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NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histological variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who never smoked.
As a class, NSCLC is usually less sensitive to chemotherapy and radiation therapy than SCLC. Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy. Local control can be achieved with radiation therapy in many patients with unresectable disease, but cure is seen in relatively few patients. Patients with locally advanced unresectable disease may achieve long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy, targeted agents, and other supportive measures.
Incidence and Mortality
Estimated new cases and deaths from lung cancer (NSCLC and SCLC combined) in the United States in 2024:[
Lung cancer is the leading cause of cancer-related mortality in the United States. The 5-year relative survival rate from 2013 to 2019 for patients with lung cancer was 25%. The 5-year relative survival rate varies markedly for patients diagnosed at local stage (63%), regional stage (35%), or distant stage (8%).[
Anatomy
NSCLC arises from the epithelial cells of the lung of the central bronchi to terminal alveoli. The histological type of NSCLC correlates with site of origin, reflecting the variation in respiratory tract epithelium of the bronchi to alveoli. Squamous cell carcinoma usually starts near a central bronchus. Adenocarcinoma and bronchioloalveolar carcinoma usually originate in peripheral lung tissue.
Anatomy of the respiratory system.
Pathogenesis
Smoking-related lung carcinogenesis is a multistep process. Squamous cell carcinoma and adenocarcinoma have defined premalignant precursor lesions. Before becoming invasive, lung epithelium may undergo morphological changes that include:
Dysplasia and carcinoma in situ are considered the principal premalignant lesions because they are more likely to progress to invasive cancer and less likely to spontaneously regress.
Risk Factors
Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include the following:
The single most important risk factor for the development of lung cancer is smoking. For a smoker, the risk of lung cancer is, on average, tenfold higher than in a lifetime nonsmoker (defined as a person who has smoked <100 cigarettes in his or her lifetime). The risk increases with the quantity of cigarettes, duration of smoking, and starting age.
Smoking cessation results in a decrease in precancerous lesions and a reduction in lung cancer risk. Former smokers continue to have an elevated risk of lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on lung cancer risk.[
In addition, after resection of a lung cancer, there is a 1% to 2% risk per patient per year that a second lung cancer will occur.[
A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers.[
Because of the persistent risk of developing second lung cancers in former smokers, various chemoprevention strategies have been evaluated in randomized control trials. None of the phase III trials using the agents beta carotene, retinol, 13-cis -retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results.[
For more information, see Lung Cancer Prevention.
Screening
In patients considered at high risk of developing lung cancer, the only screening modality for early detection that has been shown to alter mortality is low-dose helical CT scanning.[
For more information, see the Screening by low-dose computed tomography: benefit section in Lung Cancer Screening.
Clinical Presentation
Lung cancer may present with symptoms or be found incidentally on chest imaging. The most common symptoms at presentation include:
Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck.
Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases. Infrequently, patients may present with symptoms and signs of paraneoplastic diseases such as hypertrophic osteoarthropathy with digital clubbing or hypercalcemia from parathyroid hormone-related protein.
Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease or pulmonary fibrosis.
Diagnosis
Investigations of patients with suspected NSCLC focus on confirming the diagnosis and determining the extent of the disease. Treatment options are determined by histology, stage, and general health and comorbidities of the patient.
The procedures used to determine the presence of cancer include:
Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathological material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[
For more information on tests and procedures used for staging, see the General Staging Evaluation section.
Prognostic Factors
Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathological factors.[
For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%. These patients have been excluded from clinical trials evaluating aggressive multimodality interventions.
In multiple retrospective analyses of clinical trial data, advanced age alone has not been shown to influence response or survival with therapy.[
Because treatment is not satisfactory for almost all patients with NSCLC, eligible patients should consider clinical trials. Information about ongoing clinical trials is available from the
References:
Malignant non-small cell epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). The three main subtypes of non-small cell lung cancer (NSCLC) include:
Additional types include adenosquamous carcinoma, sarcomatoid carcinomas, salivary gland type tumors, carcinoid tumors, and other unclassified carcinomas. There are many subtypes in these categories.[
Tumor Types
Squamous cell carcinoma
Most squamous cell carcinomas of the lung are located centrally, in the larger bronchi of the lung. Squamous cell carcinomas are linked more strongly with smoking than other forms of NSCLC. The incidence of squamous cell carcinoma of the lung has been decreasing in recent years.
Adenocarcinoma
Adenocarcinoma is now the most common histological subtype in many countries, and subclassification of adenocarcinoma is important. One of the biggest problems with lung adenocarcinomas is the frequent histological heterogeneity. Mixtures of adenocarcinoma histological subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation.
Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/IASLC definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors.
If stromal, vascular, or pleural invasion are identified in an adenocarcinoma that has an extensive bronchioloalveolar carcinoma component, the classification would be an adenocarcinoma of mixed subtype with predominant bronchioloalveolar pattern and a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. However, the future of bronchioloalveolar carcinoma as a distinct clinical entity is unclear; a multidisciplinary expert panel representing the IASLC, the American Thoracic Society, and the European Respiratory Society proposed a major revision of the classification of adenocarcinomas in 2011 that entails a reclassification of what was called bronchioloalveolar carcinoma into newly defined histological subgroups.
The following variants of adenocarcinoma are recognized in the WHO/IASLC classification:
Large cell carcinoma
In addition to the general category of large cell carcinoma, several uncommon variants are recognized in the WHO/IASLC classification, including:
Basaloid carcinoma is also recognized as a variant of squamous cell carcinoma, and rarely, adenocarcinomas may have a basaloid pattern; however, in tumors without either of these features, they are regarded as a variant of large cell carcinoma.
Neuroendocrine tumors
LCNEC is recognized as a histologically high-grade non-small cell carcinoma. It has a very poor prognosis similar to that of small cell lung cancer (SCLC). Atypical carcinoid is recognized as an intermediate-grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and high-grade SCLC and LCNEC.
Neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLCs that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme because the clinical and therapeutic significance of neuroendocrine differentiation in NSCLC is not firmly established. These tumors are referred to collectively as NSCLC with neuroendocrine differentiation.
Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements
This is a group of rare tumors. Spindle cell carcinomas and giant cell carcinomas comprise only 0.4% of all lung malignancies, and carcinosarcomas comprise only 0.1% of all lung malignancies. In addition, this group of tumors reflects a continuum in histological heterogeneity, as well as epithelial and mesenchymal differentiation. On the basis of clinical and molecular data, biphasic pulmonary blastoma is regarded as part of the spectrum of carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.
Molecular Features
The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[
EGFR and ALK mutations predominate in adenocarcinomas that develop in nonsmokers, and KRAS and BRAF mutations are more common in smokers or former smokers. EGFR mutations strongly predict the improved response rate and progression-free survival of patients who take EGFR inhibitors. In a set of 2,142 lung adenocarcinoma specimens from patients treated at Memorial Sloan Kettering Cancer Center, EGFR exon 19 deletions and L858R were found in 15% of tumors from former smokers (181 of 1,218; 95% confidence interval [CI], 13%–17%), 6% from current smokers (20 of 344; 95% CI, 4%–9%), and 52% from never-smokers (302 of 580; 95% CI, 48%–56%; P < .001 for ever- vs. never-smokers).[
Fusions of ALK with EML4 genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. Sensitizing fusions of ALK with other genes have also been reported.
References:
General Staging Evaluation
In non-small cell lung cancer (NSCLC), the determination of stage has important therapeutic and prognostic implications. Careful initial diagnostic evaluation to define the location and to determine the extent of primary and metastatic tumor involvement is critical for the appropriate care of patients.
