Stage IV Non-Small Cell Lung Cancer without Driver Alterations
Publication Date: February 28, 2024
Last Updated: February 29, 2024
Treatment
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 and toxicity with each patient.
Clinical Question 1: What are the most effective first-line treatment options for patients with good performance status and the following biomarkers:
Non-Squamous Cell Carcinoma (Non-SCC)
Patients with programmed death-ligand 1 or programmed cell death protein 1 (PD-L1) expression tumor proportion score (TPS) ≥50%:
1.1. For patients with a programmed death-ligand 1 or programmed cell death protein 1 (PD-L1) expression tumor proportion score (TPS) ≥50%, clinicians should offer single-agent pembrolizumab or cemiplimab or atezolizumab. ( EB , , H , S )
618
1.2. For patients with a programmed death-ligand 1 or programmed cell death protein 1 (PD-L1) expression tumor proportion score (TPS) ≥50%, clinicians may offer pembrolizumab + carboplatin + pemetrexed or cemiplimab + carboplatin + pemetrexed. ( EB , , I , W )
618
1.3. For patients with a programmed death-ligand 1 or programmed cell death protein 1 (PD-L1) expression tumor proportion score (TPS) ≥50%, clinicians may offer atezolizumab + carboplatin + nanoparticle albumin-bound (nab) -paclitaxel with or without bevacizumab (in the absence of contraindications to bevacizumab). ( EB , , I , W )
618
1.4. For patients with a programmed death-ligand 1 or programmed cell death protein 1 (PD-L1) expression tumor proportion score (TPS) ≥50%, clinicians may offer nivolumab and ipilimumab. ( EB , , I , W )
618
1.5. For patients with a programmed death-ligand 1 or programmed cell death protein 1 (PD-L1) expression tumor proportion score (TPS) ≥50%, clinicians may offer nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy. ( EB , , I , W )
618
1.6. For patients with a programmed death-ligand 1 or programmed cell death protein 1 (PD-L1) expression tumor proportion score (TPS) ≥50%, clinicians may offer durvalumab and tremelimumab plus platinum-based chemotherapy. ( EB , , I , W )
618
Patients with PD-L1 expression TPS, 1–49%:
1.7. For patients with PD-L1 expression TPS, 1–49%, clinicians should offer pembrolizumab + carboplatin + pemetrexed or cemiplimab + carboplatin + pemetrexed. ( EB , , I , S )
618
1.8. For patients with PD-L1 expression TPS, 1–49%, clinicians may offer atezolizumab + carboplatin + (nab)-paclitaxel ± bevacizumab in the absence of contraindications to bevacizumab. ( EB , , I , W )
618
1.9. For patients with PD-L1 expression TPS, 1–49%, clinicians may offer crizotinib and ipilimumab. ( EB , , I , W )
618
2.0. For patients with PD-L1 expression TPS, 1–49%, clinicians may offer nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy. ( EB , , I , W )
618
2.1. For patients with PD-L1 expression TPS, 1–49%, clinicians may offer durvalumab and tremelimumab plus platinum-based chemotherapy. ( EB , , I , W )
618
2.2. For patients who are ineligible for or decline the combination of doublet platinum ± anti-PD-(L)1, clinicians may offer monotherapy with anti-(programmed cell death protein 1) PD-1. ( EB , , I , W )
618
Patients with unknown or negative PD-L1 expression, TPS <1%:
2.3. For patients with unknown or negative PD-L1 expression, TPS <1%, clinicians may offer pembrolizumab + carboplatin + pemetrexed or cemiplimab + carboplatin + pemetrexed. ( EB , , I , W )
618
2.4. For patients with unknown or negative PD-L1 expression, TPS <1%, clinicians may offer atezolizumab + carboplatin + (nab)-paclitaxel ± bevacizumab in the absence of contraindications to bevacizumab. ( EB , , I , W )
618
2.5. For patients with unknown or negative PD-L1 expression, TPS <1%, clinicians may offer nivolumab and ipilimumab. ( EB , , I , W )
618
2.6. For patients with unknown or negative PD-L1 expression, TPS <1%, clinicians may offer nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy. ( EB , , I , W )
618
2.7. For patients with unknown or negative PD-L1 expression, TPS <1%, clinicians may offer durvalumab and tremelimumab plus platinum-based chemotherapy. ( EB , , I , W )
618
Squamous Cell Carcinoma (SCC)
Patients with PD-L1 expression, TPS ≥50%:
3.1. For patients with PD-L1 expression, TPS ≥50%,, clinicians should offer single-agent pembrolizumab or cemiplimab or atezolizumab. ( EB , , H , S )
618
3.2. For patients with PD-L1 expression, TPS ≥50%, clinicians may offer pembrolizumab + carboplatin + paclitaxel (or nab-paclitaxel) or cemiplimab + carboplatin + paclitaxel. ( EB , , I , W )
618
