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Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline
, MD, DM1; Sarah Temin , MSPH2; Sherman Baker Jr, MD3; Elizabeth Blanchard, MD4; Julie R. Brahmer , MD5; Paul Celano, MD6; Narjust Duma , MD7; Peter M. Ellis, MD, PhD8; Ivy B. Elkins, MBA9; Rami Y. Haddad, MD10; Paul J. Hesketh , MD11; Dharamvir Jain, MD12; David H. Johnson , MD13; Natasha B. Leighl , MD14; Hirva Mamdani , MD15; Gregory Masters , MD16; Pamela R. Moffitt17; Tanyanika Phillips, MD18; Gregory J. Riely , MD, PhD19; Andrew G. Robinson , MD20; Rafael Rosell , MD21; Joan H. Schiller , MD22; Bryan J. Schneider, MD23; David R. Spigel , MD24; and Ishmael A. Jaiyesimi, MD, MS25 Show More
*I.J. and N.S. were Expert Panel co-chairs.
Abstract
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. Updates will be made regularly and can be found at https://ascopubs.org/nsclc-non-da-living-guideline.
To provide evidence-based recommendations updating the 2020 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non–small-cell lung cancer without driver alterations.
ASCO updated recommendations on the basis of an ongoing systematic review of randomized clinical trials from 2018 to 2021.
This guideline update reflects changes in evidence since the previous update. Five randomized clinical trials provide the evidence base. Outcomes of interest include efficacy and safety.
In addition to 2020 options for patients with high programmed death ligand-1 (PD-L1) expression (tumor proportion score [TPS] ≥ 50%), nonsquamous cell carcinoma (non-SCC), and performance status (PS) 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression (TPS ≥ 50%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilumumab alone or nivolumab and ipilimumab plus chemotherapy. With negative (0%) and low positive PD-L1 expression (TPS 1%-49%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus chemotherapy. With high PD-L1 expression, SCC, and PS 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression, squamous cell carcinoma (SCC), and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy. With negative and low positive 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. With non-SCC who received an immune checkpoint inhibitor and chemotherapy as first-line therapy, clinicians may offer second-line paclitaxel plus bevacizumab. With non-SCC, who received chemotherapy with or without bevacizumab and immune checkpoint inhibitor therapy, clinicians should offer the options of third-line single-agent pemetrexed, docetaxel, or paclitaxel plus bevacizumab.
Additional information is available at www.asco.org/thoracic-cancer-guidelines.
The purpose of this guideline update is to update the ASCO and Ontario Health (Cancer Care Ontario) guidelines on the systemic treatment of patients with nondriver alteration stage IV non–small-cell lung cancer (NSCLC) last published in 2020. The update is a result of potentially practice-changing evidence published since the last update. ASCO published the last full clinical practice guideline update on systemic therapy for patients with stage IV NSCLC that included those whose cancer did not have driver alterations, in January 2020.1
This update is based on five randomized clinical trials (RCTs) that directly affected clinical questions 1, 2, and 3.
Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Guideline
What systemic therapy treatment options should be offered to patients with stage IV non–small-cell lung cancer (NSCLC) without driver alterations, depending on the subtype of the patient's cancer?
Patients with stage IV NSCLC without driver alterations in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) (with known EGFR and ALK status; plus programmed death ligand-1 [PD-L1] tumor proportion score [TPS] test results available to the clinician being optimal).
Oncology care providers (including primary care physicians, specialists, nurses, social workers, and any other relevant member of a comprehensive multidisciplinary cancer care team), patients, and their caregivers in North America and beyond.
An Expert Panel was convened to update clinical practice guideline recommendations on the basis of a systematic review of the medical literature.
In addition to 2020 options, for patients with high PD-L1 expression (TPS ≥ 50%; Table 1), nonsquamous cell carcinoma (non-SCC), and performance status (PS) 0-1, clinicians may offer single-agent atezolizumab (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Strong).
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 (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Strong).
In addition to 2020 options, for patients with high PD-L1 expression (TPS ≥ 50%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Weak).
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 ipilimumab alone or nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Weak).
In addition to 2020 options, for patients with high PD-L1 expression (TPS ≥ 50%), squamous cell carcinoma (SCC), and PS 0-1, clinicians may offer single-agent atezolizumab (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Strong).