In general, symptoms, physical signs, laboratory findings, and perceived risk of distant metastasis lead to an evaluation for distant metastatic disease. Additional tests such as bone scans and computed tomography (CT)/magnetic resonance imaging (MRI) of the brain may be performed if initial assessments suggest metastases or if patients with stage III disease are being evaluated for aggressive local and combined modality treatments.
Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors and pathological factors.[
Procedures used to determine stage include:
Procedures used to obtain tissue samples include bronchoscopy, mediastinoscopy, or anterior mediastinotomy.
Pathological staging of NSCLC requires examination of the tumor, knowledge of resection margins, and determination of lymph node status.
At diagnosis, patients with NSCLC can be divided into the following three groups that reflect both the extent of the disease and the treatment approach:
Evaluation of mediastinal lymph node metastasis
Surgical evaluation
Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy.
Accurate staging of the mediastinal lymph nodes provides important prognostic information.
Evidence (nodal status):
The corresponding results for lung cancer–specific mortality and for patients who received radiation therapy were not substantially different.
CT imaging
CT scanning is primarily used for determining the size of the tumor. The CT scan should extend inferiorly to include the liver and adrenal glands. MRI scans of the thorax and upper abdomen do not appear to yield advantages over CT scans.[
Evidence (CT scan):
18F-FDG PET scanning
The wider availability and use of 18F-FDG PET scanning for staging has modified the approach to staging mediastinal lymph nodes and distant metastases.
Randomized trials evaluating the utility of 18F-FDG PET scanning in potentially resectable NSCLC patients reported conflicting results in terms of the relative reduction in the number of noncurative thoracotomies.
Although the current evidence is conflicting, 18F-FDG PET scanning may improve results of early-stage lung cancer by identifying patients who have evidence of metastatic disease that is beyond the scope of surgical resection and that is not evident by standard preoperative staging procedures.
Evidence (18F-FDG PET scan):
Decision analyses demonstrate that 18F-FDG PET scanning may reduce the overall costs of medical care by identifying patients with falsely negative CT scans in the mediastinum or otherwise undetected sites of metastases.[
Combination of CT imaging and 18F-FDG PET scanning
The combination of CT imaging and 18F-FDG PET scanning has greater sensitivity and specificity than CT imaging alone.[
Evidence (CT/18F-FDG PET scan):
For patients with clinically operable NSCLC, the evidence supports performing a biopsy of mediastinal lymph nodes that are found to be larger than 1 cm in shortest transverse axis on chest CT scan or are found to be positive on 18F-FDG PET scan. Negative 18F-FDG PET scanning does not preclude biopsy of radiographically enlarged mediastinal lymph nodes. Mediastinoscopy is necessary for the detection of cancer in mediastinal lymph nodes when the results of the CT scan and 18F-FDG PET scan do not corroborate each other.
Evaluation of brain metastasis
Patients at risk of brain metastases may be staged with CT or MRI scans.
Evidence (staging with CT or MRI):
Whether the improved detection rate of MRI translates into improved outcome remains unknown. Not all patients are able to tolerate MRI, and for these patients contrast-enhanced CT scan is a reasonable substitute.
Evaluation of distant metastasis to sites other than the brain
Numerous nonrandomized, prospective, and retrospective studies have demonstrated that 18F-FDG PET scanning offers diagnostic advantages over conventional imaging in staging distant metastatic disease; however, standard 18F-FDG PET scans have limitations. 18F-FDG PET scans may not extend below the pelvis and may not detect bone metastases in the long bones of the lower extremities. Because the metabolic tracer used in 18F-FDG PET scanning accumulates in the brain and urinary tract, 18F-FDG PET scanning is not reliable for detection of metastases in these sites.[
The Revised International System for Staging Lung Cancer
The Revised International System for Staging Lung Cancer, based on information from a clinical database of more than 5,000 patients, was adopted in 2010 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer.[
AJCC Stage Groupings and TNM Definitions
The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define NSCLC.[
T Category | T Criteria | |
---|---|---|
a Reprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56. | ||
TX | Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy. | |
T0 | No evidence of primary tumor. | |
Tis | Carcinomain situ; SCIS =Squamous cell carcinomain situ; AIS: Adenocarcinoma in situ; Adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension. | |
T1 | Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus). | |
T1mi | Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension. | |
T1a | Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon. | |
T1b | Tumor >1 cm but ≤2 cm in greatest dimension. | |
T1c | Tumor >2 cm but ≤3 cm in greatest dimension. | |
T2 | Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm. | |
T2a | Tumor >3 cm but ≤4 cm in greatest dimension. | |
T2b | Tumor >4 cm but ≤5 cm in greatest dimension. | |
T3 | Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary. | |
T4 | Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary. |
N Category | N Criteria |
---|---|
a Reprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56. | |
NX | Regional lymph nodes cannot be assessed. |
N0 | No regional lymph node metastasis. |
N1 | Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension. |
N2 | Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s). |
N3 | Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s). |
M Category | M Criteria | |
---|---|---|
a Reprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56. | ||
M0 | No distant metastasis. | |
M1 | Distant metastasis. | |
M1a | Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor. | |
M1b | Single extrathoracic metastases in a single organ (including involvement of a single nonregional node). | |
M1c | Multiple extrathoracic metastases in a single organ or in multiple organs. |
Stage | TNM Classification | Illustration |
---|---|---|
T = primary tumor; N = regional lymph node; M = distant metastasis. | ||
a Reprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56. | ||
Occult carcinoma | TX, N0, M0 | |
0 | Tis, N0, M0 | |
IA1 | T1mi, N0, M0 | |
T1a, N0, M0 | ||
IA2 | T1b, N0, M0 | |
IA3 | T1c, N0, M0 | |
IB | T2a, N0, M0 | |
IIA | T2b, N0, M0 | |
IIB | T1a, N1, M0 | |
T1b, N1, M0 | ||
T1c, N1, M0 | ||
T2a, N1, M0 | ||
T2b, N1, M0 | ||
T3, N0, M0 | ||
IIIA | T1a, N2, M0 | |
T1b, N2, M0 | ||
T1c, N2, M0 | ||
T2a, N2, M0 | ||
T2b, N2, M0 | ||
T3, N1, M0 | ||
T4, N0, M0 | ||
T4, N1, M0 | ||
IIIB | T1a, N3, M0 | |
T1b, N3, M0 | ||
T1c, N3, M0 | ||
T2a, N3, M0 | ||
T2b, N3, M0 | ||
T3, N2, M0 | ||
T4, N2, M0 | ||
IIIC | T3, N3, M0 | |
T4, N3, M0 | ||
IV | Any T, Any N, M1 | |
IVA | Any T, Any N, M1a | |
Any T, Any N, M1b | ||
IVB | Any T, Any N, M1c | |
References:
In non-small cell lung cancer (NSCLC), results of standard treatment are poor except for the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment.
Treatment decisions are based on some of the following factors:
Surgery is potentially the most curative therapeutic option for this disease. Postoperative chemotherapy may provide an additional benefit to patients with resected NSCLC. Radiation therapy combined with chemotherapy can produce a cure in a small number of patients and can provide palliation in most patients. Prophylactic cranial irradiation may reduce the incidence of brain metastases, but there is no evidence of a survival benefit and the effect of prophylactic cranial irradiation on quality of life is not known.[
Chemotherapy has produced short-term improvement in disease-related symptoms in patients with advanced NSCLC. Several clinical trials have attempted to assess the impact of chemotherapy on tumor-related symptoms and quality of life. In total, these studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life;[
The identification of gene mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[
The treatment options for each stage of NSCLC are presented in Table 5.
