This site is intended for UK healthcare professionals
Medscape UK Univadis Logo
Medscape UK Univadis Logo

Welcome to the new home for Guidelines

Summary for secondary care

Guideline Essentials: 2023 ESMO Recommendations on Management of Non-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 non-oncogene addicted NSCLC.  

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

Related to This Summary:

General Recommendations 

  • Consider histology, molecular pathology, age, performance status, comorbidities, and patient preferences when deciding on treatment strategy
  • Offer systemic therapy to all stage IV patients with PS 0–2
  • Strongly encourage smoking cessation at all stages of NSCLC because it improves outcomes
  • For patients with oligometastatic disease, discuss treatment strategy upfront with the multidisciplinary tumour board (MTB)
  • Restrict pemetrexed to non-squamous non-small cell carcinoma.

First-line Treatment Recommendations

Table 1: First-line Treatment Options for Non-oncogene Addicted NSCLC

Patient GroupRecommended Treatment Options
First-line Combinations for Advanced NSCLC Regardless of PD-(L)1 Status in Patients with PS 0–1 Without Contraindications for ICIs   
  • Use combinations of platinum-based ChT and anti-PD-(L)1 inhibitors in preference to platinum-based ChT
  • Adjust treatment duration according to tolerability and clinical efficacy
  • In most registered strategies, ICI treatment was limited to 2 years
Non-squamous non-small cell carcinoma
  • Pembrolizumab–pemetrexed–platinum
  • Atezolizumab–bevacizumab–paclitaxel–carboplatin
  • Atezolizumab–carboplatin–nab–paclitaxel
  • Nivolumab–ipilimumab, plus 2 cycles of ChT
Squamous cell carcinoma
  • Pembrolizumab–carboplatin–(nab)–paclitaxel
  • Nivolumab–ipilimumab, plus 2 cycles of ChT 
Options regardless of histology
  • Cemiplimab–platinum-doublet ChT (with pemetrexed maintenance for non-squamous histology)
  • Durvalumab–tremelimumab–platinum-doublet ChT 
PD-(L)1 ≥1% tumours, regardless of histology
  • Nivolumab–ipilimumab is an option
First-line Options for Advanced NSCLC with PD-(L)1 50% in Patients with PS 0–1 Without Contraindications for ICIs
  • Monotherapy ICI is not recommended for patients with tumours with a PD-(L)1 expression <50%, or for never smokers
  • Adjust treatment duration according to tolerability and clinical efficacy
  • In most registered strategies, ICI treatment was limited to 2 years
  • In particular, discontinue nivolumab–ipilimumab after 2 years due to toxicity risk
Standard first-line option
  • Pembrolizumab
  • Atezolizumab (also if ICs ≥10%)
  • Cemiplimab
PS 0–1, PD-(L)1 ≥50%, without contraindications for immunotherapy, and need fast tumour load reductionInstead of monotherapy anti-PD-(L)1:
  • ChT–ICI
  • Nivolumab–ipilimumab with 2 cycles of ChT 
First-line Options for Advanced NSCLC in Patients with PS ≥2
Eligible patients with PS 2 
  • Platinum-based doublets, preferably carboplatin
  • Single-agent ChT with gemcitabine, vinorelbine, docetaxel, or pemetrexed (restricted to non-squamous non-small cell carcinoma)
PS 3–4
  • Offer BSC
Insufficient data are available to date on the use of monotherapy ICI for patients with PS 2, but it can be considered
First-line Treatment for Elderly Patients with Advanced NSCLC
  • Discuss platinum doublet toxicity
  • Carboplatin is the preferred option when toxicity is deemed tolerable
Elderly, good PS, and adequate organ function
  • Similar options to those for the general population, although the benefit of ChT–ICI is unclear in patients ≥75 years
Not eligible for doublet ChT
  • Single-agent ChT remains the standard of care
First-line Treatment for Advanced NSCLC in Patients with PS 0–2 and Contraindications for ICI 
Without major comorbidities, PS 0–2
  • ChT with platinum doublets (see below)
Suitable/eligible for maintenance monotherapy
  • 4 cycles of platinum-based doublets followed by less toxic maintenance monotherapy
Not suitable/eligible for maintenance monotherapy
  • 4 cycles, up to a maximum of 6 cycles
At greater risk of neurotoxicity, pre-existing hypersensitivity to paclitaxel, or contraindications for standard paclitaxel premedication 
  • Consider the carboplatin–nab–paclitaxel regimen as a chemotherapeutic option, particularly in this group
Squamous cell carcinoma, without major comorbidities, and PS 0–2
  • Platinum-based doublets with a third-generation cytotoxic agent (gemcitabine, vinorelbine, taxanes) 
Non-squamous non-small cell carcinoma
  • Pemetrexed-based combination ChT is preferred to gemcitabine- or docetaxel-based combinations
In the absence of contraindications
  • Consider bevacizumab with a carboplatin—paclitaxel- or carboplatin–pemetrexed-based regimen 
  • Only offer maintenance ChT to patients with PS 0–1 after first-line ChT
  • Consider histology, response to platinum-doublet ChT, remaining toxicity after first-line ChT, patient preferences, and PS when making decisions about maintenance
  • Individualise treatment duration based on disease control and toxicity, except in cases of disease progression
PS 0–1, non-squamous non-small cell carcinoma, and disease control following 4 cycles of non-pemetrexed-containing platinum-based ChT
  • Consider pemetrexed switch maintenance 
Disease control following 4 cycles of cisplatin–pemetrexed
  • Consider pemetrexed continuation maintenance 
4 cycles of cisplatin–gemcitabine
  • Continuation maintenance with gemcitabine is an option
NSCLC=non-small cell lung cancer; PD-(L)1=programmed death ligand 1; PS=performance status; ICI=immune checkpoint inhibitor; ChT=chemotherapy; IC=immune cell; BSC=best supportive care