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 (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Strong).
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 (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Weak).
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 nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Weak).
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 (Type: Evidence based; Evidence quality: Low; Strength of recommendation: Weak).
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 (Type: Evidence based; Evidence quality: Low; Strength of recommendation: Weak).
Definitions for the quality of the evidence and strength of recommendation ratings are available in Appendix Table A1 (online only). More information, including a supplement with additional evidence tables, slide sets, and clinical tools and resources, is available at www.asco.org/thoracic-cancer-guidelines. The Methodology Manual (available at www.asco.org/guideline-methodology) provides additional information about the methods used to develop this guideline. Patient information is available at www.cancer.net.
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.
This clinical practice guideline addresses one clinical question with three subquestions: (1) What systemic therapy treatment options should be offered to patients with stage IV NSCLC without driver alterations, depending on the subtype of the patient's cancer?
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1. What is the most effective first-line therapy?
2. What is the most effective second-line therapy?
3. Is there a role for a third-line therapy or beyond?
This systematic review-based guideline product was developed by a multidisciplinary Expert Panel, which included a patient representative and an ASCO guidelines staff member with health research methodology expertise (Appendix Table A2, online only). ASCO reconvened the original guideline Expert Panel, with some new members. The Expert Panel met via webinar and corresponded through e-mail. Based upon the consideration of the evidence, the authors were asked to contribute to the development of the guideline, provide critical review, and finalize the guideline recommendations. The guideline recommendations were sent for an open comment period of two weeks allowing the public to review and comment on the recommendations after submitting a confidentiality agreement. These comments were taken into consideration while finalizing the recommendations. Members of the Expert Panel were responsible for reviewing and approving the penultimate version of the guideline, which was then circulated for external review, and submitted to the Journal of Clinical Oncology (JCO) for editorial review and consideration for publication. All ASCO guidelines are ultimately reviewed and approved by the Expert Panel and the ASCO Evidence Based Medicine Committee (EBMC) before publication. All funding for the administration of the project was provided by ASCO.
The recommendations were developed by using a systematic review of evidence identified through online searches of PubMed June 2018 through December 2021 of phase III RCTs, and clinical experience. Articles were selected for inclusion in the systematic review on the basis of the following criteria:
Population: Patients with stage IV NSCLC whose test results show:
Programmed death ligand-1 (PD-L1) TPS test results available to the clinician being optimal and without driver alterations in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) (with known EGFR and ALK) status.
Interventions: Chemotherapy, monoclonal antibodies, immunotherapy, palliative care, and no treatment
Comparisons: Chemotherapy, monoclonal antibodies, immunotherapy, palliative care, and no treatment
Outcomes: Included progression-free survival (PFS), overall survival (OS), treatment toxicity (adverse events [AEs]; usually grade 3-4 AEs), overall response rates, and quality of life (if reported).
Sample size:
Minimum sample size of 20 patients for immune checkpoint therapy and 50 patients for chemotherapy.
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, and narrative reviews; and (3) published in a non-English language. The guideline recommendations are crafted, in part, using the Guidelines Into Decision Support (GLIDES) methodology and accompanying BRIDGE-Wiz software.7 In addition, a guideline implementability review was conducted. On the basis of the implementability review, revisions were made to the draft to clarify recommended actions for clinical practice. Ratings for type and strength of the recommendation, and evidence quality are provided with each recommendation. The quality of the evidence for each outcome was assessed using the Cochrane Risk of Bias tool and elements of the GRADE quality assessment and recommendations development process.8,9 GRADE quality assessment labels (ie, high, moderate, low, and very low) were assigned for each outcome by the project methodologist in collaboration with the Expert Panel co-chairs and reviewed by the full Expert Panel.
The ASCO Expert Panel and guidelines staff will work with co-chairs to keep abreast of any substantive updates to the guideline. On the basis of formal review of the emerging literature, ASCO will determine the need to update. The ASCO Guidelines Methodology Manual (available at www.asco.org/guideline-methodology) provides additional information about the guideline update process. This is the most recent information as of the publication date.