Stage ( TNM Definitions) | Treatment Options | |
---|---|---|
ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; HER2 = human epidermal growth factor receptor 2; mTOR = mammalian target of rapamycin; NSCLC = non-small cell lung cancer; NTRK = neurotrophic tyrosine kinase; TKIs = tyrosine kinase inhibitors; TNM = tumor, node, metastasis. | ||
Occult NSCLC | Surgery | |
Stage 0 NSCLC | Surgery | |
Endobronchial therapies | ||
Stages IA and IB NSCLC | Surgery | |
Adjuvant therapy | ||
Radiation therapy | ||
Stages IIA and IIB NSCLC | Surgery with or without adjuvant and/or neoadjuvant therapy | |
Radiation therapy | ||
Stage IIIA NSCLC | Resected or resectable disease | Surgery with neoadjuvant and/or adjuvant therapy |
Neoadjuvant therapy | ||
Perioperative (neoadjuvant and adjuvant) immunotherapy with chemotherapy | ||
Adjuvant therapy | ||
Unresectable disease | Chemoradiation therapy | |
Radiation therapy | ||
Superior sulcus tumors | Surgery | |
Chemoradiation therapy followed by surgery | ||
Radiation therapy alone | ||
Tumors that invade the chest wall | Surgery | |
Surgery and radiation therapy | ||
Radiation therapy alone | ||
Chemotherapy combined with radiation therapy and/or surgery | ||
Stages IIIB and IIIC NSCLC | Sequential or concurrent chemotherapy and radiation therapy | |
Radiation therapy alone | ||
Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC | Cytotoxic combination chemotherapy | |
Combination chemotherapy with monoclonal antibodies | ||
Maintenance therapy after first-line chemotherapy(for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy) | ||
EGFR TKIs with or without chemotherapy(for patients withEGFRmutations) | ||
EGFR-directed therapy(for patients withEGFRexon 20 insertion mutations) | ||
ALK inhibitors(for patients withALKtranslocations) | ||
BRAF V600E and MEK inhibitors(for patients withBRAFV600E mutations) | ||
ROS1 inhibitors(for patients withROS1rearrangements) | ||
NTRK inhibitors(for patients withNTRKfusions) | ||
RET inhibitors(for patients withRETfusions) | ||
MET inhibitors(for patients withMETexon 14 skipping mutations) | ||
Immune checkpoint inhibitors with or without chemotherapy | ||
mTOR inhibitors(for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors) | ||
Local therapies and special considerations | ||
Progressive Stage IV, Relapsed, and Recurrent NSCLC | Chemotherapy | |
EGFR-directed therapy | ||
ALK-directed TKIs | ||
BRAF V600E and MEK inhibitors(for patients withBRAFV600E mutations) | ||
ROS1-directed therapy | ||
NTRK inhibitors(for patients withNTRKfusions) | ||
RET inhibitors(for patients withRETfusions) | ||
MET inhibitors(for patients withMETexon 14 skipping mutations) | ||
KRAS G12C inhibitors(for patients withKRASG12C mutations) | ||
HER2-targeted therapy(for patients withHER2mutations) | ||
Immunotherapy | ||
mTOR inhibitors(for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors) |
In addition to the treatment options presented in Table 5, treatment options under clinical evaluation include:
Current Clinical Trials
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References:
In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomography scan), when needed, to define the site and nature of the primary tumor; tumors discovered in this fashion are generally early stage and curable by surgery.
After discovery of the primary tumor, treatment involves establishing the stage of the tumor. Therapy is identical to that recommended for other non-small cell lung cancer (NSCLC) patients with similar-stage disease.
Treatment Options for Occult NSCLC
Treatment options for occult NSCLC include:
Current Clinical Trials
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Stage 0 non-small cell lung cancer (NSCLC) frequently progresses to invasive cancer.[
Treatment Options for Stage 0 NSCLC
Treatment options for stage 0 NSCLC include:
Surgery
Segmentectomy or wedge resection are used to preserve maximum normal pulmonary tissue because patients with stage 0 NSCLC are at a high risk of second lung cancers. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, such lesions, when identified, are often centrally located and may require a lobectomy.
Endobronchial therapies
Patients with central lesions may be candidates for curative endobronchial therapy. Endobronchial therapies that preserve lung function include photodynamic therapy, electrocautery, cryotherapy, and Nd-YAG laser therapy.[
Evidence (endobronchial therapies):
Efficacy of these treatment modalities in the management of patients with early NSCLC remains to be proven in definitive randomized controlled trials.
A high incidence of second primary cancers develop in these patients.[
Current Clinical Trials
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References:
Treatment Options for Stages IA and IB NSCLC
Treatment options for stages IA non-small cell lung cancer (NSCLC) and IB NSCLC include:
Chemotherapy and radiation therapy have not been shown to improve survival in patients with stage I NSCLC that has been completely resected.
Surgery
Surgery is the treatment of choice for patients with stage I NSCLC. A lobectomy or segmental, wedge, or sleeve resection may be performed as appropriate. Patients with impaired pulmonary function are candidates for segmental or wedge resection of the primary tumor. Careful preoperative assessment of the patient's overall medical condition, especially the patient's pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age related, but a 3% to 5% mortality rate with lobectomy can be expected.[
Evidence (surgery):
These results suggest that sublobar resection by anatomical segmentectomy or wedge resection is effective for management of clinical stage T1a, N0 NSCLC when intraoperative sampling of hilar and mediastinal lymph nodes is negative.
Current evidence suggests that lung cancer resection combined with CMLND is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.[
Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and the potential methodological weaknesses of the trials.
Adjuvant therapy
Many patients who have surgery subsequently develop regional or distant metastases.[
Adjuvant chemotherapy
Based on a meta-analysis, postoperative chemotherapy is not recommended outside of a clinical trial for patients with completely resected stage I NSCLC.[
Evidence (adjuvant chemotherapy for patients with stage IB NSCLC):
Given the magnitude of observed survival differences, CALGB-9633 may have been underpowered to detect small but clinically meaningful improvements in survival. In addition, the use of a carboplatin versus a cisplatin combination might have affected the results. At present, there is no reliable evidence that postoperative chemotherapy improves survival of patients with stage IB NSCLC.[
Adjuvant targeted therapy (for patients with stage IB NSCLC withEGFRmutations)
Adjuvant targeted therapy with osimertinib for patients with EGFR-mutated NSCLC and resected stage IB to IIIA NSCLC was studied in a phase III clinical trial and showed improved OS.
Evidence (adjuvant targeted therapy with osimertinib for patients with stage IB EGFR-mutated NSCLC):
The U.S. Food and Drug Administration (FDA) approved osimertinib as adjuvant therapy for patients with stage IB to IIIA NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.
Adjuvant immunotherapy
Evidence (adjuvant immunotherapy with pembrolizumab for patients with stage IB tumors >4 cm):
The FDA approved pembrolizumab as a single agent for adjuvant treatment following resection and platinum-based chemotherapy for patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Of note, the FDA label specifies that pembrolizumab can be used as adjuvant therapy after platinum-based chemotherapy. However, chemotherapy was not required in the overall study patient population evaluated in KEYNOTE-091.
Adjuvant external radiation therapy
The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated and has not been found to improve the outcome of patients with completely resected stage I NSCLC.[
Adjuvant brachytherapy
The value of intraoperative (adjuvant) brachytherapy applied to the suture line has been evaluated in patients undergoing sublobar resections for stage I NSCLC to improve local control; it has not been found to improve outcomes.
