Overview of the initial treatment of advanced non-small cell lung cancer

INTRODUCTION — Treatment of patients with lung cancer depends upon the cell type (non-small cell versus small cell), tumor stage, molecular characteristics, and an assessment of the patient's overall medical condition. (See "Overview of the initial treatment and prognosis of lung cancer".)

Patients with stage I, II, or III non-small cell lung cancer (NSCLC) are generally treated with curative intent using surgery, chemotherapy, radiation therapy, or a combined-modality approach (table 1). Immunotherapy may be part of the treatment strategy for some with unresectable stage III disease. (See "Management of stage I and stage II non-small cell lung cancer" and "Management of stage III non-small cell lung cancer".)

Systemic therapy is generally indicated for patients who present with advanced disease, including those who present with metastases (stage IV) or recur following initial definitive treatment. For patients with a solitary metastasis, surgical resection or definitive irradiation of the metastasis may be appropriate. Systemic therapy and/or metastasectomy is also used for patients who have relapsed with advanced disease following prior definitive treatment. (See "Oligometastatic non-small cell lung cancer".)

This topic presents an overview of the management of patients with advanced NSCLC. More detailed discussions of specific issues are presented in the relevant topics, as indicated below.

●(See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation".)

●(See "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation".)

●(See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)

●(See "Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer".)

●(See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

FACTORS IN CHOOSING INITIAL THERAPY — The goals of patient management for patients with advanced NSCLC are to prolong survival and to maintain quality of life for as long as possible, while minimizing the side effects due to treatment. The approach should recognize the palliative intent of treatment.

Key factors that influence the choice of initial therapy for advanced NSCLC include (algorithm 1):

●The presence of a high level of programmed cell death ligand 1 (PD-L1) expression

●The presence or absence of a driver mutation (eg, epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], c-ROS oncogene 1 [ROS1], BRAF, etc) for which a specific inhibitor is available. Analysis of either the primary tumor or of a metastasis for EGFR and ALK is indicated for all patients whose tumor contains an element of adenocarcinoma, regardless of the clinical characteristics of the tumor [1]. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Molecular testing'.)

●The extent of disease, including the number and sites of metastases, as well as the presence or absence of symptoms related to a specific site of metastasis.

●Squamous versus nonsquamous histology.

When patients progress during or after their initial treatment, there are a range of options that are dependent upon the initial treatment, specific aspects of the patient's original treatment, as well as the patient's overall condition and comorbidities. (See 'Initial systemic therapy' below.)

MOLECULAR TESTING — Whenever feasible, patients with advanced NSCLC should have tumor assessed for the presence of a driver mutation. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Molecular testing'.)

Additionally, we recommend routine programmed cell death ligand 1 (PD-L1) testing in all patients with newly diagnosed advanced NSCLC to inform the use of immunotherapy in the front-line setting. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'Limitations in biomarkers' and "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'Factors in choosing initial therapy'.)

INITIAL SYSTEMIC THERAPY

Driver mutation absent or unknown — Initial systemic therapy for those without an activating genetic driver alteration is discussed below and in the algorithm (algorithm 1).

Initial therapy

For patients with nonsquamous or squamous NSCLC, our preferred approach depends on the level of tumor programmed cell death ligand 1 (PD-L1) expression.

●For those with tumor PD-L1 expression of 50 percent or higher, we favor pembrolizumab or atezolizumab monotherapy, which has demonstrated improvement in overall survival (OS) compared with doublet chemotherapy alone in this population [2]. However, the combination of chemotherapy and pembrolizumab is preferred for those with rapidly progressive disease and is an acceptable alternative for others. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'Factors in choosing initial therapy' and "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'PD-L1 low (<50 percent) or unselected tumors'.)

•An exception is for those with such a high tumor burden or rapidly progressive disease in which early progression might preclude the option of chemotherapy in the second-line setting, due to functional decline. For such patients, we favor a combination of doublet chemotherapy with concurrent pembrolizumab.

•Contraindications to immunotherapy include connective tissue, rheumatologic, or interstitial lung disease. For patients who have contraindications to immunotherapy, a histology-appropriate platinum doublet may be used.