The Clinical Practice Guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc (ASCO) to assist providers in clinical decision making. The information herein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating provider, as the information does not account for individual variation among patients. Recommendations specify the level of confidence that the recommendation reflects the net effect of a given course of action. The use of words like “must,” “must not,” “should,” and “should not” indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO does not endorse third party drugs, devices, services, or therapies used to diagnose, treat, monitor, manage, or alleviate health conditions. Any use of a brand or trade name is for identification purposes only. ASCO provides this information on an “as is” basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information, or for any errors or omissions.
The Expert Panel was assembled in accordance with ASCO's Conflict of Interest Policy Implementation for Clinical Practice Guidelines (“Policy,” found at https://www.asco.org/guideline-methodology). All members of the Expert Panel completed ASCO's disclosure form, which requires disclosure of financial and other interests, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include employment; leadership; stock or other ownership; honoraria, consulting or advisory role; speaker's bureau; research funding; patents, royalties, other intellectual property; expert testimony; travel, accommodations, expenses; and other relationships. In accordance with the Policy, the majority of the members of the Expert Panel did not disclose any relationships constituting a conflict under the Policy.
After applying the eligibility criteria, five RCTs remained, forming the evidentiary basis for the guideline recommendations (Fig 1).3,5,6,10,11
FIG 1. Algorithm. (A) First-line treatment options for patients with stage IV NSCLC without driver alterations. (B) Third-line treatment options for patients with stage IV non-small cell lung cancer without driver alterations. (C) Third-line treatment options for patients with stage IV NSCLC without driver alterations. aThis does not apply to patients with stage IV NSCLC with rarer histologies, eg, large cell neuroendocrine, etc. bKalemkerian et al.26 cDriver alterations including EGFR, ALK, ROS-1, BRAF V600E, MET exon 14, NTRK, KRAS, and RET. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; non-SCC, nonsquamous cell carcinoma; NSCLC, non–small-cell; lung cancer; PD-L1, program death ligand-1; PS, performance status; SCC, squamous cell carcinoma; TPS, tumor proportion score.
The identified trials were published between 2020 and 2021. The randomized trials compared similar interventions. The primary outcome for five of the trials was therapeutic efficacy,3,5,6,10,11 although they were framed in a variety of ways such as PFS and OS. Tables 2-11 present the included articles from the literature search pertinent to the development of the recommendations.
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Study design aspects related to individual study quality, quality of evidence, strength of recommendations, and risk of bias were assessed. Refer to the Methodology Manual for more information and for definitions of ratings for overall potential risk of bias.
As seen in Tables 3-11, study quality was formally assessed for the five RCTs identified. Design aspects related to the individual study quality were assessed by one reviewer, with factors such as blinding, allocation concealment, placebo control, intention to treat, funding sources, etc, generally indicating a low to moderate potential risk of bias for most of the identified evidence. Follow-up times varied between studies, lowering the comparability of the results.
Additional data on key outcomes of interest and key AEs are reported in Tables 3-11. Data analysis regarding unchanged recommendations is reviewed in the prior 2020 update.
For patients with stage IV NSCLC without driver alterations, what are the most effective first-line therapies?
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 (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Strong).
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 (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Strong).
In addition to 2020 options, for patients with high PD-L1 expression (TPS ≥ 50%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Weak).
Note: 2020 options:
Single-agent pembrolizumab (Evidence quality: High; Strength of recommendation: Strong)
Pembrolizumab + carboplatin + pemetrexed (Evidence quality: High; Strength of recommendation: Strong)
Atezolizumab + carboplatin + paclitaxel + bevacizumab in the absence of contraindications to bevacizumab (Evidence quality: Intermediate; Strength of recommendation: Moderate)
Atezolizumab + carboplatin + nab-paclitaxel (Evidence quality: Low; Strength of recommendation: Weak)
There are insufficient data to recommend any other checkpoint inhibitors or to recommend combination checkpoint inhibitors or any other combinations of immune checkpoint inhibitors (ICIs) with chemotherapy in the first-line setting (Evidence quality: High; Strength of recommendation: Strong).
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 ipilimumab alone or nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Weak).
Note: 2020 options:
Pembrolizumab + carboplatin + pemetrexed (Evidence quality: High; Strength of recommendation: Strong)
Atezolizumab + carboplatin + paclitaxel + bevacizumab in the absence of contraindications to bevacizumab (Evidence quality: Intermediate; Strength of recommendation: Moderate).