Evidence (adjuvant brachytherapy):
Radiation therapy
A substantial number of patients are ineligible for standard surgical resection because of comorbid conditions that are associated with unacceptably high perioperative risk. Patients with potentially resectable tumors with medical contraindications to surgery or those with inoperable stage I disease and with sufficient pulmonary reserve may be candidates for radiation therapy with curative intent.[
Conventional radiation therapy
Historically, conventional primary radiation therapy consisted of approximately 60 Gy to 70 Gy delivered with megavoltage equipment to the midplane of the known tumor volume using conventional fractionation (1.8–2.0 Gy per day).
Improvements in radiation techniques include planning techniques to account for tumor motion, more conformal planning techniques (e.g., 3-D conformal radiation therapy and intensity-modulated radiation therapy), and image guidance during treatment. Modern approaches to delivery of external-beam radiation therapy (EBRT) include hypofractionated radiation therapy and stereotactic body radiation therapy (SBRT). However, there are limited reliable data from comparative trials to determine which approaches yield superior outcomes.[
Evidence (conventional radiation therapy):
Hypofractionated radiation therapy
Hypofractionated radiation therapy involves the delivery of a slightly higher dose of radiation therapy per day (e.g., 2.4–4.0 Gy) over a shorter period of time compared with conventionally fractionated radiation therapy. Multiple prospective phase I/II trials have demonstrated that hypofractionated radiation therapy to a dose of 60 Gy to 70 Gy delivered over 3 to 4 weeks with 2.4 Gy to 4.0 Gy per day resulted in a low incidence of moderate to severe toxicity, 2-year OS rates of 50% to 60%, and 2-year tumor local control of 80% to 90%.[
Stereotactic body radiation therapy (SBRT)
SBRT involves the delivery of highly conformal, high-dose radiation therapy over an extremely hypofractionated course (e.g., one to five treatments) delivered over 1 to 2 weeks. Commonly used regimens include 18 Gy × 3, 12 Gy to 12.5 Gy × 4, and 10 Gy to 12 Gy × 5, and deliver a substantially higher biologically effective dose compared with historic conventional radiation therapy regimens.
Multiple prospective phase I/II trials and institutional series have demonstrated that SBRT results in a low incidence of pulmonary toxicity (<10% risk of symptomatic radiation pneumonitis), 2-year OS rates of 50% to 60%, and 2-year tumor control of 90% to 95%.[
Evidence (SBRT):
A randomized trial of hypofractionated radiation therapy versus SBRT (LUSTRE [NCT01968941]) is ongoing to determine the optimal radiation therapy regimen, but SBRT has been widely adopted for patients with medically inoperable stage I NSCLC.
Current Clinical Trials
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Treatment Options for Stages IIA and IIB NSCLC
Treatment options for stages IIA non-small cell lung cancer (NSCLC) and IIB NSCLC include:
Adjuvant radiation therapy has not been shown to improve outcomes in patients with stage II NSCLC.
Surgery with or without adjuvant or neoadjuvant therapy
Surgery alone
Surgery is the treatment of choice for patients with stage II NSCLC. A lobectomy, pneumonectomy, segmental resection, wedge resection, or sleeve resection may be performed as appropriate. Careful preoperative assessment of the patient's overall medical condition, especially the patient's pulmonary reserve, is critical in considering the benefits of surgery. In addition to the immediate and age-related postoperative mortality rate, a 5% to 8% mortality rate with pneumonectomy or a 3% to 5% mortality rate with lobectomy can be expected.
Evidence (surgery):
Evidence suggests that lung cancer resection combined with CMLND is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.[
Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied and potential methodological weaknesses of the trials.
Adjuvant chemotherapy
The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected stage II NSCLC. Preoperative chemotherapy may also provide survival benefit. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC remain to be determined.
After surgery, many patients develop regional or distant metastases.[
Evidence (adjuvant chemotherapy):
Based on these data, patients with completely resected stage II lung cancer may benefit from postoperative cisplatin-based chemotherapy.[
Adjuvant targeted therapy (for patients withEGFRmutations)
Adjuvant targeted therapy with osimertinib for patients with EGFR-mutated NSCLC and resected stage IB to IIIA NSCLC was studied in a phase III clinical trial and showed improved OS.
Evidence (adjuvant targeted therapy with osimertinib for patients with stages IIA and IIB EGFR-mutated NSCLC):
The U.S. Food and Drug Administration (FDA) approved osimertinib as adjuvant therapy for patients with stage IB to IIIA NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.
Adjuvant immunotherapy
Adjuvant immunotherapy for patients with resected stage IB to IIIA NSCLC has been found to significantly increase DFS.[
Evidence (adjuvant immunotherapy with pembrolizumab for patients with stage IIA and IIB tumors >4 cm):
The FDA approved pembrolizumab as a single agent for adjuvant treatment following resection and platinum-based chemotherapy for patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Of note, the FDA label specifies that pembrolizumab can be used as adjuvant therapy after platinum-based chemotherapy. However, chemotherapy was not required in the overall study patient population evaluated in KEYNOTE-091.
Evidence (adjuvant immunotherapy with atezolizumab for patients with stages IIA and IIB NSCLC):
The FDA approved atezolizumab for adjuvant treatment of patients with stage II to IIIA NSCLC whose tumors express PD-L1 on at least 1% of tumor cells.
Adjuvant radiation therapy
The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated.[
Evidence (adjuvant radiation therapy):
Further analysis is needed to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.
Neoadjuvant chemotherapy
The role of chemotherapy before surgery was tested in clinical trials. The proposed benefits of preoperative chemotherapy include:
Preoperative chemotherapy may, however, delay potentially curative surgery.
Evidence (neoadjuvant chemotherapy):
Neoadjuvant immunotherapy with chemotherapy
Nivolumab plus platinum-based chemotherapy
The CheckMate 816 trial evaluated the combination of nivolumab (an anti-programmed death 1 antibody) and platinum-based chemotherapy as neoadjuvant therapy in patients with resectable (≥4 cm or node positive) NSCLC. Nivolumab therapy improved event-free survival (EFS) and pathological complete response rates compared with chemotherapy alone.
Evidence (nivolumab plus platinum-based chemotherapy):
The FDA approved nivolumab in combination with platinum-doublet chemotherapy for neoadjuvant treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC.
Perioperative (neoadjuvant and adjuvant) immunotherapy with chemotherapy
Several immune checkpoint inhibitors have been approved by the FDA for select patient populations with potentially resectable NSCLC, either in the neoadjuvant setting (nivolumab) or adjuvant setting (atezolizumab, durvalumab, or pembrolizumab). Ongoing phase III trials are evaluating the role of perioperative immune checkpoint inhibitors. These regimens for patients with potentially resectable stages II to III NSCLC include neoadjuvant immune checkpoint inhibitors with chemotherapy followed by surgery and adjuvant immune checkpoint inhibitors. Compared with neoadjuvant chemotherapy alone, early results from studies of perioperative immune checkpoint inhibitor regimens have shown improvements in several key outcomes including EFS, major pathological response, pathological complete response, and OS.
