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American Society of Clinical OncologyMedical Oncology2026advanced

Stage IV Non-Small Cell Lung Cancer without Driver Alterations

Published by American Society of Clinical Oncology (ASCO) · ASCO Quality of Evidence (High, Moderate, Low, Very Low) and Strength of Recommendation (Strong, Conditional/Weak)

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Summary

AI-generated

In 2022, ASCO launched living clinical practice guidelines for systemic therapy for patients with stage IV NSCLC with and without driver alterations. This version (2026.3.1) reviews evidence from a routine literature search up to January 21, 2026, and provides updated recommendations on new therapeutics, such as the inclusion of retifanlimab plus platinum-based chemotherapy as a first-line option.

NSCLCstage IV NSCLCretifanlimabplatinum chemotherapyASCOmedical oncologyguidelinesrecommendations

Key Takeaways

  • 1
    Retifanlimab plus platinum-based chemotherapy is a new conditional first-line treatment option for patients with good performance status and nonsquamous cell carcinoma across all PD-L1 expression levels.
  • 2
    Biomarker testing with broad multigene panels and IHC for PD-L1, HER2, and MET should be universally accessible for all patients diagnosed with NSCLC.
  • 3
    Early referral to interdisciplinary palliative care alongside active treatment is strongly recommended for all patients with advanced lung cancer.
  • 4
    For patients ineligible for immunotherapy, platinum-doublet chemotherapy remains the standard strong recommendation.

What's New in This Version

Version 2026.3.1 is an update that reviews recent literature and explicitly incorporates retifanlimab plus platinum-based chemotherapy as a conditional first-line treatment option for patients with nonsquamous cell carcinoma and any PD-L1 expression, based on the Phase III POD1UM-304 trial.

Key Recommendations

Biomarker testing

  • 1.0

    Biomarker testing with a validated tissue and/or blood-based broad multigene panel and a validated tissue IHC assay for PD-L1, HER2, and MET protein expression should be universally accessible for all patients diagnosed with NSCLC.

    StrongEvidence: HighDiagnostic

Nonsquamous cell carcinoma, PD-L1 expression TPS >=50%

  • 1.1

    Clinicians should offer single-agent pembrolizumab or cemiplimab or atezolizumab.

    StrongEvidence: HighFirst-Line Treatment
  • 1.8

    Clinicians may offer retifanlimab plus platinum-based chemotherapy.

    ConditionalEvidence: ModerateFirst-Line Treatment (Updated)

Nonsquamous cell carcinoma, PD-L1 expression TPS 1%-49%

  • 1.9

    Clinicians should offer Pembrolizumab + carboplatin + pemetrexed.

    StrongEvidence: ModerateFirst-Line Treatment
  • 1.10

    Clinicians should offer Cemiplimab + carboplatin + pemetrexed.

    StrongEvidence: ModerateFirst-Line Treatment
  • 1.15

    Clinicians may offer retifanlimab plus platinum-based chemotherapy.

    ConditionalEvidence: ModerateFirst-Line Treatment (Updated)

Nonsquamous cell carcinoma, Unknown or negative PD-L1 expression TPS <1%

  • 1.17

    Clinicians may offer Pembrolizumab + carboplatin + pemetrexed.

    ConditionalEvidence: ModerateFirst-Line Treatment
  • 1.18

    Clinicians may offer Cemiplimab + carboplatin + pemetrexed.

    ConditionalEvidence: ModerateFirst-Line Treatment
  • 1.23

    Clinicians may offer retifanlimab plus platinum-based chemotherapy.

    ConditionalEvidence: ModerateFirst-Line Treatment (Updated)

Squamous cell carcinoma, PD-L1 expression TPS >=50%

  • 2.1

    Clinicians should offer single-agent pembrolizumab or cemiplimab or atezolizumab.

    StrongEvidence: HighFirst-Line Treatment

Squamous cell carcinoma, PD-L1 expression TPS 1%-49%

  • 2.6

    Clinicians should offer Pembrolizumab + carboplatin + paclitaxel (or nab-paclitaxel).

    StrongEvidence: ModerateFirst-Line Treatment
  • 2.7

    Clinicians should offer Cemiplimab + carboplatin + paclitaxel.