●For patients with PD-L1 expression of less than 50 percent, we favor a combination of doublet chemotherapy with concurrent pembrolizumab. Although pembrolizumab monotherapy is a US Food and Drug Administration (FDA)-approved option for patients with PD-L1 expression of 1 to 49 percent, a chemotherapy/pembrolizumab combination is preferred when feasible. In the randomized trial leading to this approval, results demonstrating superiority of pembrolizumab monotherapy over chemotherapy among patients with tumor PD-L1 expression of 1 percent or greater were driven by the subset of patients with high tumor PD-L1 expression (50 percent or higher).

Regarding chemotherapy selection, there is no single optimal chemotherapy combination. Cisplatin-based regimens are slightly more effective than carboplatin-based combinations or nonplatinum regimens, but are associated with increased nonhematologic toxicity. Given that treatment is palliative in this setting, we opt for a carboplatin-based regimen for the majority of patients who will receive a chemotherapy doublet. Pemetrexed-based regimens should only be used in patients with nonsquamous histology. When combination chemotherapy is the initial treatment, it generally is limited to four to six cycles. Specifically, our approach to initial chemotherapy selection is as follows:

•For patients with nonsquamous NSCLC and PD-L1 expression <50 percent, our preferred option is the combination of pemetrexed, carboplatin or cisplatin, and pembrolizumab. This regimen has demonstrated improvements in multiple efficacy endpoints, including OS, relative to pemetrexed and carboplatin alone [3]. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'PD-L1-high tumors (at least 50 percent)'.)

•Alternative options for patients with nonsquamous NSCLC and PD-L1 expression <50 percent are as follows:

-The platinum-based doublet may instead be combined with bevacizumab, which increases progression-free survival (PFS) and OS relative to chemotherapy alone. A choice among these options takes into account patient and provider preferences, given that head-to-head comparisons of platinum combinations with either bevacizumab or pembrolizumab are not available. However, the magnitude of PFS improvement is more impressive with pembrolizumab than in the bevacizumab trials.

-The combination of platinum-based doublet chemotherapy, bevacizumab, and atezolizumab is another potential alternative, and this regimen now has regulatory approval for patients without an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation.

•For patients with squamous NSCLC and PD-L1 expression <50 percent, our preferred regimen is carboplatin with either paclitaxel or nabpaclitaxel, and pembrolizumab, based on the demonstrated survival benefit of this regimen over chemotherapy alone for patients with advanced, squamous NSCLC. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'In squamous cancers'.)

●Although we typically use the strategies discussed above, nivolumab plus ipilimumab is another FDA-approved option for patients with PD-L1 expression ≥1 percent; nivolumab and ipilimumab is also approved with two cycles of platinum-based chemotherapy in tumors, irrespective of PD-L1 expression. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'Nivolumab plus ipilimumab, with or without chemotherapy'.)

Maintenance therapy

●For those initially treated with combination chemotherapy, treatment is generally limited to four to six cycles. In the absence of disease progression, maintenance systemic therapy has been shown to prolong PFS and OS. For such patients, options include:

•For those who were initially treated with the combination of pemetrexed, carboplatin, and pembrolizumab, pembrolizumab with pemetrexed maintenance is typically administered. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'Factors in choosing initial therapy' and "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'Maintenance therapy' and "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'Duration of therapy'.)

•For others treated with chemotherapy, single-agent chemotherapy may be offered, although many patients discontinue due to cumulative toxicity.

The approach to maintenance therapy and choice of agents is discussed separately. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'Maintenance therapy'.)

●For patients treated with pembrolizumab monotherapy, treatment is typically continued until progression. However, for those with acquired resistance to programmed cell death receptor 1 (PD-1) axis inhibitors limited to one or two sites, local therapy with continuation of the PD-1 axis inhibitor represents an acceptable alternative, recognizing that supporting data are limited. (See "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation", section on 'Patients treated with initial immunotherapy only'.)

Driver mutation present — An improved understanding of the molecular pathways that drive malignancy in NSCLC has led to the development of agents that target specific molecular pathways in malignant cells. These agents have been a significant step forward in the treatment of patients whose tumors contain specific mutations in these pathways. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

EGFR mutation-positive — Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors ([TKIs] osimertinib, erlotinib, gefitinib, afatinib) as single agents is indicated for the initial management of patients whose tumors contain an activating mutation in EGFR. This is preferred over chemotherapy- and immunotherapy-based approaches for patients with an identified driver mutation.