Perioperative pembrolizumab plus platinum-based chemotherapy
Evidence (neoadjuvant pembrolizumab plus chemotherapy and adjuvant pembrolizumab):
Perioperative durvalumab plus platinum-based chemotherapy
Evidence (durvalumab plus platinum-based chemotherapy):
Perioperative nivolumab plus platinum-based chemotherapy
Evidence (neoadjuvant nivolumab plus chemotherapy and adjuvant nivolumab):
Perioperative toripalimab plus platinum-based chemotherapy
Evidence (toripalimab plus platinum-based chemotherapy):
The FDA has not approved this drug for patients with lung cancer.
Radiation therapy
Patients with potentially operable tumors with medical contraindications to surgery or those with inoperable stage II disease and with sufficient pulmonary reserve are candidates for radiation therapy with curative intent.[
Among patients with excellent performance status, a 3-year survival rate of 20% may be expected if a course of radiation therapy with curative intent can be completed.
Evidence (radiation therapy):
Current Clinical Trials
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References:
Patients with stage IIIA non-small cell lung cancer (NSCLC) are a heterogenous group. Patients may have metastases to ipsilateral mediastinal nodes, potentially resectable T3 tumors invading the chest wall, or mediastinal involvement with metastases to peribronchial or hilar lymph nodes (N1). Presentations of disease range from resectable tumors with microscopic metastases to lymph nodes to unresectable, bulky disease involving multiple nodal stations.
Patients with clinical stage IIIA N2 disease have a 5-year overall survival (OS) rate of 10% to 15%; however, patients with bulky mediastinal involvement (i.e., visible on chest radiography) have a 5-year survival rate of 2% to 5%. Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage IIIA NSCLC are radiation therapy, chemotherapy, surgery, and combinations of these modalities.
Treatment options vary according to the location of the tumor and whether it is resectable.
Treatment Options for Resected/Resectable Stage IIIA NSCLC
Treatment options for resected/resectable disease include:
Despite careful preoperative staging, some patients will be found to have metastases to mediastinal N2 lymph nodes at thoracotomy.
The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC with occult N2 disease discovered at surgery. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC are yet to be determined.
Surgery
If complete resection of tumor and lymph nodes is possible, such patients may benefit from surgery followed by postoperative chemotherapy. Current evidence suggests that lung cancer resection combined with complete ipsilateral mediastinal lymph node dissection (CMLND) is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.[
The addition of surgery to chemoradiation therapy for patients with stage IIIA NSCLC did not result in improved OS in a phase III trial but did improve progression-free survival (PFS) and local control.[
Evidence (surgery):
Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and by the potential methodological weaknesses of the trials.
Neoadjuvant therapy
Neoadjuvant chemotherapy
The role of chemotherapy before surgery in patients with stage IIIA NSCLC has been extensively tested in clinical trials. The proposed benefits of preoperative (neoadjuvant) chemotherapy include:
Evidence (neoadjuvant chemotherapy):
Neoadjuvant chemoradiation therapy
Administering concurrent neoadjuvant chemotherapy and radiation therapy before surgery may intensify treatment and increase the likelihood of downstaging the tumor burden. Commonly used regimens that have been tested in the phase II setting include cisplatin/etoposide (EP5050) and weekly carboplatin/paclitaxel.[
Evidence (neoadjuvant chemoradiation therapy):
A direct comparison of neoadjuvant chemotherapy versus neoadjuvant chemoradiation therapy using modern treatment regimens has not been performed to date; the optimal neoadjuvant approach remains unclear.
Neoadjuvant immunotherapy with chemotherapy
Nivolumab plus platinum-based chemotherapy
The CheckMate 816 trial evaluated the combination of nivolumab (an anti-programmed death 1 antibody) and platinum-based chemotherapy as neoadjuvant therapy in patients with resectable (≥4 cm or node positive) NSCLC. Nivolumab therapy improved event-free survival (EFS) and pathological complete response rates compared with chemotherapy alone.
Evidence (nivolumab plus platinum-based chemotherapy):
Circulating tumor DNA (ctDNA) from plasma samples obtained before and after neoadjuvant treatment (but before surgery) was analyzed with the hybridization capture–based TruSight Oncology 500 ctDNA next-generation sequencing assay on a NovaSeq sequencer (Illumina).
The U.S. Food and Drug Administration (FDA) approved nivolumab in combination with platinum-doublet chemotherapy for neoadjuvant treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC.
Perioperative (neoadjuvant and adjuvant) immunotherapy with chemotherapy
Several immune checkpoint inhibitors have been approved by the FDA for select patient populations with potentially resectable NSCLC, either in the neoadjuvant setting (nivolumab) or adjuvant setting (atezolizumab, durvalumab, or pembrolizumab). Ongoing phase III trials are evaluating the role of perioperative immune checkpoint inhibitors. These regimens for patients with potentially resectable stages II to III NSCLC include neoadjuvant immune checkpoint inhibitors with chemotherapy followed by surgery and adjuvant immune checkpoint inhibitors. Compared with neoadjuvant chemotherapy alone, early results from studies of perioperative immune checkpoint inhibitor regimens have shown improvements in several key outcomes including EFS, major pathological response, pathological complete response, and OS.
Perioperative pembrolizumab plus platinum-based chemotherapy
Evidence (neoadjuvant pembrolizumab plus chemotherapy and adjuvant pembrolizumab):
Perioperative durvalumab plus platinum-based chemotherapy
Evidence (durvalumab plus platinum-based chemotherapy):
Perioperative nivolumab plus platinum-based chemotherapy
Evidence (neoadjuvant nivolumab plus chemotherapy and adjuvant nivolumab):
Perioperative toripalimab plus platinum-based chemotherapy
Evidence (toripalimab plus platinum-based chemotherapy):
The FDA has not approved this drug for patients with lung cancer.
Adjuvant therapy
Adjuvant chemotherapy
Patients with completely resected stage IIIA NSCLC may benefit from postoperative cisplatin-based chemotherapy.[
Evidence (adjuvant chemotherapy):
Evidence from randomized controlled clinical trials indicates that when stage IIIA NSCLC is encountered unexpectedly at surgery, chemotherapy given after complete resection improves survival.
Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.[
Adjuvant targeted therapy (for patients withEGFRmutations)
Adjuvant targeted therapy with osimertinib for patients with EGFR-mutated NSCLC and resected stage IB to IIIA NSCLC was studied in a phase III clinical trial and showed improved OS.
Evidence (adjuvant targeted therapy with osimertinib for patients with stage IIIA EGFR-mutated NSCLC):
The FDA approved osimertinib as adjuvant therapy for patients with stage IB to IIIA NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.
Adjuvant immunotherapy
Adjuvant immunotherapy for patients with resected stage IB to IIIA NSCLC has been found to significantly increase DFS.[
Evidence (adjuvant immunotherapy with pembrolizumab for patients with stage IIIA NSCLC):
The FDA approved pembrolizumab as a single agent for adjuvant treatment following resection and platinum-based chemotherapy for patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Of note, the FDA label specifies that pembrolizumab can be used as adjuvant therapy after platinum-based chemotherapy. However, chemotherapy was not required in the overall study patient population evaluated in KEYNOTE-091.
Evidence (adjuvant immunotherapy with atezolizumab for patients with resected stage IIIA NSCLC):
The FDA approved atezolizumab for adjuvant treatment of patients with stage II to IIIA NSCLC whose tumors express PD-L1 on at least 1% of tumor cells.
Adjuvant chemoradiation therapy
Combination chemotherapy and radiation therapy administered before or following surgery should be viewed as investigational and requiring evaluation in future clinical trials.