3.3. For patients with PD-L1 expression, TPS ≥50%, clinicians may offer nivolumab and ipilimumab. ( EB , , I , W )
618
3.4. For patients with PD-L1 expression, TPS ≥50%, clinicians may offer nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy. ( EB , , I , W )
618
3.5. For patients with PD-L1 expression, TPS ≥50%, clinicians may offer durvalumab and tremelimumab plus platinum-based chemotherapy. ( EB , , I , W )
618
Patients with PD-L1 expression TPS, 1–49%:
3.6. For patients with PD-L1 expression TPS, 1–49%, clinicians should offer pembrolizumab + carboplatin + paclitaxel (or nab-paclitaxel) or cemiplimab + carboplatin + paclitaxel. ( EB , , I , S )
618
3.7. For patients with PD-L1 expression TPS, 1–49%, clinicians may offer nivolumab and ipilimumab. ( EB , , I , W )
618
3.8. For patients with PD-L1 expression TPS, 1–49%, clinicians may offer nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy. ( EB , , I , W )
618
3.9. For patients with PD-L1 expression TPS, 1–49%, clinicians may offer durvalumab and tremelimumab plus platinum-based chemotherapy. ( EB , , I , W )
618
4.0. For patients with PD-L1 expression TPS, 1–49% who are ineligible for or decline the combination of doublet platinum ± anti-PD-(L)1, clinicians may offer single-agent anti-PD-1. ( EB , , I , W )
618
Patients with unknown or negative PD-L1 expression, TPS <1%:
4.1. For patients with unknown or negative PD-L1 expression, TPS <1%, clinicians should offer pembrolizumab + carboplatin + paclitaxel (or nab-paclitaxel) or cemiplimab + carboplatin + paclitaxel. ( EB , , I , W )
618
4.2. For patients with unknown or negative PD-L1 expression, TPS <1%, clinicians may offer nivolumab and ipilimumab. ( EB , , I , W )
618
4.3. For patients with unknown or negative PD-L1 expression, TPS <1%, clinicians may offer nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy. ( EB , , I , W )
618
4.4. For patients with unknown or negative PD-L1 expression, TPS <1%, clinicians may offer durvalumab and tremelimumab plus platinum-based chemotherapy. ( EB , , I , W )
618
Patients with Unspecified Histology
4.5. For patients with unknown or negative PD-L1 expression, TPS <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. ( EB , , H , S )
618
4.6. For patients with unknown or negative PD-L1 expression, TPS <1%, and who are not candidates for immune checkpoint inhibitor therapy, clinicians should offer platinum doublet combination therapy for patients with preserved performance status (PS). ( EB , , H , S )
618
4.7. For patients with unknown or negative PD-L1 expression, TPS <1%, clinicians may offer nonplatinum therapy combinations for patients who have contraindications to platinum therapy. ( EB , , I , W )
618
4.8. 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. ( EB , , H , S )
618
Patients with contraindications to bevacizumab:
Patients with Unspecified Histology
4.8. 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. ( EB , , H , S )
618
4.9. Maintenance bevacizumab given with pemetrexed has no survival advantage and significant increased toxicity compared to maintenance pemetrexed or bevacizumab alone. ( EB , , I , W )
618
Clinical Question 2: What are the most effective second-line and subsequent treatment options for patients with good performance status:
Patients previously treated with immune checkpoint therapy without chemotherapy:
5.0. For patients previously treated with immune checkpoint therapy without chemotherapy, clinicians should offer platinum doublet chemotherapy. ( IC , , L , S )
618
Patients previously treated with chemotherapy and immune checkpoint therapy
5.1. In patients previously treated with chemotherapy and immune checkpoint therapy, clinicians should offer docetaxel with or without ramucirumab if the patient has already received platinum-based chemotherapy. ( EB , , L , S )
618
5.2. In patients previously treated with chemotherapy and immune checkpoint therapy, clinicians may offer pemetrexed or gemcitabine if the patient has already received platinum-based chemotherapy. ( EB , , L , W )
618
Recommendation Grading
Overview
Title
Stage IV Non-Small Cell Lung Cancer without Driver Alterations
Authoring Organization
American Society of Clinical Oncology
Publication Month/Year
February 28, 2024
Last Updated Month/Year
November 7, 2024
Supplemental Implementation Tools
Document Type
Guideline
External Publication Status
Published
Country of Publication
US
Document Objectives
To provide evidence-based recommendations for patients with stage IV non–small cell lung cancer (NSCLC) without driver alterations.