Atezolizumab + carboplatin + nab-paclitaxel (Evidence quality: Intermediate; Strength of recommendation: Moderate).
If have contraindications to ± declines immunotherapy, clinicians should offer standard chemotherapy with platinum-based two drug combinations as outlined in the 2015 update (Evidence quality: High; Strength of recommendation: Strong).
If 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 (Evidence quality: Low; Strength of recommendation: Weak).
(1%-49% only): If ineligible for or decline combination of doublet platinum ± pembrolizumab, clinicians may offer single-agent pembrolizumab (Evidence quality: Low; Strength of Recommendation: Weak).
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 (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Strong).
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 (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Strong).
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 (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Weak).
Note: 2020 options:
Single-agent pembrolizumab (Evidence quality: High; Strength of recommendation: Strong)
Pembrolizumab + carboplatin + paclitaxel or nab-paclitaxel (Evidence quality: Intermediate; Strength of recommendation: Moderate).
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 (Evidence quality: High; Strength of recommendation: Strong).
The updated systematic review identified four RCTs in the non-SCC and SCC settings.3,6,10,11 Herbst 2021, IMpower 110 was a RCT of 554 participants comparing atezolizumab with platinum-based chemotherapy.10 In the primary outcome of OS, the results for 155 participants with non-SCC showed a modest benefit in the absolute effect estimate of 150/1,000 fewer deaths (95% CI, 255 fewer to 14 fewer). For PFS, 205 participants with non-SCC showed similar results in absolute effect estimate and hazard ratio (HR). With a moderate certainty, atezolizumab probably improves OS and PFS in patients with high PD-L1 compared with platinum-based chemotherapy. In AE results, there were lower numbers of grade 3-5 AEs, with a relative risk of 0.60 (95% CI, 0.49 to 0.73), with the caveat that the investigators analyzed AEs in patients with either histology and any PD-L1 status.
This study is also relevant to first-line treatment for patients with high PD-L1 expression (TPS ≥ 50%) and SCC. Fifty patients in the SCC, high PD-L1 subgroup were included for the OS analysis. It is unclear whether atezolizumab increases survival in the immature analysis. For 12-month PFS, atezolizumab improved PFS compared with platinum-based chemotherapy in the 205 patients in this subgroup. There was a statistically significant decrease in relative risks of grade 3-5 serious adverse events with the immunotherapy.
The CheckMate-9LA trial study3 randomly assigned patients to nivolumab and ipilimumab plus chemotherapy versus chemotherapy. There were 174 patients in the subgroup of patients with stage IV NSCLC and high PD-L1 expression (TPS ≥ 50%). For these patients, nivolumab plus ipilimumab probably improved the OS in patients with high PD-L1 compared with chemotherapy, with a HR of 0.66 (95% CI, 0.44 to 0.89), as well as for all patients with SCC NSCLC (n = 227; HR, 0.62 [95% CI, 0.45 to 0.86]) and non-SCC NSCLC (n = 492; HR, 0.69 [95% CI, 0.55 to 0.87]). In this subgroup of patients with advanced NSCLC and high PD-L1 expression, PFS was also improved with nivolumab plus ipilimumab (HR, 0.61 [95% CI, 0.42 to 0.89]) as it was for all patients (irrespective of PD-L1 expression) with SCC NSCLC (HR, 0.57 [95% CI, 0.42 to 0.78]) and non-SCC NSCLC (HR, 0.74 [95% CI, 0.60 to 0.92]). Grade 3-4 treatment-related adverse events (TRAEs) were increased with the immunotherapy and chemotherapy intervention (in either histology or PD-L1 subgroup). The certainty of the evidence was low, due to indirectness; therefore, the strength of recommendation is weak.
In addition, this study included data on first-line treatment for patients with advanced NSCLC and either negative (< 1%) or low PD-L1 expression (TPS 1%-49%) SCC.3 The subgroup analysis of OS included patients in low PD-L1 (n = 233) and negative PD-L1 (n = 264) subgroups. Nivolumab + ipilimumab + chemotherapy probably improved OS in patients with low (HR, 0.61 [95% CI, 0.44 to 0.84]) and negative (HR, 0.62 [95% CI, 0.45 to 0.85]) PD-L1 expression compared with chemotherapy alone. Similarly, for PFS, the triplet combination may have improved PFS compared with platinum-based chemotherapy in both subgroups of patients, namely those with low PD-L1 (HR, 0.69 [95% CI, 0.51 to 0.94]) and negative PD-L1 (HR, 0.71 [95% CI, 0.53 to 0.94]) expression. There was a statistically significant increase in relative risks of grade 3-4 TRAEs with the immunotherapy and chemotherapy regimen.
