Key Points
- This guideline provides near real-time clinical guidance for the systemic treatment of patients with stage IV non-small cell lung cancer (NSCLC) without driver alterations.
- All previous updates are consolidated herein and reflect the current body of evidence informing this topic.
Treatment
General Note: For recommendations with multiple treatment options of the same evidence quality and strength of recommendation, the decision of which agent to offer should be tailored based on discussion of efficacy, toxicity, drug access, and cost with each patient. Unless otherwise specified the recommended number of cycles of platinum doublet chemotherapy is four.
Biomarker Testing
Recommendation 1.0
Biomarker testing with a validated tissue and/or blood-based broad multi-gene panel and a validated tissue immunohistochemistry (IHC) assay for programmed death ligand 1 (PD-L1), human epidermal receptor factor 2 (HER2), and mesenchymal epithelial transition (MET) protein expression should be universally accessible for all patients diagnosed with NSCLC. ( H, S )
Qualifying Statement for Recommendation 1.0: Combination of blood and tissue testing may maximize chance of detecting molecular alterations. Comprehensive ribonucleic acid (RNA)-based next-generation sequencing (NGS) for detecting genomic alterations is preferred. Tissue testing has the advantage of histologic assessment and should be attempted when feasible, and the false negative rate of liquid biopsy should be considered. PD-L1 IHC alone should not be used to guide treatment decisions.
First-Line Therapy
Non-squamous Cell Carcinoma (Non-SCC), PD-L1 Expression, Tumor Proportion Score (TPS) ≥50%
Recommendation 1.4
Clinicians may offer
atezolizumab +
carboplatin + nanoparticle albumin-bound (nab)-
paclitaxel ± bevacizumab (in the absence of contraindications to bevacizumab).
( M, C ) Recommendation 1.6
Clinicians may offer
nivolumab and
ipilimumab with two cycles of platinum-based chemotherapy.
( M, C ) Recommendation 1.8
Clinicians may offer retifanlimab plus platinum-based chemotherapy. ( M, C )
Non-SCC, PD-L1 Expression, TPS 1%–49%
Recommendation 1.13
Nivolumab and
ipilimumab plus two cycles of platinum-based chemotherapy.
( M, C ) Recommendation 1.14
Durvalumab and
tremelimumab plus platinum-based chemotherapy.
( M, C ) Recommendation 1.15
Clinicians may offer retifanlimab plus platinum-based chemotherapy. ( M, C )
Recommendation 1.16
Pembrolizumab monotherapy may be offered to patients who are ineligible for or decline combination therapy. ( M, C )
Non-SCC, Unknown or Negative PD-L1 Expression, TPS <1%
Recommendation 1.20
Clinicians may offer
nivolumab and
ipilimumab plus two cycles of platinum-based chemotherapy.
( M, C )
Non-SCC, PD-L1 Expression, TPS 1%–49%
Recommendation 1.23
Clinicians may offer retifanlimab plus platinum-based chemotherapy. ( M, C )
SCC, PD-L1 Expression, TPS ≥50%
Recommendation 2.4
Clinicians may offer
nivolumab and
ipilimumab plus two cycles of platinum-based chemotherapy.
( M, C )
SCC, PD-L1 Expression, TPS 1%–49%
Recommendation 2.9
Clinicians should offer
nivolumab and
ipilimumab plus two cycles of platinum-based chemotherapy.
( M, C ) Recommendation 2.11
Pembrolizumab monotherapy may be offered to patients who are ineligible for or decline combination therapy. ( M, C )
SCC, Unknown or Negative PD-L1 Expression, TPS <1%
Recommendation 2.14
Clinicians may offer
nivolumab and
ipilimumab plus two cycles of platinum-based chemotherapy.
