Last updated July 21, 2022

Stage IV Non-Small Cell Lung Cancer without Driver Alterations

Treatment

A1. Chemotherapy

a. For patients with performance status (PS) of 0 or 1 receiving chemotherapy, a combination of two cytotoxic drugs is recommended. Platinum combinations are recommended over nonplatinum therapy. However, nonplatinum therapy combinations are recommended for patients who have contraindications to platinum therapy. Chemotherapy may also be used to treat selected patients with PS of 2 who desire aggressive treatment after a thorough discussion of the risks and benefits of such treatment. (, , , )
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b. Because there is no cure for patients with stage IV NSCLC, early concomitant palliative care assistance has improved the survival and well-being of patients and is therefore recommended. (, , , )
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A2. First-line Therapy

For patients with high PD-L1/PD1 expression (TPS ≥50%), in the absence of contraindications to immune checkpoint inhibitor therapies, non-squamous cell carcinoma (SCC) PS 0–1:
1.1. Clinicians should offer single-agent pembrolizumab (, , H , S )
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1.2. Clinicians may offer pembrolizumab/carboplatin/pemetrexed (, , H , S )
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1.3. Clinicians may offer atezolizumab/carboplatin/paclitaxel/bevacizumab in the absence of contraindications to bevacizumab (, , I , M )
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1.4. Clinicians may offer atezolizumab/carboplatin/nab-paclitaxel (, , L , W )
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1.5. In addition to 2020 options, for patients with high PD-L1 expression (TPS ≥50%), non-SCC, and PS 0–1, clinicians may offer single-agent atezolizumab (Quality of Evidence - Medium) (, , , S )
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1.6. In addition to 2020 options, for patients with high PD-L1 expression (TPS ≥50%), non-SCC, and PS 0–1, clinicians may offer single-agent cemiplimab (Quality of Evidence - Medium) (, , , S )
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1.7. In addition to 2020 options, for patients with high PD-L1 expression (TPS ≥ 50%), non-SCC, and PS 0 to 1, clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (Quality of Evidence - Medium) (, , , W )
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1.8. (previously #1.5.) There are insufficient data to recommend any other checkpoint inhibitors or to recommend combination checkpoint inhibitors or any other combinations of ICIs with chemotherapy in the first-line setting (, , H , S )
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No Contraindications to Bevacizumab

For patients receiving carboplatin plus paclitaxel, the guideline update panel recommends the addition of bevacizumab 15 mg/kg once every 3 weeks, except for patients with SCC histologic type, clinically significant hemoptysis, inadequate organ function, Eastern Cooperative Oncology Group PS >1, clinically significant cardiovascular disease, or medically uncontrolled hypertension. (, , , )
Note: Bevacizumab may be continued, as tolerated, until disease progression.
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There is insufficient evidence to recommend bevacizumab in combination with pemetrexed plus carboplatin for patients who do not have contraindications to bevacizumab. (, , , )
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Non-SCC, and Negative or Unknown PD-L1 status (TPS 0–49%), and PS 0–1

For patients with negative (<1% or unknown) and low positive (TPS 1%–49%) PD-L1 expression, non-SCC, PS 0–1, AND are eligible for chemotherapy and pembrolizumab:
2.1. Clinicians should offer pembrolizumab/carboplatin/pemetrexed (, , H , S )
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2.2. Clinicians may offer atezolizumab/carboplatin/paclitaxel/bevacizumab in the absence of contraindications to bevacizumab (, , I , M )
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2.3. Clinicians may offer atezolizumab/carboplatin/nab-paclitaxel (, , I , M )
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2.4. Patients who have the above characteristics AND have contraindications to/declines immunotherapy, clinicians should offer standard chemotherapy with platinum-based two drug combinations as outlined in the 2015 update (, , H , S )
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2.5. Patients with above characteristics AND have contraindications to/declines immunotherapy AND not deemed candidates for platinum-based therapy, clinicians should offer nonplatinum based two-drug therapy as outlined in the 2015 update (, , L , W )
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2.6. For patients with low positive PD-L1 expression (TPS 1%–49%), non-SCC, PS 0–1, AND who are ineligible for or decline combination of doublet platinum ± pembrolizumab, clinicians may offer single-agent pembrolizumab (, , L , W )
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2.7. In addition to 2020 options, for patients with negative (0%) and low positive PD-L1 expression (TPS 1%–49%), non-SCC, and PS 0–1, clinicians may offer nivolumab and ipilumumab alone or nivolumab and ipilumumab plus two cycles of platinum-based chemotherapy (Quality of Evidence - Moderate) (, , , W )
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PS 2

In the context of shared decision making, combination therapy, single agent therapy, or palliative therapy alone may be used for patients with the characteristics described in Clinical Question A3a:
Chemotherapy ( EB , B , I , W )
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Palliative care ( EB , B , I , S )
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A3. High PD-L1 Status (TPS ≥50%), and PS 0–1

For patients with high PD-L1 expression (TPS ≥ 50%) SCC, PS 0–1, in the absence of contraindications to immune checkpoint inhibitor therapy:
3.1. Clinicians should offer single-agent pembrolizumab (, , H , S )
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3.2. Clinicians may offer pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel) (, , I , M )
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3.3. In addition to 2020 options, for patients with high PD-L1 expression (TPS ≥50%), SCC, and PS 0–1, clinicians may offer single-agent atezolizumab (Quality of Evidence - Moderate) (, , , S )
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3.4. In addition to 2020 options, for patients with high PD-L1 expression (TPS ≥50%), SCC, and PS 0–1, clinicians may offer single-agent cemiplimab (Quality of Evidence - Moderate) (, , , S )
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3.5. In addition to 2020 options, for patients with high PD-L1 expression (TPS ≥50%), SCC, and PS 0–1, clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (Quality of Evidence - Moderate) (, , , W )
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3.6. (previously #3.3.) There are insufficient data to recommend any other checkpoint inhibitors or to recommend combination checkpoint inhibitors or any other combinations of ICIs with chemotherapy in the first-line setting (, , H , S )
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Negative or Unknown PD-L1 Status (TPS 0%–49%), and PS 0–1