An additional study was identified of pembrolizumab and ipilimumab11 (see Table 9 for the data). The trial was negative and did not support changing a recommendation.
Patients with advanced or metastatic NSCLC (who do not harbor sensitizing EGFR mutations or ALK rearrangements) and have high PD-L1 expression (≥ 50%) have been consistently shown to have better outcomes (OS, PFS, and relative risk) when treated with monotherapy that may either be a PD-1 ICI (pembrolizumab) or a PD-L1 ICI (atezolizumab or cemiplimab) versus standard platinum-doublet chemotherapy. This approach is also associated with a more favorable side-effect and toxicity profile with monoimmunotherapy compared with chemotherapy. Pembrolizumab efficacy and safety has a much longer follow-up from the KEYNOTE-024 trial including 5-year OS data,13-15 and no ambiguity regarding PD-L1 testing method (IHC 22C3 assay). By contrast, the IMpower110 trial involving atezolizumab is associated with complexity in both PD-L1 testing methods used (IHC SP142, SP263, and 22C3 assays) as well as the hierarchical testing design for primary outcome. Moreover, in the updated OS analysis,16 even for the high PD-L1 expression group, the 95% CI of the HR (0.76) ranged from 0.54 to 1.09, although the median OS (20.2 months v 14.7 months for chemotherapy) and the safety data both continued to favor atezolizumab over chemotherapy. Cemiplimab is the third PD-L1 immune check point inhibitor (immunotherapy) to have been tested as monotherapy for high PD-L1 advanced or metastatic NSCLC without a targetable oncogenic driver. Although not practice-changing, the EMPOWER-Lung 1 trial does reinforce the findings of previous trials (involving pembrolizumab and subsequently atezolizumab) in this setting, thereby making cemiplimab another immunotherapy drug that can be offered to eligible patients for this particular indication. The dual immunotherapy and chemotherapy approach (nivolumab and ipilimumab) while improving clinical outcomes versus chemotherapy alone for patients with high PD-L1 advanced or metastatic NSCLC is also associated with increased adverse effects and toxicities that are not insignificant and therefore shows no advantage for monoimmunotherapy alone for routine clinical practice (the reason for a weak recommendation). In patients with high symptom burden or disease burden, clinicians may choose an option of a combination of chemotherapy with immunotherapy despite a high PD-L1 value on the basis of the results of the KEYNOTE-189 and KEYNOTE-407 trials involving pembrolizumab for non-SCC and SCC histologic types, respectively (data with atezolizumab being much less impressive). Although there is no head-to-head comparison between the triple combination strategy (PD-1 ICI + doublet chemotherapy) with the quadruple combination strategy (PD-1 ICI + cytotoxic T-cell lymphocyte-4 ICI + doublet chemotherapy), clinicians should keep the additive toxicity of two ICIs in mind while making decisions regarding choice of treatment in these settings.
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 nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (Type: Evidence based; Evidence quality: Moderate; Strength of recommendation: Weak).
Note: 2020 options:
Pembrolizumab + carboplatin + (paclitaxel or nab-paclitaxel (Evidence quality: Intermediate; Strength of recommendation: Strong).
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 (Evidence quality: High; Strength of recommendation: Strong).
For patients with contraindications to immunotherapy AND not deemed candidates for platinum-based therapy, clinicians should offer standard chemotherapy with nonplatinum-based two drug combinations as outlined in the 2015 update (Evidence quality: Intermediate; Strength of recommendation: Weak).
(TPS 1%-49%) 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 (Evidence quality: Low; Strength of recommendation: Weak).
See discussion under Recommendations 1.6, 2.7, and 3.4 above.