In this setting, first-line treatment with an EGFR TKI improves outcomes compared with standard platinum-based chemotherapy. The impact on OS is less evident since EGFR TKIs were frequently used as second-line therapy after chemotherapy in the clinical trials demonstrating the efficacy of this approach. Among the EGFR TKIs, osimertinib has demonstrated improvements in PFS over erlotinib and gefitinib and is our preferred frontline agent [4]. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Initial therapy for common mutations'.)

EGFR TKIs generally are not combined with platinum-based doublet chemotherapy as initial therapy, given increased toxicity and the fact that trials were conducted prior to routine use of osimertinib, which is our preferred initial treatment.

In the absence of significant toxicity, treatment with an EGFR TKI is continued until there is evidence of progression. In carefully selected patients (eg, an isolated site of recurrence that can be treated with local therapy, those with extremely mild and asymptomatic progression), EGFR TKI therapy may be continued after initial evidence of progressive disease. If chemotherapy is added at the time of progression, treatment with an EGFR TKI should be discontinued. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Duration of therapy'.)

ALK fusion oncogene-positive — For patients with advanced NSCLC whose tumors contain the anaplastic lymphoma kinase (ALK) fusion oncogene, treatment with an ALK TKI is the preferred treatment. (See "Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer".)

●Alectinib is preferred as first-line therapy in these patients. In the absence of significant toxicity, treatment is continued until there is evidence of progression. (See "Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer", section on 'Alectinib'.)

●Ceritinib is another potent, second generation ALK inhibitor and is an acceptable frontline alternative to alectinib. (See "Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer", section on 'Ceritinib'.)

●Brigatinib is another next-generation ALK inhibitor that is approved for clinical use in patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. (See "Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer", section on 'Brigatinib'.)

Other mutations — A number of other less common driver mutations have been identified, which define specific subsets of patients with NSCLC. Examples include c-ROS oncogene 1 (ROS1), BRAF, RET, TRK, MET, and Kirsten rat sarcoma viral oncogene homolog (KRAS). For most of these, specific inhibitors are available, and these should be integrated into the overall sequence of treatments for a given patient. Our suggested approach is discussed elsewhere. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

OLDER ADULT PATIENTS

No driver mutation — Although data are more limited for older patients, a similar approach may be used in older adult patients, after incorporating a consideration of comorbidity, and concerns and preferences regarding treatment. (See 'Initial systemic therapy' above.)

Factors that may be useful in selecting patients for chemotherapy and/or immunotherapy and determining the appropriate regimen include performance status, comorbidities, and a baseline comprehensive geriatric assessment. (See "Comprehensive geriatric assessment for patients with cancer" and "Systemic chemotherapy for cancer in older adults".)

●Although data are mixed, phase III trials suggest that chemotherapy prolongs survival in appropriately selected older adult patients and those with a marginal performance status (PS 2 (table 2)) with NSCLC [5-9]. Therefore, chemotherapy, if indicated, should not be avoided on the basis of age alone.

●In appropriately selected older adult patients and those with borderline performance status (PS 2), single-agent chemotherapy can improve overall survival (OS) without adversely impacting quality of life (QOL) compared with best supportive care (BSC) for advanced NSCLC [10]. The most extensive data are available for vinorelbine and docetaxel [10,11], although other agents (eg, gemcitabine or pemetrexed) may also have a role in selected patients.

●Systemic chemotherapy is, however, generally not indicated in patients with poor performance status (PS 3 or 4), and these patients are generally managed with best supportive care alone.

●Checkpoint inhibitor immunotherapy appears to have similar efficacy and toxicity in those ≥65 years and those <65 years of age, and chronologic age alone should not preclude the use of these agents. Toxicities are discussed in more detail elsewhere. (See "Toxicities associated with immune checkpoint inhibitors" and "Toxicities associated with immune checkpoint inhibitors", section on 'Older adult patients'.)

Data are mixed regarding whether combination chemotherapy in the older adult patient improves survival relative to single-agent chemotherapy. For example, a French Intergroup study (IFCT-0501) randomly assigned 451 patients age 70 to 89 years with advanced NSCLC to a combination of carboplatin plus paclitaxel for four cycles or to single-agent therapy with either gemcitabine or vinorelbine [5]. Approximately 30 percent of these were PS 2. At a median follow-up of 30 months, median OS was prolonged with combination chemotherapy compared with single-agent chemotherapy (10.3 versus 6.2 months; hazard ratio [HR] 0.64, 95% CI 0.52-0.78), as was progression-free survival (PFS, 6.0 versus 2.8 months; HR, 0.51). Grade 3 or 4 neutropenia was more common with the combination compared with monotherapy (48 versus 12 percent). Ten deaths (4.4 percent) in the combination arm were attributed to treatment, compared with three (1.3 percent) in the monotherapy group.