( M, C )
General Approaches
Recommendation 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. ( H, S )
Recommendation 3.2
For patients who are not candidates for immune checkpoint inhibitor therapy, clinicians should offer platinum doublet combination therapy for patients with preserved performance status (PS). ( H, S )
Recommendation 3.3
Clinicians may offer nonplatinum therapy combinations for patients who have contraindications to platinum therapy. ( M, C )
Patients With Contraindications to Bevacizumab
Recommendation 3.4
Bevacizumab should be avoided for patients with squamous cell carcinoma histologic type, clinically significant hemoptysis, inadequate organ function, Eastern Cooperative Oncology Group (ECOG) PS >1, clinically significant cardiovascular disease, or medically uncontrolled hypertension. ( H, S )
Recommendation 3.5
Maintenance bevacizumab given with
pemetrexed has no survival advantage and significant increased toxicity compared to maintenance
pemetrexed or bevacizumab alone.
( M, C )
Second-Line and Subsequent Therapies
Patients Previously Treated With Immune Checkpoint Therapy Without Chemotherapy
Recommendation 4.1
Clinicians should offer platinum doublet chemotherapy. ( L, S )
Patients Previously Treated With Chemotherapy and Immune Checkpoint Therapy
Recommendation 4.2
Clinicians should offer
docetaxel with or without ramucirumab if the patient has already received platinum-based chemotherapy.
( L, S ) Recommendation 4.3
Clinicians may offer
pemetrexed, nab-
paclitaxel, or gemcitabine if the patient has already received platinum-based chemotherapy.
( L, C ) Recommendation 4.4
Clinicians may offer telisotuzumab vedotin (Teliso-V) for patients with c-Met protein-overexpressing NSCLC. ( L, C )
Recommendation 4.5
Clinicians may offer trastuzumab deruxtecan for patients with HER2 overexpressing NSCLC defined as HER2 IHC 31 (by gastric scoring). ( VL, C )
Figure 1. First-Line Treatment Options for Patients With Stage IV NSCLC Without Driver Alterations and Non-SCC
Figure 2. First-Line Treatment Options for Patients With Stage IV NSCLC Without Driver Alterations and SCC
Figure 3. Second-Line and Subsequent Treatment Options for Patients With Stage IV NSCLC Without Driver Alterations
Recommendation Rating Definitions
GRADE Handbook, Schünemann, et al. 2013.
Abbreviations
- ALK
- anaplastic lymphoma kinase
- ASCO
- American Society of Clinical Oncology
- EGFR
- epidermal growth factor receptor
- NSCLC
- non-small cell lung cancer
- OH (CCO)
- Ontario Health (Cancer Care Ontario)
- PD-L1
- anti-programmed death-ligand 1
- PS
- performance status
- TPS
- tumor proportion score
Source Citation
Reuss JE, Bazhenova L, Ismaila N, et al. Therapy for stage IV non–small cell lung cancer without driver alterations: ASCO living guideline, 2026.3.0. J Clin Oncol. 2026;44(7):e56-e88. doi:10.1200/JCO-25-02825
Reuss JE, Bazhenova L, Ismaila N, et al. Therapy for stage IV non–small cell lung cancer without driver alterations: ASCO living guideline, 2026.3.2. Online ahead of print.
Disclaimer
Living guidelines are routinely updated guidelines that are developed for selected topic areas with rapidly evolving evidence that drives frequent change in clinical practice. These guidelines are updated on a regular schedule, based on the work of a standing panel that reviews the literature on a continuous basis.
Versioning and Numbering Statement
To ensure transparency and facilitate the tracking of evidence updates, ASCO has implemented a structured numbering system for living guidelines. This system reflects the status of the recommendations as follows:
1. Major Updates (eg, 2026.2.0): These represent full updates or significant revisions approved by the Expert Panel and the Evidence Based Medicine Committee (EBMC).
They typically incorporate comprehensive literature reviews and involves resubmission of the entire guideline.
2. Rapid Updates (eg, 2026.2.1): These “mini updates” serve as timely notifications of revised recommendations or supporting evidence, ensuring the guideline remains current between full update cycles.
This pocket guide is derived from recommendations in the American Society of Clinical Oncology Guideline. This resource is a practice tool based on ASCO® practice guidelines and is not intended to substitute for the independent professional judgment of the treating physician. Practice guidelines do not account for individual variation among patients. This pocket guide does not purport to suggest any particular course of medical treatment. Use of the practice guidelines and this resource are voluntary. The practice guidelines and additional information are available at www.asco.org/living-guidelines. Copyright © 2026 by American Society of Clinical Oncology. All rights reserved.
