What are the guidelines for molecular testing and treatment in non–small cell lung cancer (NSCLC)?

Updated: Jun 05, 2020
  • Author: Winston W Tan, MD, FACP; Chief Editor: Nagla Abdel Karim, MD, PhD  more...
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Answer

International evidence-based guidelines jointly published by the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) in 2013 recommend all lung cancer patients with adenocarcinomas should be tested for the genetic abnormalities that indicate suitability for treatment with targeted agents, irrespective of clinical variables such as sex, ethnicity, or smoking status. [57]  These guidelines were endorsed by the American Society for Clinical Oncology (ASCO) in 2014  [221]

National Comprehensive Cancer Network recommendations

In patients with adenocarcinoma, large cell NSCLC, and NSCLC not otherwise specified, the NCCN recommends the following molecular testing, conducted as part of broad molecular profiling [91] :

  • EGFR mutation testing (category 1)
  • ALK testing (category 1)
  • ROS1 testing
  • BRAF testing
  • MET exon 14 skipping testing
  • RET testing
  • Programmed death ligand 1( PD-L1) testing (category 1)

In patients with squamous cell NSCLC, the NCCN recommends the following molecular testing, conducted as part of broad molecular profiling:

  • Consider  EGFR mutation and  ALK testing in never smokers or small biopsy specimens or mixed histology
  • Consider  ROS1, BRAF, MET exon 14 skipping, and  RET testing in small biopsy specimens or mixed histology
  • PD-L1 testing

For patients with a sensitizing EGFR mutation, the NCCN recommends the following for first-line therapy:

  • Osimertinib (preferred; also recommended for subsequent therapy)
  • Afatinib
  • Erlotinib
  • Dacomitinib
  • Gefitinib
  • Erlotinib + ramucirumab
  • Erlotinib + bevacizumab (nonsquamous)

For ALK rearrangement–positive patients, the NCCN recommends the following for first-line therapy:

  • Alectinib (preferred)
  • Brigatinib
  • Ceritinib
  • Crizotinib (useful for patients with performance status 0-4)

For subsequent therapy in ALK rearrangement–positive patients, the NCCN recommends the following:

  • Alectinib
  • Brigatinib
  • Ceritinib
  • Lorlatinib

For ROS1 rearrangement–positive patients, the NCCN recommends the following for first-line therapy:

  • Ceritinib
  • Crizotinib
  • Entrectinib

For BRAF V600E mutation–positive patients, the NCCN recommends dabrafenib/trametinib for first-line as well as subsequent therapy.

For NTRK gene fusion–positive patients, the NCCN recommends larotrectinib or entrectinib for first-line as well as subsequent therapy.

For patients with PD-L1 ≥1%, the NCCN recommends the following for first-line therapy:

  • Pembrolizumab
  • (Carboplatin or cisplatin)/pemetrexed/pembrolizumab (nonsquamous)
  • Carboplatin/paclitaxel/bevacizumab/atezolizumab (nonsquamous)
  • Carboplatin/(paclitaxel or albumin-bound paclitaxel)/pembrolizumab (squamous)
  • Carboplatin/albumin-bound paclitaxel/atezolizumab (nonsquamous)
  • Nivolumab/ipilimumab

For MET exon 14 skipping mutation–positive patients, the NCCN recommends capmatinib or crizotinib for first-line as well as subsequent therapy.

For MET rearrangment–positive patients, the NCCN recommends selpercatinib, cabozantinib, or vandetanib for first-line as well as subsequent therapy.

ESMO recommendations

Guidelines from the European Society for Medical Oncology (ESMO) contain the following recommendations on molecular testing in patients wqith NSCLC [222] :

  • EGFR mutation status should be systematically analysed in advanced NSCC. At a minimum, when resources or material are limited, the most common activating mutations (exon 19 deletion, exon 21 L858R point mutation) should be determined; T790M mutation testing is mandatory on disease relapse.
  • Testing for  ALK rearrangement should be systematically carried out in advanced nonsquamous NSCLC.
  • Testing for  ROS1 rearrangement should be systematically carried out in advanced NSCLC.
  • BRAF V600 mutation status should be systematically analysed in advanced NSCLC
  • Molecular  EGFR and  ALK testing are not recommended in patients with a confident diagnosis of squamous cell NSCLC, except in unusual cases (eg, never/former light smokers or long-time ex-smokers)
  • If available, multiplex platforms (NGS) for molecular testing are preferable.
  • PD-L1 inmunohistochemistry should be systematically determined in advanced NSCLC.

In patients with metastatic NSCLC with positive molecular tests, ESMO treatment recommendations are as follows:

  • Sensitizing  EGFR mutation: Osimertinib; gefitinib; erlotinib, erlotinib + bevacizumab, erlotinib + ramucirumab, afatinib, dacomitinib, gefitinib/carboplatin/pemetrexed
  • ALK translocation: Alectinib, crizotinib, ceritinib, brigatinib
  • BRAF V600 mutation: Dabrafenib/trametinib
  • ROS1 translocation: Crizotinib

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