Second-line Treatment Recommendations

Table 2: Second-line Treatment Options for Non-oncogene Addicted NSCLC

Patient GroupRecommended Treatment Options
Second-line Treatment for Advanced NSCLC in Patients with PS 0–2 Treated First Line with ICI    
  • Offer second-line treatment to patients without major comorbidities and PS 0–2
  • The choice of second-line treatment depends on the agents used in the first line
Substantial previous clinical benefit from (ChT)–ICI (provided ICI was previously discontinued but not because of progressive disease or severe toxicity)
  • Consider rechallenge with anti-PD-(L)1, since this has shown reasonable efficacy and good tolerability 
Monotherapy ICI first-line treatment
  • Refer to the recommendations for first-line treatment with contraindication for ICI
ChT–ICI first-line treatment
  • Refer to the recommendations for second-line treatment with contraindication for ICI
Second-line Treatment for Advanced NSCLC in Patients with PS 0–2 not Treated First Line with ICI but Without Contraindications for ICI
Treatment of choice for most patients (except never smokers)
  • PD-(L)1 inhibitors (nivolumab, pembrolizumab, and atezolizumab)
Recommended irrespective of PD-(L)1 expression
  • Nivolumab
  • Atezolizumab
PD-(L)1 expression ≥1%
  • Pembrolizumab
Second Line and Beyond in Patients with Contraindications for ICI
PS 0–2, clinically or radiologically progressing after first-line therapy 
  • Offer second-line therapy irrespective of administration of maintenance treatment
  • Treatment can be prolonged if disease is controlled, and toxicity is acceptable
Adenocarcinoma progressing after previous ChT
  • Nintedanib–docetaxel is an option 
NSCLC progressing after first-line ChT
  • Ramucirumab–docetaxel is an option 
  • Pemetrexed (if not given first line and for non-squamous non-small cell carcinoma only) or docetaxel (all histologies); pemetrexed has a more favourable tolerability profile
PS 0–2, not fit for ChT, advanced squamous cell carcinoma with unknown EGFR status or EGFR-wildtype tumours
  • Afatinib is a potential option 
NSCLC=non-small-cell lung cancer; PS=performance status; ICI=immune checkpoint inhibitor; ChT=chemotherapy; PD-L1=programmed death ligand 1; EGFR=epidermal growth factor receptor

Oligometastatic Disease 

  • Offer local radical therapy (LRT) as well as systemic treatment because it may increase overall survival and progression-free survival
  • Discuss the choice of LRT with the MTB; radiotherapy and surgery are both safe and effective
  • In most cases, consider solitary lesions in the contralateral lung as synchronous second primary tumours and, if possible, treat with curative-intent therapy.

Palliative Radiotherapy in Stage IV Disease 

  • For patients with haemoptysis and symptomatic airway obstruction, offer external beam radiotherapy (EBRT)
  • Consider radiotherapy for symptom control in:
    • haemoptysis
    • symptomatic airway obstruction
    • painful chest wall disease and bone metastasis
    • superior vena cava syndrome
    • soft-tissue or neural invasion
  • High-dose radiotherapy does not result in greater levels of palliation
  • EBRT alone is more effective than endobronchial brachytherapy (EBB) alone for palliation; however, consider EBB in selected patients previously treated with EBRT who are symptomatic from recurrent endobronchial central obstruction
  • Early radiotherapy can relieve neurological symptoms from spinal cord compression. 

Surgery in Stage IV Disease 

  • Consider lung resection with therapeutic intent for highly selected patients
  • Consider surgery as a salvage procedure for highly selected patients who have primary or metastatic lesions with specific complications that can be treated with surgery
  • Manage persisting or recurrent pleural effusions by pleurodesis to improve dyspnoea
    • talc is the preferred agent; for patients who have primary lung cancer, thoracoscopic poudrage may be better than talc slurry injection
    • recurrent malignant pleural effusions can be managed using indwelling pleural catheters and talc poudrage
  • For trapped lung caused by thickened visceral pleural peel, consider indwelling pleural catheters or pleuroperitoneal shunts for symptomatic relief. 

Minimally Invasive Procedures in Stage IV Disease 

  • The following procedures may be helpful:
    • endoscopy debulking by laser, cryotherapy, or stent placement for symptomatic major airway obstruction or post-obstructive infection
    • endoscopy (endobronchial or by guiding endovascular embolisation) for diagnosis and treatment of haemoptysis
    • vascular stenting for NSCLC-related superior vena cava compression.