By contrast, in a combined analysis of the MILES-3 and MILES-4 trials, 531 patients older than 70 years with advanced NSCLC and PS 0 or 1 were assigned to gemcitabine or pemetrexed with or without cisplatin [12]. At a median follow-up of two years, OS (HR 0.86, 95% CI 0.70-1.05) was not improved with the addition of cisplatin, although PFS (HR 0.76, 95% CI 0.63-0.92) and objective response rate (16 versus 9 percent) were better. Cisplatin was associated with greater toxicities.

Driver mutation present — The oral administration and toxicity profile of inhibitors of driver mutations may offer some special advantages for the initial treatment of advanced NSCLC in older adult patients and those with a poor performance status (PS 3 or 4 (table 2)). This approach is particularly useful in those with an epidermal growth factor receptor (EGFR) mutation, a BRAF mutation, the presence of the anaplastic lymphoma kinase (ALK) fusion oncogene, or a c-ROS oncogene 1 (ROS1) translocation, though other targetable mutations are also emerging. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

MANAGEMENT OF SPECIFIC METASTATIC SITES — Although systemic therapy is the primary approach to the management of metastatic disease, therapy directed against specific sites of disease may also play an important role in some patients.

Oligometastatic disease — Occasional patients will present initially with an isolated metastasis combined with a potentially resectable primary tumor, or with a recurrence at a single site. In this situation, surgical resection or definitive radiation therapy (RT) of the metastatic disease may produce durable benefit [13]. The most frequent sites of such metastases are the brain and the adrenal gland [14]. (See "Oligometastatic non-small cell lung cancer".)

Bone metastases — Bone metastases are a frequent complication in patients with metastatic NSCLC and can impair quality of life.

Treatment — In addition to systemic therapy, treatment may include RT for localized, painful lesions or surgical intervention to treat or prevent pathologic fractures. (See "Radiation therapy for the management of painful bone metastases" and "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults".)

Prevention of complications — Osteoclast inhibition with denosumab or zoledronic acid is recommended for patients with bone metastases to prevent skeletal-related complications. Data to support benefit and indications for osteoclast inhibitor therapy are presented elsewhere. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)

Central nervous system metastases

Brain metastases — Brain metastases are a frequent complication in patients with metastatic NSCLC. The management of patients with brain metastases may include surgical resection, RT, or systemic therapy. (See "Overview of the treatment of brain metastases".)

Brain metastases in patients whose tumor harbors an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) activating mutation are frequently responsive to next-generation targeted therapies (eg, alectinib rather than crizotinib), which makes it feasible to initiate a trial of systemic therapy prior to, or potentially instead of, local therapy to treat brain metastases. This is a particularly good option for brain metastases that are small (ideally <1 cm) and asymptomatic. This approach is also being examined for immunotherapy with or without concurrent chemotherapy in the setting of advanced NSCLC. This general approach is discussed in detail elsewhere. (See "Brain metastases in non-small cell lung cancer", section on 'Patients with oncogenic drivers'.)

Leptomeningeal metastases — Leptomeningeal carcinomatosis from NSCLC is associated with a particularly poor prognosis, with a median survival of approximately three months [15]. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors" and "Treatment of leptomeningeal disease from solid tumors".)

Standard treatment with whole-brain RT and/or intrathecal chemotherapy does not appear to have a significant effect on survival. There is some limited evidence that treatment with EGFR inhibitors may be beneficial in patients whose tumors contain an EGFR mutation. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Patients with non-small cell lung cancer'.)

SYMPTOM PALLIATION — Short courses of radiation therapy (RT) are useful for patients who require palliation of symptoms (eg, dyspnea due to airway obstruction, dysphagia, or hemoptysis), either as part of their initial management or after other treatment has failed [16,17].

Multiple randomized trials have compared lower-dose schedules using fewer fractions with more protracted, higher-dose schedules. A meta-analysis analyzed results from 13 trials that included 3473 patients who received palliative thoracic radiation [18]. The doses and schedules varied widely in different trials. Longer courses using higher doses were associated with longer survival, but also increased toxicity, primarily manifested as dysphagia.