Treatment of stage IV (metastatic) NSCLC—both SCC and non-SCC histologic types—with low (TPS = 1%-49%) or negative (TPS = 0%) PD-L1 expression continues to be a combination of chemotherapy and immunotherapy, in the absence of any contraindications for either of the two therapies. The strongest data for this combination continue to be from the KEYNOTE-18917 (non-SCC) and KEYNOTE-40718 (SCC) trials where pembrolizumab was combined with pemetrexed-platinum and paclitaxel or nab-paclitaxel + carboplatin, respectively. The results of other trials including IMPOWER-15019 (paclitaxel + carboplatin + bevacizumab + atezolizumab) and IMPOWER-13020 (nab-paclitaxel + carboplatin + atezolizumab) both for non-SCC NSCLC have been less impressive and some such as IMPOWER-13121 (nab-paclitaxel + carboplatin + atezolizumab for SCC NSCLC) and IMPOWER-13222 (pemetrexed + platinum + atezolizumab for non-SCC NSCLC) failed to demonstrate improvement in OS (the majority of these studies are described in the 2020 guideline). The CheckMate-9LA trial adopted a different strategy of two cycles of chemotherapy with a combination of two ICIs (PD-1 inhibitor nivolumab and cytotoxic T-cell lymphocyte-4 inhibitor ipilimumab) and did demonstrate improvements in both OS and PFS for all histologic types and for all levels of PD-L1 expression (including when the latter was either low or negative). However, the concerns related to using four drugs (including two ICIs) with the associated increase in toxicities (especially immune-related adverse events) do not offer any significant advantages over the pembrolizumab-chemotherapy combination; data that are more robust and have greater follow-up are available.
(2) What is the most effective second-line therapy? (3) Is there a role for a third-line therapy, or beyond?
For patients with non-SCC who received an ICI and chemotherapy as first-line therapy, clinicians may offer paclitaxel plus bevacizumab in the second-line setting (Type: Evidence based; Evidence quality: Low; Strength of recommendation: Weak).
For the majority of patients with non-SCC, who received chemotherapy with or without bevacizumab and ICI therapy (in either sequence), clinicians should offer the options of single-agent pemetrexed or docetaxel or paclitaxel plus bevacizumab in the third-line setting (Type: Evidence based; Evidence quality: Low; Strength of recommendation: Weak).
The systematic review identified one relevant trial5 (Tables 10 and 11). The RCT by Cortot et al5 included 166 participants with non-SCC histology with prior treatment and allocated them to paclitaxel and bevacizumab versus docetaxel. The RCT's primary outcome was 6-month PFS. The result was HR 0.61 (95% CI, 0.44 to 0.86) and indicate the doublet may improve PFS. Grade 3-4 AEs showed no significant differences. Using the GRADE methodology,9 study quality was downgraded from high to low because patients with EGFR mutations and ALK rearrangement were included, although the numbers are not reported.
For the majority of patients with stage IV NSCLC (without an oncogenic driver alteration), the treatment options at progression or after relapse on first-line therapy (a platinum doublet chemotherapy and immunotherapy combination) typically include single-agent chemotherapy with a different agent than what was used previously. Docetaxel (all histologic types), pemetrexed (non-SCC NSCLC), and weekly paclitaxel and bevacizumab (non-SCC NSCLC) are all options that can be discussed in this setting. For patients in whom the initial treatment was not a chemoimmunotherapy combination should receive the treatment not given earlier, i.e., platinum doublet chemotherapy (if the initial treatment was monotherapy with an ICI) and immunotherapy (if the initial treatment was platinum doublet chemotherapy).
The draft recommendations were released to the public for open comment from January 10, 2022, through January 24, 2022. Response categories of “Agree as written,” “Agree with suggested modifications” and “Disagree. See comments” were captured for every proposed recommendation with 21 written comments received. A total of 89% of the 21 of the responses either agreed or agreed with slight modifications to the recommendations and 11 of the responses disagreed. Expert Panel members reviewed comments from all sources and determined whether to maintain original draft recommendations, revise with minor language changes, or consider major recommendation revisions. All changes were incorporated before EBMC review and approval.
The draft was submitted to one external reviewer with content expertise. It was rated as high quality, and it was agreed it would be useful in practice. Review comments, including those regarding cemiplimab, were reviewed by the Expert Panel and integrated into the final manuscript before approval by the EBMC.
