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Summary for secondary care

Guideline Essentials: 2023 ESMO Recommendations on Management of Oncogene Addicted Metastatic Non-small Cell Lung Cancer


In 2023, the European Society for Medical Oncology (ESMO) published guidelines on the diagnosis, treatment, and follow up of patients with oncogene addicted and non-oncogene addicted metastatic non-small cell lung cancer (NSCLC).

This specialist Guidelines overview for secondary care oncologists outlines recommendations on the management of patients with advanced and metastatic oncogene addicted NSCLC. 

Please refer to the full ESMO guidelines for all of the recommendations, rationale, and background information.

Related to This Summary:

Epidermal Growth Factor Receptor Mutated NSCLC 

Table 1: Treatment Options for Epidermal Growth Factor Receptor Mutated NSCLC

Patient GroupRecommended Treatment Options
First-line Treatment Options
All patients with a sensitising EGFR mutation, irrespective of clinical parameters including gender, tobacco exposure, histology, and PS
  • Offer first-line treatment with EGFR TKIs
  • Single-agent EGFR TKIs can be used as standard due to potential increase in toxicity, costs, and patient inconvenience as each additional treatment is added
Patients with activating EGFR mutation (exon 19 deletion or exon 21 L858R), particularly those who have CNS metastases
  • Osimertinib is preferable
Patients with a major uncommon, non-exon 20 insertion, sensitising EGFR mutation
  • Afatinib or osimertinib are options
Other first-line treatment options
  • Single agents: erlotinib, gefitinib, afatinib, and dacomitinib
  • Gefitinib combined with carboplatin–pemetrexed
  • EGFR TKIs combined with anti-angiogenic therapy, e.g. erlotinib–bevacizumab or erlotinib–ramucirumab
Continue with EGFR TKIs in patients with moderate radiological progression and ongoing clinical benefit
Progression and Treatment Resistance Options
Resistance to first-line first- or second-generation EGFR TKIs
  • Test for EGFR exon 20 T790M mutation from plasma cfDNA and/or tumour re-biopsy 
T790M-positive resistance
  • Osimertinib as second line
T790M-negative resistance
  • Platinum-based ChT
Develops resistance to osimertinib
  • Genomic analysis by NGS (either tissue or cfDNA followed by tissue if no target found with cfDNA)
Progression on osimertinib
  • Platinum-doublet ChT; encourage clinical trial enrolment, particularly if a targetable resistance mechanism is identified
EGFR TKI failure, PS 0–1, and no contraindications for ICIs
  • Consider the combination of atezolizumab–bevacizumab–paclitaxel–carboplatin
Progression on EGFR TKIs and ChT
  • Consider single-agent ICIs only in these circumstances
NSCLC=non-small cell lung cancer; EGFR=epidermal growth factor receptor; PS=performance status; TKIs=tyrosine kinase inhibitors; CNS=central nervous system; cfDNA=cell-free DNA; ChT=chemotherapy; NGS=next generation sequencing; ICI=immune checkpoint inhibitor

Anaplastic Lymphoma Kinase Rearranged NSCLC

Table 2: Treatment Options for Anaplastic Lymphoma Kinase Rearranged NSCLC

Patient GroupRecommended Treatment Options
First line
  • Alectinib, brigatinib, or lorlatinib in preference to crizotinib or ceritinib
Progression on crizotinib; intolerance of crizotinib
  • Alectinib 
Crizotinib resistance
  • Brigatinib and ceritinib are additional treatment options
Progression on second-generation ALK TKI
  • Lorlatinib is an option
Progression on lorlatinib
  • ChT with a platinum–pemetrexed-based combination is recommended
  • Consider atezolizumab–bevacizumab–paclitaxel–carboplatin
NSCLC=non-small cell lung cancer; ALK=anaplastic lymphoma kinase; TKI=tyrosine kinase inhibitor; ChT=chemotherapy

ROS1 Rearranged NSCLC

Table 3: Treatment Options for ROS1 Rearranged NSCLC

Patient GroupRecommended Treatment Options
First line
  • Crizotinib or entrectinib
  • Repotrectinib, if available, is an option
Brain metastases
  • Entrectinib, if available, is preferred to crizotinib
Progression on first-line crizotinib 
  • Offer a newer-generation TKI, if available, or platinum-based ChT 
TKI=tyrosine kinase inhibitor; ChT=chemotherapy

BRAF Mutations

Table 4: Treatment Options for BRAF V600 Mutations in Oncogene Addicted NSCLC

Patient GroupRecommended Treatment Options
First line
  • BRAF–MEK inhibition with dabrafenib–trametinib
No smoking history, received BRAF–MEK inhibition first line 
  • Platinum-based ChT, with or without immunotherapy, second line 
Smoking history, received BRAF–MEK inhibition first line 
NSCLC=non-small cell lung cancer; ChT=chemotherapy; mNSCLC=metastatic non-small cell lung cancer

Other Oncogenic Drivers

Table 5: Treatment Options for Other Oncogenic Drivers of NSCLC

Patient GroupRecommended Treatment Options
RET fusion-positive NSCLC
  • First line: selpercatinib or pralsetinib 
MET amplification, NTRK gene fusion, HER2 mutation, and EGFR exon 20 mutation
  • First line: platinum-doublet ChT, with or without ICIs
MET exon 14 skipping mutation
  • First or second line: capmatinib or tepotinib
MET exon 14 skipping mutation, MET TKI not available
  • First line: platinum-doublet ChT, with or without ICIs
HER2 exon 20 mutations following previous first-line therapy
  • Trastuzumab–deruxtecan, if available
NTRK gene fusion with no satisfactory treatment options
  • Larotrectinib and entrectinib
KRAS G12C-mutated NSCLC
  • See first-line treatment for non-oncogene addicted mNSCLC 
KRAS G12C-mutated NSCLC and progression on first-line monotherapy ICI
  • Platinum-doublet ChT
KRAS G12C-mutated NSCLC following failure of previous therapy
  • Sotorasib
  • Adagrasib
NSCLC=non-small cell lung cancer; RET=rearranged during transfection; MET=mesenchymal epithelial transition; NTRK=neurotrophic tyrosine receptor kinase; HER2=human epidermal growth factor receptor 2; EGFR=epidermal growth factor receptor; ChT=chemotherapy; ICI=immune checkpoint inhibitor; TKI=tyrosine kinase inhibitor; KRAS=Kirsten rat sarcoma virus; mNSCLC=metastatic non-small cell lung cancer