The optimal dose and schedule for symptom palliation is unclear. Longer courses (30 Gy in 10 fractions) represent a reasonable approach for patients with a relatively favorable prognosis for short-term survival. Shorter courses may be more appropriate for those with a poorer prognosis or limited access to an RT facility [18].

In some cases, such symptoms may be due predominantly to endobronchial recurrence. In carefully selected patients, endobronchial brachytherapy or other interventional techniques may be useful in providing symptom palliation. (See "Airway stents" and "Bronchoscopic laser in the management of airway disease in adults" and "Endobronchial electrocautery" and "Bronchoscopic cryotechniques in adults".)

PALLIATIVE CARE — Early integration of palliative care into the disease-specific therapies for patients with advanced NSCLC may offer a number of benefits [19]. In a trial in which 151 patients were randomly assigned to early palliative care or standard management, a formal program with a palliative care team resulted in improved quality of life and mood [20]. The active intervention arm focused on assessment of physical and psychosocial issues, the establishment of goals for care, decision-making related to treatment, and coordination of care. Although patients had less aggressive care at the end of life, median survival was significantly longer in patients randomized to early palliative care (11.6 versus 8.9 months).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Non-small cell lung cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Non-small cell lung cancer treatment; stage IV cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Systemic therapy options – Advanced non-small cell lung cancer (NSCLC) generally requires the sequential use of systemic therapies in an effort to prolong overall survival (OS) while maintaining quality of life. Available systemic therapy options that are widely used include immunotherapy, cytotoxic chemotherapy, biologics, and targeted agents. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation" and "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

●Factors in choosing initial therapy – Factors that influence the choice and sequence of therapies for an individual patient include histology (squamous versus nonsquamous), the presence or absence of driver mutations, and patient-specific factors such as age, comorbidity, and concerns and preferences regarding treatment (algorithm 1).

●Molecular testing – Whenever possible, patients should have tumor tissue assessed for expression of programmed cell death ligand 1 (PD-L1) expression. Patients with nonsquamous NSCLC should also have their tumor tested for the presence of a driver mutation, such as mutated epidermal growth factor receptor (EGFR), the anaplastic lymphoma kinase (ALK) fusion oncogene, and other targetable mutations. (See 'Factors in choosing initial therapy' above and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

●Driver mutation present – For patients whose tumor contains a driver mutation, use of a specific inhibitor is the preferred initial approach. If tolerated, such treatment is continued until there is evidence of progressive disease. The available data indicate that immunotherapy-based approaches are not appropriate as first-line treatment for these patients. (See 'Driver mutation present' above and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer" and "Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer" and "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)

●Driver mutation absent – The initial treatment for patients whose tumor does not contain a driver mutation depends on the level of expression of PD-L1 (algorithm 1).

•For most patients with advanced, nonsquamous or squamous NSCLC, and high PD-L1 expression (≥50 percent of tumor cells with staining), we favor first-line treatment with pembrolizumab or atezolizumab monotherapy. However, for those with rapidly progressive disease or such a high tumor burden that early progression may lead to functional decline precluding treatment with chemotherapy in the subsequent line, we prefer concurrent chemotherapy and immunotherapy. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'Factors in choosing initial therapy' and "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation".)

•For those with low or intermediate PD-L1 expression (<50 percent of tumor cells with staining), we offer a combination of a histology-appropriate, platinum-based chemotherapy doublet with immunotherapy, which has been shown to improve survival and other efficacy endpoints compared with chemotherapy alone. Although pembrolizumab monotherapy is a US Food and Drug Administration (FDA)-approved option for patients with PD-L1 expression of 1 to 49 percent, a chemotherapy/pembrolizumab combination is preferred when feasible. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'PD-L1 low (<50 percent) or unselected tumors'.)

-For those with nonsquamous NSCLC, the combination of either cisplatin or carboplatin with pemetrexed and pembrolizumab has shown survival benefits over the same chemotherapy.

-For patients with squamous NSCLC, a combination of carboplatin with paclitaxel or nabpaclitaxel and pembrolizumab is now a leading option based on a survival benefit compared with the same chemotherapy.

•For patients who have contraindications to immunotherapy, a histology-appropriate platinum doublet may be used, with bevacizumab added for those with nonsquamous histology NSCLC.

●Management of specific metastatic sites – In addition to systemic therapy, treatment directed at specific sites of metastases and toward symptom control can play an important part in the overall management of patients. (See 'Management of specific metastatic sites' above and 'Symptom palliation' above and 'Palliative care' above.)