ASCO guidelines are developed for implementation across health settings. Each ASCO guideline includes a member from ASCO's Practice Guideline Implementation Network (PGIN) on the panel. The additional role of this PGIN representative on the guideline panel is to assess the suitability of the recommendations to implementation in the community setting, but also to identify any other barrier to implementation a reader should be aware of. Barriers to implementation include the need to increase awareness of the guideline recommendations among front-line practitioners and survivors of cancer and caregivers, and also to provide adequate services in the face of limited resources. The guideline Bottom Line Box was designed to facilitate implementation of recommendations. This guideline will be distributed widely through the ASCO PGIN. ASCO guidelines are posted on the ASCO website and most often published in the Journal of Clinical Oncology.
Limitations of the research include that OS data for atezolizumab was interim, uncertainties in the role of tumor mutational burden, and for Checkmate 9LA, indirectness in analysis by both histologic and PD-L1 subgroups. The Expert Panel suggests more research on these topics.
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.
More information, including a supplement with additional evidence tables, slide sets, and clinical tools and resources, is available at www.asco.org/thoracic-cancer-guidelines. Patient information is available at www.cancer.net.
Integration of Palliative Care into Standard Oncology Care23 (http://ascopubs.org/doi/10.1200/JCO.2016.70.1474)
Patient-Clinician Communication24 (http://ascopubs.org/doi/10.1200/JCO.2017.75.2311)
Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations1 (https://ascopubs.org/doi/10.1200/JCO.19.03022)
Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations25 (https://ascopubs.org/doi/10.1200/JCO.20.03570)
Molecular Testing for the Selection of Patients With Lung Cancer for Treatment With Targeted Tyrosine Kinase Inhibitors26 (http://ascopubs.org/doi/10.1200/JCO.2017.76.7293)
Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy27 (https://ascopubs.org/doi/10.1200/JCO.21.01440)
Evidence Based Medicine Committee approval: March 22, 2022
This American Society of Clinical Oncology (ASCO) Clinical Practice Guideline provides recommendations, with comprehensive review and analyses of the relevant literature for each recommendation. Additional information, including a supplement with additional evidence tables, slide sets, clinical tools and resources, and links to patient information at www.cancer.net, is available at www.asco.org/thoracic-cancer-guidelines.
Conception and design: All authors
Administrative support: Sarah Temin
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Sherman Baker Jr
Consulting or Advisory Role: Boehringer Ingelheim
Elizabeth Blanchard
Travel, Accommodations, Expenses: Mitra Biotech
Julie R. Brahmer
Honoraria: Janssen
Consulting or Advisory Role: Bristol Myers Squibb, Lilly, Merck, Amgen, Genentech, GlaxoSmithKline, AstraZeneca, Regeneron, Sanofi, Eisai, Turning Point Therapeutics
Research Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Spectrum Pharmaceuticals (Inst), Revolution (Inst), RAPT Therapeutics (Inst)
Other Relationship: Bristol Myers Squibb
Narjust Duma
Consulting or Advisory Role: AstraZeneca, Pfizer, NeoGenomics Laboratories, Janssen, Bristol Myers Squibb/Medarex, Merck, Mirati Therapeutics
Speakers' Bureau: MJH Life Sciences
Peter M. Ellis
Honoraria: AstraZeneca, Pfizer, Takeda, Lilly, Bristol Myers Squibb, Merck, Jazz Pharmaceuticals, Novartis Canada Pharmaceuticals Inc, Janssen Oncology
Ivy B. Elkins
Honoraria: Bayer, Janssen, Sanofi, Daiichi, Merck
Consulting or Advisory Role: AstraZeneca, BMS, Boehringer Ingelheim, Blueprint Medicines
(OPTIONAL) Uncompensated Relationships: Lilly
Rami Y. Haddad