Target Patient Population
Patients with stage IV NSCLC without driver alterations
Target Provider Population
Oncology care providers including primary care physicians, specialists, nurses, social workers, and others
PICO Questions
What are the most effective second-line and subsequent treatment options for patients with stage IV NSCLC without driver alterations based on cancer subtype?
Inclusion Criteria
Male, Female, Adolescent, Adult, Child, Older adult
Health Care Settings
Ambulatory, Outpatient
Intended Users
Nurse, nurse practitioner, physician, physician assistant, social worker
Scope
Treatment
Diseases/Conditions (MeSH)
D002289 - Carcinoma, Non-Small-Cell Lung
Keywords
lung cancer, non-small cell lung cancer, non-small-cell lung carcinoma (NSCLC), NSCLC, Non Small Cell Lung Cancer, non_small_cell_lung_cancer
Source Citation
Jaiyesimi IA, Leighl NB, Ismaila N, et al. Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.3. J Clin Oncol. 2024 Feb 28. doi: 10.1200/JCO.23.02746
Supplemental Methodology Resources
Methodology
Number of Source Documents
58
Literature Search Start Date
December 10, 2015
Literature Search End Date
September 9, 2018
Description of External Review Process
The Expert Panel thanks Clinical Practice Guideline Committee reviewers Harold Y. Lau, MD, and David W. Ollila, MD; the Clinical Practice Guidelines Committee for their thoughtful reviews and insightful comments on this guideline. No Dates are provided.
Description of Public Comment Process
ASCO has a rigorous review process for guidelines. After the draft has been approved by the Expert Panel, the guideline is independently reviewed and approved by the Clinical Practice Guideline Oversight Committee (CPGC). Select members of the CPGC are asked to critically review the guideline prior to the next scheduled CPGC meeting. The CPGC members then present the results of their reviews to the full committee, discuss the review with the full committee, and the CPGC votes on whether to approve the guideline (with recusals from members who have relationships with affected companies). Approved ASCO Guidelines are then submitted to the Society’s journal for consideration of publication.
Specialties Involved
Oncology, Pulmonology, Medical Oncology, Oncology
Description of Systematic Review
The Protocol specifies the purpose of the guideline product, target patient population, clinical outcomes of interest, key features of the systematic literature review, and a proposed timeline for completion. ASCO staff, the Expert Panel Co‐Chairs, and possibly other panel members selected by the Co‐Chairs (the Expert Panel Steering Committee), will typically draft the protocol for full panel review. A standard protocol worksheet is used for consistency.
Once the Co‐Chairs have approved a first draft of the Protocol, the Protocol will be shared with the full Expert Panel. At the discretion of the Guidelines Director, the CPGC leadership and/or the CPGC Methodology Subcommittee may review the Protocol to make suggestions for revision intended to clarify aspects of the plan for developing the guideline. These suggestions are sent to the Expert Panel Co‐Chairs. Work on the systematic literature review can proceed upon the sign‐off of the Protocol by the Expert Panel.
List of Questions
This clinical practice guideline addresses three overarching clinical questions. For patients with stage IV NSCLC without driver alterations:
What is the most effective first-line therapy?
What is the most effective second-line therapy?
Is there a role for a third-line therapy or beyond?
The guideline addresses patients with NSCLC in the following histologic or subgroups, including squamous cell carcinoma (SCC), nonsquamous cell carcinoma (non-SCC), and programmed death ligand 1 (PD-L1)/PD-1 positive or negative.
The update does not apply to patients with stage IV NSCLC and alterations in any of the following molecular targets: epidermal growth factor receptor (EGFR), ALK, ROS1, or BRAF (the latter driver alterations will be covered in a separate guideline update). The guideline also does not apply to patients with stage IV NSCLC with rarer histologies (eg, large cell, neuroendocrine, and so on).
Description of Study Criteria
The recommendations were developed by using a systematic review (2015 to 2018) of phase II and phase III RCTs and clinical experience. Articles were selected for inclusion in the systematic review of the evidence based on the following criteria:
Patients with stage IV NSCLC without driver alterations (some trials that also included patients with stage IIIB NSCLC were included if separate analyses were conducted).
Fully published presentations of English-language reports of phase II or III RCTs, rigorously conducted (see the Data Supplement for ASCO method of quality assessment) systematic reviews, or meta-analyses.
Meeting abstracts with this population with fully available presentations: ASCO, European Society for Medical Oncology 2017 to 2018, and International Association for the Study of Lung Cancer 2018.
Minimal sample size of 20 patients for immune checkpoint therapy and 50 patients for chemotherapy.
Outcomes included progression-free survival, overall survival, treatment toxicity (adverse events), and quality of life (if reported).