Evidence (adjuvant chemoradiation therapy):
Adjuvant radiation therapy
The value of PORT has been assessed.[
As referred to in the National Cancer Institute of Canada (NCIC) Clinical Trials Group JBR.10 study (NCT00002583), PORT may be considered in selected patients to reduce the risk of local recurrence, if any of the following are present:[
Evidence (adjuvant radiation therapy):
Evidence from one large meta-analysis, subset analyses of randomized trials, and one large population study suggest that PORT may reduce local recurrence. Results from these studies on the effect of PORT on OS are conflicting.
There is benefit of PORT in stage IIIA (N2) disease, and the role of PORT in early stages of NSCLC should be clarified in ongoing phase III trials. Further analysis is needed to determine whether these outcomes can be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.[
Treatment Options for Unresectable Stage IIIA NSCLC
Treatment options for patients with unresectable stage IIIA NSCLC include:
Chemoradiation therapy
The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials and meta-analyses. Overall, concurrent treatment may provide the greatest benefit in survival with an increase in toxic effects.
Concomitant platinum-based radiation chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.[
Evidence (chemoradiation therapy):
Concurrent versus sequential chemoradiation therapy
The results from two randomized trials (including RTOG-9410 [NCT01134861]) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy may provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.[
Evidence (concurrent vs. sequential chemoradiation therapy):
Radiation therapy dose escalation for concurrent chemoradiation
With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.[
Consolidation therapy following concurrent chemoradiation
Evidence (consolidation therapy following concurrent chemoradiation):
The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS HR of 0.74 with a type 1 error of .05. This study randomly assigned 598 patients (arm A, 301; arm B, 297) and treated 555 patients (arm A, 283; arm B, 272).
Consolidation immunotherapy
Durvalumab
Durvalumab is a selective human IgG1 monoclonal antibody that blocks PD-L1 binding to programmed death 1 (PD-1) and CD80, allowing T cells to recognize and kill tumor cells.[
Evidence (durvalumab following concurrent chemoradiation):
Osimertinib (for patients withEGFRmutations)
Evidence (osimertinib following concurrent chemoradiation therapy):
Other systemic consolidation therapies
The addition of induction chemotherapy before concurrent chemotherapy and radiation therapy has not been shown to improve survival.[
Randomized trials of other consolidation systemic therapies, including docetaxel,[
Radiation therapy
Locally advanced unresectable tumors
Radiation therapy alone may provide benefit to patients with locally advanced unresectable stage IIIA NSCLC.
Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[
Evidence (radiation therapy for locally advanced unresectable tumor):
Although patients with unresectable stage IIIA disease may benefit from radiation therapy, long-term outcomes have generally been poor because of local and systemic relapse.
Palliative treatment
Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as:
In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[
Evidence (radiation therapy for palliative treatment):
Treatment Options for Superior Sulcus Tumors
Treatment options for superior sulcus tumors include:
NSCLC of the superior sulcus, frequently termed Pancoast tumors, occurs in less than 5% of patients.[
Adverse prognostic factors include the presence of mediastinal nodal metastases (N2 disease), spine or subclavian-vessel involvement (T4 disease), and limited resection (R1 or R2).
Surgery
Evidence (surgery):
Chemoradiation therapy followed by surgery
Evidence (chemoradiation therapy):
Radiation therapy dose escalation for concurrent chemoradiation
With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.[
Radiation therapy alone
While radiation therapy is an integral part of the treatment of Pancoast tumors, variations in dose, treatment technique, and staging that were used in various published series make it difficult to determine its effectiveness.[
Small, retrospective series of radiation therapy in patients who were only clinically staged have reported 5-year survival rates of 0% to 40%, depending on T stage, total radiation dose, and other prognostic factors. Induction radiation therapy and en bloc resection was shown to be potentially curative.
Evidence (radiation therapy):
Treatment Options for Tumors That Invade the Chest Wall
Treatment options for tumors that invade the chest wall include:
Selected patients with bulky primary tumors that directly invade the chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected.
Evidence (radical surgery):
Adjuvant chemotherapy is recommended, and radiation therapy is reserved for cases with unclear resection margins. Survival rates were lower in patients who underwent incomplete resection and had mediastinal lymph node involvement. Combined-modality approaches have been evaluated to improve ability to achieve complete resection.
Current Clinical Trials
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References:
On the basis of the Surveillance, Epidemiology, and End Results (SEER) Program registry, the estimated incidence of stage IIIB non-small cell lung cancer (NSCLC) is 17.6%.[
Treatment Options for Stages IIIB and IIIC NSCLC
Treatment options for stages IIIB NSCLC and IIIC NSCLC include:
In general, patients with stages IIIB and IIIC NSCLC do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on:
Most patients with excellent performance status are candidates for combined-modality chemotherapy and radiation therapy with the following exceptions:
Patients with stages IIIB or IIIC NSCLC are candidates for clinical trials, which may lead to improvement in the control of disease.
Sequential or concurrent chemotherapy and radiation therapy
Many randomized studies of patients with unresectable stage III NSCLC show that treatment with preoperative or concurrent cisplatin-based chemotherapy and radiation therapy to the chest is associated with improved survival compared with treatment that uses radiation therapy alone. Although patients with unresectable stages IIIB or IIIC disease may benefit from radiation therapy, long-term outcomes have generally been poor, often the result of local and systemic relapse. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials.
Evidence (sequential or concurrent chemotherapy and radiation therapy):
Radiation therapy dose escalation for concurrent chemoradiation
With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.[
Systemic consolidation therapy before or after concurrent chemoradiation therapy
Consolidation immunotherapy
Durvalumab
Durvalumab is a selective human IgG1 monoclonal antibody that blocks programmed death-ligand 1 (PD-L1) binding to programmed death 1 (PD-1) and CD80, allowing T cells to recognize and kill tumor cells.[
Evidence (durvalumab):
Osimertinib (for patients withEGFRmutations)
Evidence (osimertinib following concurrent chemoradiation therapy):
Other systemic consolidation therapies
The addition of induction chemotherapy before concurrent chemotherapy and radiation therapy has not been shown to improve survival.[
Randomized trials of other consolidation systemic therapies, including docetaxel,[
The role of consolidation systemic therapy after concurrent chemotherapy and radiation therapy for unresectable NSCLC remains unclear. Phase III trials of consolidation systemic therapy including conventional chemotherapy (docetaxel),[
Radiation therapy alone
For treatment of locally advanced unresectable tumor in patients who are not candidates for chemotherapy
Radiation therapy alone may provide benefit to patients with locally advanced unresectable stage III NSCLC.
Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[
Evidence (radiation therapy for locally advanced unresectable tumor):
For patients requiring palliative treatment
Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as:
In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[
Evidence (radiation therapy for palliative treatment):
Patients with stages IIIB or IIIC disease with poor performance status are candidates for chest radiation therapy to palliate pulmonary symptoms (e.g., cough, shortness of breath, hemoptysis, or pain).[
Current Clinical Trials
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References:
Factors Affecting Treatment Selection
Forty percent of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage IV disease. Treatment goals are to prolong survival and control disease-related symptoms. Treatment options include cytotoxic chemotherapy, targeted agents, and immunotherapy. Factors influencing treatment selection include comorbidity, performance status, histology, and molecular and immunologic features of the cancer. Therefore, assessment of tumor-genomic changes and programmed death-ligand 1 (PD-L1) expression is critical before initiating therapy. Radiation therapy and surgery are generally used in selective cases for symptom palliation.
