions of the NCCN Guidelines, NCCN Guidelines with NCCN Evidence Blocks™, the NCCN Drugs & Biologics Compendium (NCCN Compendium®), the NCCN Biomarkers Compendium®, the NCCN Chemotherapy Order Templates (NCCN Templates®), the NCCN Radiation Therapy Compendium™, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™), please visit NCCN.org.

To view the NCCN Guidelines for Patients®, please visit NCCN.org/patientguidelines.

Free NCCN Guidelines apps for iPhone, iPad, and Android devices are now available! Visit NCCN.org/apps.

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