Articles were excluded from the systematic review if they were (1) meeting abstracts not subsequently published in peer-reviewed journals; (2) editorials, commentaries, letters, news articles, case reports, or narrative reviews; or (3) published in a non-English language.
Description of Search Strategy
Upon approval of the Protocol, a systematic review of the medical literature is conducted. ASCO staff use the information entered into the Protocol, including the clinical questions, inclusion/exclusion criteria for qualified studies, search terms/phrases, and range of study dates, to perform the systematic review. Literature searches of selected databases, including The Cochrane Library and Medline (via PubMed) are performed. Working with the Expert Panel, ASCO staff complete screening of the abstracts and full text articles to determine
eligibility for inclusion in the systematic review of the evidence.
Unpublished data from meeting abstracts are not generally used as part of normal ASCO guideline development (“Meeting Data”). However, abstract data from reputable scientific meetings and congresses may be included on a case‐by‐case basis after review by the CPGC leadership. Expert Panels should present a rationale to support integration of abstract data into a guideline. The CPGC leadership will consider the following inclusion criteria for the unpublished scientific meeting data: 1) whether the data were independently peer reviewed in connection with a reputable scientific meeting or congress; 2) the potential clinical impact of the unpublished data; 3) the methodological quality and validity of the associated study; 3) the potential harms of not including the data; and 4) the availability of other published data to inform the guideline recommendations.
Description of Study Selection
Literature search results were reviewed and deemed appropriate for full text review by two ASCO staff reviewers in consultation with the Expert Panel Co-Chairs. Data were extracted by two staff reviewers and subsequently checked for accuracy through an audit of the data by another ASCO staff member. Disagreements were resolved through discussion and consultation with the Co-Chairs if necessary. Evidence tables are provided in the manuscript and/or in Data Supplements 1.
Description of Evidence Analysis Methods
ASCO guideline recommendations are crafted, in part, using the GuideLines Into DEcision Support (GLIDES) methodology. ASCO adopted a five‐step approach to carry out quality appraisal, strength of evidence ratings and strength of recommendations ratings. The ASCO approach was primarily adapted from those developed by the AHRQ,, USPSTF, and GRADE, however with the validation of the GRADE methodology, the sole use of GRADE is being evaluated by the Clinical Practice Guidelines Committee.
Description of Evidence Grading
High: High confidence that the available evidence reflects the true magnitude and direction of the net effect (i.e., balance of benefits v harms) and that further research is very unlikely to change either the magnitude or direction of this net effect.
Intermediate: Moderate confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research is unlikely to alter the direction of the net effect; however, it might alter the magnitude of the net effect.
Low: Low confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research may change either the magnitude and/or direction this net effect.
Insufficient: Evidence is insufficient to discern the true magnitude and direction of the net effect. Further research may better inform the topic. The use of the consensus opinion of experts is reasonable to inform outcomes related to the topic.
Description of Recommendation Grading
ASCO uses a formal consensus methodology based on the modified Delphi technique in clinically important areas where there is limited evidence or a lack of high‐quality evidence to inform clinical guidance recommendations.
This Guideline (a Focused Update) has a "Expert Panel Note" on interpretation of the clinical recommendations in practice.
Evidence Based: There was sufficient evidence from published studies to inform a recommendation to guide clinical practice.
Formal Consensus: The available evidence was deemed insufficient to inform a recommendation to guide clinical practice. Therefore, the Expert Panel used a formal consensus process to reach this recommendation, which is considered the best current guidance for practice. The Panel may choose to provide a rating for the strength of the recommendation (i.e., "strong," "moderate," or "weak"). The results of the formal consensus process are summarized in the guideline and reported in the Data Supplement (see the Supporting Documents" field).
Informal Consensus: The available evidence was deemed insufficient to inform a recommendation to guide clinical practice. The recommendation is considered the best current guidance for practice, based on informal consensus of the Expert Panel. The Panel agreed that a formal consensus process was not necessary for reasons described in the literature review and discussion. The Panel may choose to provide a rating for the strength of the recommendation (i.e., "strong," "moderate," or "weak").
No recommendation: There is insufficient evidence, confidence, or agreement to provide a recommendation to guide clinical practice at this time. The Panel deemed the available evidence as insufficient and concluded it was unlikely that a formal consensus process would achieve the level of agreement needed for a recommendation.
Description of Funding Source
ASCO provides funding for Guideline Development.
Company/Author Disclosures
ASCO Conflict of Interest Policy complies with the CMSS Code for Interactions with Companies. ASCO requires disclosure by individuals involved in drafting, reviewing, and approving guideline recommendations.
Percentage of Authors Reporting COI
100