Factors that affect selection of treatment include:
History and molecular features
Patients with nonsquamous cell histology, good performance status, no history of hemoptysis or other bleeding, or recent history of cardiovascular events may benefit from the addition of bevacizumab to paclitaxel and carboplatin. Patients with tumors harboring sensitizing mutations in exons 19 or 21 of EGFR, particularly those from East Asia, never smokers, and those with adenocarcinoma may benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as an alternative to first- or second-line chemotherapy. Patients with tumors harboring ALK translocations, ROS1 rearrangements, or NTRK fusions may benefit from anaplastic lymphoma kinase (ALK), ROS1, or neurotrophic tyrosine kinase (NTRK) inhibitors as an alternative to first- or second-line chemotherapy.
Patients with tumors expressing PD-L1 (>50% by immunohistochemistry) have improved survival with pembrolizumab. The addition of pembrolizumab to carboplatin-plus-pemetrexed chemotherapy for nonsquamous advanced lung cancer improves survival irrespective of PD-L1 expression.[
The role of systemic therapy in patients with an Eastern Cooperative Oncology Group (ECOG) performance status below 2 is less certain.
Patients with adenocarcinoma may benefit from pemetrexed [
Age and comorbidity
Evidence supports the concept that older patients with good performance status and limited comorbidity may benefit from combination chemotherapy. Age alone should not dictate treatment-related decisions in patients with advanced NSCLC. Older patients with a good performance status enjoy longer survival and a better quality of life when treated with chemotherapy compared with supportive care alone. Caution should be exercised when extrapolating data for patients aged 70 to 79 years to patients aged 80 years or older because only a very small number of patients aged 80 years or older have been enrolled in clinical trials, and the benefit in this group is uncertain.[
Evidence (age and comorbidity):
Performance status
Performance status is among the most important prognostic factors for survival of patients with NSCLC.[
The results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced NSCLC; however, the efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Outside of a clinical trial setting, chemotherapy should only be given to patients with good performance status and evaluable tumor lesions, who desire this treatment after being fully informed of its anticipated risks and limited benefits.
Randomized controlled trials of patients with stage IV disease and good performance status have shown that cisplatin-based chemotherapy improves survival and palliates disease-related symptoms.[
Evidence (performance status):
This study, which was performed in eight centers in Brazil and one center in the United States, reported rates of OS and PFS that were higher than has historically been noted in most, although not all, other published studies. This may indicate differences in patient selection.
Treatment Options for Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC (First-Line Therapy)
Treatment options for patients with newly diagnosed stage IV, relapsed, and recurrent disease include:
Cytotoxic combination chemotherapy
Combination chemotherapy
The type and number of chemotherapy drugs to be used for the treatment of patients with advanced NSCLC has been extensively evaluated in randomized controlled trials and meta-analyses.
Several randomized trials have evaluated various drugs combined with either cisplatin or carboplatin in previously untreated patients with advanced NSCLC. On the basis of meta-analyses of the trials, the following conclusions can be drawn:
Evidence (combination chemotherapy):
Drug and dose schedule
Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made, except for carboplatin, pemetrexed, and pembrolizumab for patients with nonsquamous tumor histology.
Evidence (drug and dose schedule):
Combination chemotherapy with monoclonal antibodies
Bevacizumab
Evidence (bevacizumab):
Cetuximab
Evidence (cetuximab):
Necitumumab
Evidence (necitumumab):
Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)
One extensively investigated treatment strategy in NSCLC is maintenance therapy after initial response to chemotherapy. Options for maintenance therapy that have been investigated include:
Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.
Evidence (maintenance therapy following first-line chemotherapy):
These data suggest that PFS and OS for patients with nonsquamous NSCLC may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events including additional cytotoxic chemotherapy and no consistent improvement in quality of life. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of combination cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy before disease progression. Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it can be administered for no more than six cycles.[
Evidence (first-line platinum-based combination chemotherapy followed by pemetrexed):
The findings of two randomized trials (NCT00102804 and NCT00789373) have shown improved outcomes with the addition of pemetrexed after standard first-line platinum-based combination chemotherapy.[
EGFR tyrosine kinase inhibitors (TKIs) with or without chemotherapy (for patients withEGFRmutations)
Select patients with activating mutations in EGFR may benefit from single-agent EGFR TKIs. Randomized controlled trials of patients with chemotherapy-naïve NSCLC and EGFR mutations have shown that EGFR inhibitors alone improved both PFS and OS and have favorable toxicity profiles compared with combination chemotherapy. The combination of EGFR TKIs with chemotherapy showed improved PFS compared with EGFR TKI monotherapy and represents another treatment option.
Osimertinib alone
Evidence (osimertinib alone):
The FDA approved osimertinib for first-line treatment of EGFR-mutant NSCLC (exon 19 deletion or L858R).
Longer PFS and OS, activity against the EGFR T790M mutation in addition to EGFR-TKI−sensitizing mutations, decreased frequency of CNS progression, and good tolerability make osimertinib the preferred choice for treatment of patients with advanced EGFR-mutated NSCLC compared with first- and second-generation EGFR TKIs.
Osimertinib plus chemotherapy
Evidence (osimertinib plus chemotherapy):
Analysis of OS, a secondary end point, requires further follow-up (data maturity, 27%).
Dacomitinib
Evidence (dacomitinib):
The FDA approved dacomitinib for first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test.
Gefitinib
Evidence (gefitinib):
Erlotinib
Evidence (erlotinib):
Afatinib
Evidence (afatinib):
EGFR-directed therapy (for patients withEGFRexon 20 insertion mutations)
Amivantamab
Amivantamab has been previously approved for patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.
Evidence (amivantamab plus chemotherapy):
The study supports amivantamab plus chemotherapy as an effective first-line treatment option for patients with NSCLC and EGFR exon 20 insertions based on superior PFS when compared with chemotherapy alone.[
ALK inhibitors (for patients withALKtranslocations)
Alectinib
Evidence (alectinib):
Lorlatinib
Evidence (lorlatinib):
The FDA approved lorlatinib for patients with metastatic NSCLC whose tumors are ALK-positive, as detected by an FDA-approved test.
Crizotinib
Evidence (crizotinib):
Ceritinib
Evidence (ceritinib):
Brigatinib
Evidence (brigatinib):
BRAF V600E and MEK inhibitors (for patients withBRAFV600E mutations)
BRAF V600E mutations occur in 1% to 2% of lung adenocarcinomas.
Dabrafenib and trametinib
Evidence (dabrafenib and trametinib):
The FDA approved the combination of dabrafenib and trametinib in the treatment of patients with NSCLC whose tumors harbor BRAF V600E mutations as detected by an FDA-approved test.
ROS1 inhibitors (for patients withROS1rearrangements)
ROS1 rearrangements occur in approximately 1% of patients with NSCLC.[
Entrectinib
The FDA approved entrectinib for treatment of patients with metastatic NSCLC whose tumors are ROS1-positive, regardless of the number of previous systemic therapies.
Evidence (entrectinib):
Seventeen (32%) patients had received no previous systemic therapy, 23 (43%) had received one previous therapy, and 13 (25%) had received two or more lines of treatment. CNS disease was present in 23 (43%) patients at baseline. Thirty-one (59%) patients were never-smokers and 52 (98%) patients had adenocarcinoma histology.
Crizotinib
Crizotinib was approved for patients with metastatic NSCLC whose tumors are ROS1-positive, regardless of the number of previous systemic therapies.
Evidence (crizotinib):
NTRK inhibitors (for patients withNTRKfusions)
Somatic gene fusions in NTRK occur across a range of solid tumors including in fewer than 0.5% of NSCLC tumors.[
Larotrectinib
Evidence (larotrectinib):
The FDA
Entrectinib
The FDA granted accelerated approval to entrectinib for the treatment of solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic, have progressed after treatment, have no satisfactory alternative therapy, or for cases in which surgical resection is likely to result in severe morbidity.