For patients with negative (TPS 0%, <1%, or unknown) and/or low positive (TPS 1%–49%) PD-L1 expression and SCC, in the absence of contraindications to immune checkpoint inhibitor therapies:
4.1. Clinicians should offer pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel (, , I , S )
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4.2. For patients who have the above characteristics AND with contraindications to immunotherapy AND not deemed candidates for platinum-based therapy, clinicians should offer standard chemotherapy with non-platinum-based two drug combinations as outlined in the 2015 update (, , H , S )
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4.3. For patients with contraindications to immunotherapy AND not deemed candidates for platinum-based therapy, clinicians should offer standard chemotherapy with non-platinum-based two drug combinations as outlined in the 2015 update (, , I , W )
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4.4. For patients with low positive PD-L1 (TPS 1%–49%) AND who are ineligible for or decline combination of doublet platinum/pembrolizumab AND have contraindications to doublet-chemotherapy, clinicians may offer single-agent pembrolizumab, in the absence of contraindications to immune checkpoint therapies (, , L , W )
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4.5. In addition to 2020 recommendations 4.1–4.4, for patients with negative (TPS 0%) and low positive (TPS 1%–49%) PD-L1 expression, SCC, and PS 0–1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy (Quality of Evidence - Moderate) (, , , W )
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PS 2

a. In the context of shared decision making, combination chemotherapy, single-agent therapy, or palliative therapy alone may be used for patients with stage IV NSCLC, SCC, and PS2:
Chemotherapy ( EB , B , I , W )
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Palliative care ( EB , B , I , S )
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B1. Second-line Therapy for Patients and PS 0–1

Squamous and Non-squamous and Negative/Unknown EGFR mutation, ALK or ROS-1 Gene Rearrangement

For patients who received first-line chemotherapy and have not received prior immune checkpoint inhibitor therapy, clinicians should use single-agent nivolumab, pembrolizumab, or atezolizumab in patients with positive tumor PDL-1 expression (TPS ≥1%, 22C3 assay), in the absence of contraindications to immune checkpoint therapy. ( EB , B , H , S )
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For patients with negative or unknown tumor PDL-1 expression (TPS <1%) who received first-line therapy chemotherapy, clinicians should use single-agent nivolumab or atezolizumab in the absence of contraindications to immune checkpoint therapy. ( EB , B , H , S )
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For patients who received an immune checkpoint inhibitor as first-line therapy, clinicians should offer
standard platinum-based chemotherapy as outlined in the 2015 update ( EB , B , H , S )
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or nonplatinum based two-drug therapy if platinum contraindicated as outlined in the 2015 update ( IC , B , L , S )
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For patients with contraindications to immune checkpoint inhibitor therapy after first-line chemotherapy, docetaxel is recommended as second-line therapy ( EB , B , I , M )
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Non-squamous Only

Patients with non-SCC who have not previously received pemetrexed-based first-line or maintenance therapy should be offered pemetrexed second-line. ( EB , B , H , S )
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5.1. (New) In addition to previously recommended regimens, for patients with non-SCC who received an immune checkpoint inhibitor and chemotherapy as first-line therapy, clinicians may offer paclitaxel plus bevacizumab in the second-line setting. (, , L , W )
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B2. One Prior Chemotherapy Regimen

The evidence does not support the selection of a specific second-line chemotherapy drug or combination based on age alone. This recommendation has not changed. As stated in Recommendation A8, age alone is not a contraindication to chemotherapy for NSCLC. (, , , )
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C1. Third-line Therapy

6.1. For the majority of patients with non-SCC, who received chemotherapy with or without bevacizumab and immune checkpoint inhibitor therapy (in either sequence), clinicians should offer the options of single-agent pemetrexed or docetaxel or paclitaxel plus bevacizumab in the third-line setting. (, , L , W )
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D1. For Cytotoxic Therapy for Patients Who Have Received Three Prior Regimens and Good PS

Data are not sufficient to make a recommendation for or against using cytotoxic drugs as fourth-line therapy. Patients should consider experimental treatment, clinical trials, and continued best supportive (palliative) care. (, , , )
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Recommendation Grading

Overview

Title

Stage IV Non-Small Cell Lung Cancer without Driver Alterations

Authoring Organizations

Publication Month/Year

July 11, 2022

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

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

Inclusion Criteria

Female, Male, Adolescent, Adult, Child, Older adult

Health Care Settings

Ambulatory, Outpatient

Intended Users

Social worker, physician assistant, physician, nurse practitioner, nurse

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

Singh N, Temin S, Baker, Jr. S, et al. Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Guideline Update. 2022 July 11. doi: 10.1200/JCO.22.00825

Hanna NH, Schneider BJ, Temin S, et al. Therapy for stage IV non-small cell lung cancer without driver alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol. 2021 Feb 16. doi: 10.1200/JCO.19.03022

The guideline was a cooperative effort among the American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario).

Supplemental Methodology Resources

Data Supplement

Methodology

Number of Source Documents
20
Literature Search Start Date
December 1, 2015
Literature Search End Date
August 31, 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.
Public Comment Process Start Date
April 2, 0008
Public Comment Process End Date
June 2, 0009
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