    StrongEvidence: ModerateFirst-Line Treatment

Squamous cell carcinoma, Unknown or negative PD-L1 expression TPS <1%

  • 2.12

    Clinicians may offer Pembrolizumab + carboplatin + paclitaxel (or nab-paclitaxel).

    ConditionalEvidence: ModerateFirst-Line Treatment

General approaches

  • 3.1

    Patients with advanced lung cancer should be referred to interdisciplinary palliative care teams (consultation) that provide inpatient and outpatient care early in the course of disease, alongside active treatment of their cancer.

    StrongEvidence: HighSupportive Care
  • 3.2

    For patients who are not candidates for immune checkpoint inhibitor therapy, clinicians should offer platinum-doublet combination therapy for patients with preserved PS.

    StrongEvidence: HighFirst-Line Treatment

Patients with contraindications to bevacizumab

  • 3.4

    Bevacizumab should be avoided for patients with squamous cell carcinoma histologic type, clinically significant hemoptysis, inadequate organ function, ECOG PS > 1, clinically significant cardiovascular disease, or medically uncontrolled hypertension.

    StrongEvidence: HighContraindication

Patients previously treated with immune checkpoint therapy without chemotherapy

  • 4.1

    Clinicians should offer platinum-doublet chemotherapy.

    StrongEvidence: LowSecond-Line Treatment

Patients previously treated with chemotherapy and immune checkpoint therapy

  • 4.2

    Clinicians should offer docetaxel with or without ramucirumab if the patient has already received platinum-based chemotherapy.

    StrongEvidence: LowSecond-Line Treatment

Scope & Objectives

Clinical Topic

Non-Small Cell Lung Cancer

Objectives

To review evidence and provide updated recommendations on new therapeutics for systemic therapy for patients with stage IV non-small cell lung cancer (NSCLC) without driver alterations.

Target Patient Population

Patients with stage IV non-small cell lung cancer (NSCLC) without driver alterations

Diagnostic Criteria

Biomarker testing with a validated tissue and/or blood-based broad multigene panel and a validated tissue IHC assay for PD-L1, HER2, and MET protein expression.

Target Providers

Treating cliniciansMedical oncologistsOncology care teams

Patient Criteria & Setting

Therapeutic Area

Oncology

Guideline Scope

Systemic TherapyFirst-Line TreatmentSecond-Line TreatmentSubsequent Treatment

Inclusion Criteria

  • Stage IV non-small cell lung cancer
  • Good performance status
  • Without driver alterations

Exclusion Criteria

  • Presence of targetable driver alterations

Care Settings

InpatientOutpatient

Special Populations

Patients with brain metastasesPatients aged 65 years or olderPatients with contraindications to bevacizumab

Evidence Grading

System: ASCO Quality of Evidence (High, Moderate, Low, Very Low) and Strength of Recommendation (Strong, Conditional/Weak)

Recommendation Strength

StrongIn recommendations for an intervention, the desirable effects of an intervention outweigh its undesirable effects. In recommendations against an intervention, the undesirable effects of an intervention outweigh its desirable effects. All or almost all informed people would make the recommended choice for or against an intervention.
Conditional/WeakIn recommendations for an intervention, the desirable effects probably outweigh the undesirable effects, but appreciable uncertainty exists. In recommendations against an intervention, the undesirable effects probably outweigh the desirable effects, but appreciable uncertainty exists. Most informed people would choose the recommended course of action, but a substantial number would not.

Safety & Contraindications

Contraindications

  • Squamous cell carcinoma histologic type (for bevacizumab)
  • Clinically significant hemoptysis (for bevacizumab)
  • Inadequate organ function (for bevacizumab)
  • ECOG PS > 1 (for bevacizumab)
  • Clinically significant cardiovascular disease (for bevacizumab)
  • Medically uncontrolled hypertension (for bevacizumab)

Authors & Contributors

Lyudmila BazhenovaNofisat IsmailaGreg DurmJanet Freeman-DailyHidehito HorinouchiGary R. MacVicarDeebya Raj MishraBruna PelliniErin L. SchenkNavneet SinghNatasha B. Leighl

Guideline Features

Dosing informationFlowcharts includedBased on systematic reviewMultidisciplinaryPatient involvement

Learning Context

Difficulty

advanced

Learning Paths

Non-Small Cell Lung CancerMedical OncologyImmunotherapyBiomarker TestingSystemic TherapyLiving Guideline