Consulting or Advisory Role: Aptitude Health, MJH Healthcare Holdings, LLC, Cardinal Health, Rigel, Puma Biotechnology
Travel, Accommodations, Expenses: Pharmacyclics
Paul J. Hesketh
Consulting or Advisory Role: UpToDate
David H. Johnson
Consulting or Advisory Role: Merck, Pfizer, Aileron Therapeutics, Boston University
Natasha B. Leighl
Research Funding: Roche Canada (Inst), Guardant Health (Inst), MSD (Inst), EMD Serono (Inst), Lilly (Inst), AstraZeneca Canada (Inst), Takeda (Inst), Amgen (Inst), Bayer (Inst), MSD Oncology (Inst)
Travel, Accommodations, Expenses: Merck Sharp & Dohme
Hirva Mamdani
Consulting or Advisory Role: Zentalis, MorphoSys, Seattle Genetics
Tanyanika Phillips
Travel, Accommodations, Expenses: City of Hope
Gregory J. Riely
Research Funding: Novartis (Inst), Roche/Genentech (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), Infinity Pharmaceuticals (Inst), Mirati Therapeutics (Inst), Merck (Inst), Takeda (Inst)
Patents, Royalties, Other Intellectual Property: Patent application submitted covering pulsatile use of erlotinib to treat or prevent brain metastases (Inst)
Other Relationship: Pfizer, Roche/Genentech, Takeda, Mirati Therapeutics
Andrew G. Robinson
Honoraria: Merck
Consulting or Advisory Role: AstraZeneca, Merck, Amgen
Research Funding: AstraZeneca (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Roche Canada (Inst)
Rafael Rosell
Consulting or Advisory Role: Blueprint Medicines, Merck KGaA
Joan H. Schiller
Consulting or Advisory Role: Genentech/Roche, Merck, Cancer Expert Now, AstraZeneca
Other Relationship: Lung Cancer Research Foundation
Bryan J. Schneider
Research Funding: Merck
David R. Spigel
Leadership: ASCO (Inst)
Consulting or Advisory Role: Genentech/Roche (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Pfizer (Inst), GlaxoSmithKline (Inst), EMD Serono (Inst), Molecular Templates (Inst), Amgen (Inst), Curio Science (Inst), Intellisphere (Inst), Jazz Pharmaceuticals (Inst), Mirati Therapeutics (Inst), Puma Biotechnology (Inst), Sanofi/Aventis (Inst), Exelixis (Inst), Regeneron (Inst), Lilly (Inst), Janssen (Inst), Evidera (Inst), BeiGene (Inst), Novocure (Inst)
Research Funding: Genentech/Roche (Inst), Novartis (Inst), Celgene (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), AstraZeneca (Inst), University of Texas Southwestern Medical Center - Simmons Cancer Center (Inst), Merck (Inst), G1 Therapeutics (Inst), Neon Therapeutics (Inst), Takeda (Inst), Nektar (Inst), Celldex (Inst), Clovis Oncology (Inst), Daiichi Sankyo (Inst), EMD Serono (Inst), Astellas Pharma (Inst), GRAIL (Inst), Transgene (Inst), Aeglea Biotherapeutics (Inst), Ipsen (Inst), BIND Therapeutics (Inst), Eisai (Inst), ImClone Systems (Inst), Immunogen (Inst), Janssen Oncology (Inst), MedImmune (Inst), Molecular Partners (Inst), Agios (Inst), GlaxoSmithKline (Inst), Tesaro (Inst), Cyteir (Inst), Apollomics (Inst), Novocure (Inst), Elevation Oncology (Inst), Calithera Biosciences (Inst), Arcus Biosciences (Inst), Arrys Therapeutics (Inst), Bayer (Inst), BeiGene (Inst), Blueprint Medicines (Inst), Boehringer Ingelheim (Inst), Denovo Biopharma (Inst), Hutchison MediPharma (Inst), Incyte (Inst), Kronos Bio (Inst), Loxo (Inst), Macrogenics (Inst), Molecular Templates (Inst), Oncologie (Inst), Pfizer (Inst), PTC Therapeutics (Inst), PureTech (Inst), Razor Genomics (Inst), Repare Therapeutics (Inst), Rgenix (Inst), Tizona Therapeutics, Inc (Inst), Verastem (Inst), Evelo Biosciences (Inst), BioNTech (Inst)
Travel, Accommodations, Expenses: AstraZeneca, Genentech, Novartis
No other potential conflicts of interest were reported.
ACKNOWLEDGMENT
The Expert Panel wishes to thank Dr Edwin Yau, Dr Pavan Reddy, Dr Shilpi Gupta, and the entire Evidence Based Medicine Committee for their thoughtful reviews and insightful comments on this guideline. In addition, the Expert Panel wishes to thank Dr Nasser H. Hanna, Christina Lacchetti, and Dr Nofisat Ismaila.
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