Evidence (entrectinib):
Of 54 patients in the NTRK gene fusion-positive efficacy-evaluable population, 20 (37%) had received no previous systemic therapy, 11 (20%) had received one previous systemic therapy, and 23 (43%) had received two or more systemic therapies. Twelve (22%) patients had CNS disease at baseline. Ten (19%) patients had NSCLC. Fifty-two (96%) patients had an NTRK gene fusion detected by NGS and 2 (4%) had an NTRK gene fusion detected by other nucleic acid–based tests.
RET inhibitors (for patients withRETfusions)
Somatic gene fusions of RET occur in 1% to 2% of patients with NSCLC and in patients with thyroid cancer.[
Selpercatinib
Evidence (selpercatinib):
The FDA approved selpercatinib to treat adults with locally advanced or metastatic NSCLC with RET gene fusion, as detected by an FDA-approved test.
Pralsetinib
Evidence (pralsetinib):
MET inhibitors (for patients withMETexon 14 skipping mutations)
Dysregulation of the MET proto-oncogene resulting from disruption of distinct splice sites leads to loss of MET exon 14 and enhanced MET signaling. These MET alterations drive tumor proliferation, survival, invasion, and metastasis, and occur in 3% to 4% of patients with NSCLC.[
Tepotinib
Evidence (tepotinib):
Capmatinib
Evidence (capmatinib):
Immune checkpoint inhibitors with or without chemotherapy
Pembrolizumab is a humanized monoclonal antibody that inhibits the interaction between the programmed death protein 1 (PD-1) coinhibitory immune checkpoint expressed on tumor cells and infiltrating immune cells and its ligands, PD-L1 and PD-L2.[
Pembrolizumab plus chemotherapy
Evidence (pembrolizumab plus chemotherapy):
Pembrolizumab alone
Evidence (pembrolizumab alone):
The FDA approved pembrolizumab in combination with pemetrexed and carboplatin as first-line treatment of patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. The FDA also approved pembrolizumab as a first-line monotherapy for patients with NSCLC whose tumors express PD-L1 (>1%) (staining as determined by an FDA-approved test). Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapies before receiving pembrolizumab (see the FDA label for
Cemiplimab-rwlc plus chemotherapy
Evidence (cemiplimab-rwlc plus chemotherapy):
The FDA approved cemiplimab-rwlc in combination with platinum-based chemotherapy for adult patients with advanced NSCLC and no EGFR, ALK, or ROS1 aberrations.
Cemiplimab-rwlc alone
Evidence (cemiplimab-rwlc alone):
The FDA approved cemiplimab-rwlc for patients with advanced NSCLC (locally advanced who are not candidates for surgical resection or definitive chemoradiation or metastatic) and PD-L1 tumor expression of at least 50% with no EGFR, anaplastic ALK, or ROS1 genomic aberrations.
Tremelimumab
Tremelimumab is a fully human monoclonal antibody against cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). It is an immune checkpoint blocker.
Durvalumab plus tremelimumab plus chemotherapy
Evidence (durvalumab plus tremelimumab plus chemotherapy):
The following results were observed:
The FDA approved tremelimumab in combination with durvalumab and platinum-based chemotherapy for adult patients with metastatic NSCLC with no sensitizing EGFR or ALK genomic tumor aberrations. The approval is based on a comparison of treatment arms one and three.
Atezolizumab alone
Evidence (atezolizumab alone):
Atezolizumab monotherapy is approved for first-line treatment of patients with high PD-L1 expression (PD-L1 staining ≥50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥10% of the tumor area), as determined by an FDA-approved test, in the absence of EGFR or ALK genomic aberrations.
Atezolizumab plus chemotherapy
Evidence (atezolizumab in combination with carboplatin and nab-paclitaxel chemotherapy):
Atezolizumab in combination with nab-paclitaxel and carboplatin is approved for the first-line treatment of patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic aberrations.
Atezolizumab plus bevacizumab plus chemotherapy
Evidence (atezolizumab in combination with carboplatin, paclitaxel, and bevacizumab):
Atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin is approved for the first-line treatment of patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic aberrations.
Nivolumab plus ipilimumab
Nivolumab, a fully human anti–PD-1 antibody, and ipilimumab, a fully human anti–CTLA-4 antibody, are immune checkpoint inhibitors with distinct but complementary mechanisms of action.[
Evidence (nivolumab plus ipilimumab):
The FDA approved nivolumab-plus-ipilimumab as first-line therapy for patients with advanced NSCLC with PD-L1 expression of at least 1% and no EGFR or ALK genomic aberrations. While this regimen is not FDA-approved for patients with PD-L1 expression less than 1%, these patients were noted to have durable clinical benefit in CheckMate 227.
mTOR inhibitors
Everolimus
Everolimus is used for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors.
Everolimus, an oral mTOR inhibitor, is clinically active against advanced pancreatic and nonpancreatic neuroendocrine tumors.[
Evidence (everolimus):
Local therapies and special considerations
Endobronchial laser therapy and/or brachytherapy (for obstruction lesions)
Radiation therapy may be effective in palliating symptomatic patients with local involvement of NSCLC with any of the following:
In some cases, endobronchial laser therapy and/or brachytherapy have been used to alleviate proximal obstructing lesions.[
EBRT (primarily for palliation of local symptomatic tumor growth)
Although EBRT is frequently prescribed for symptom palliation, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief,[
Evidence (radiation therapy):
Treatment of second primary tumor
A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Whether the new lesion is a new primary cancer or a metastasis may be difficult to determine. Studies have indicated that in most patients the new lesion is a second primary tumor, and after its resection, some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected, if possible.[
Treatment of brain metastases
Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged disease-free survival with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy.[
Approximately 50% of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment.[
Current Clinical Trials
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References:
Treatment Options for Progressive Stage IV, Relapsed, and Recurrent NSCLC (Second-Line Therapy)
Treatment options for patients with progressive stage IV, relapsed, and recurrent non-small cell lung cancer (NSCLC) (second-line therapy and beyond) include:
Chemotherapy
The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[
Docetaxel
Evidence (docetaxel):
Docetaxel plus ramucirumab
Evidence (docetaxel plus ramucirumab):
Pemetrexed
Evidence (pemetrexed):
Epidermal growth factor receptor (EGFR)-directed therapy
Advanced NSCLC that contains characteristic mutations in EGFR, most commonly exon 19 deletions or exon 21 L858R mutations, is highly sensitive to EGFR TKIs. The standard approach to decide whether to use an EGFR TKI for the treatment of a patient with advanced NSCLC is to analyze the tumor for the presence or absence of a driver mutation in EGFR. EGFR exon 20 insertions are uncommon mutations that are not sensitive to the EGFR TKIs used for the treatment of NSCLC with EGFR-sensitizing mutations.
EGFR-directed therapy after first-line chemotherapy (for patients withEGFR-sensitizing mutations)
Erlotinib
Evidence (erlotinib):
Two randomized placebo-controlled trials indicated that erlotinib prolongs survival and time to deterioration in symptoms in patients with NSCLC after first-line or second-line chemotherapy compared with placebo [
Gefitinib
Evidence (gefitinib):
Objective response to erlotinib and gefitinib is more likely in patients who have never smoked, are female, are of East Asian race, or have adenocarcinoma or bronchioloalveolar carcinoma.[
Afatinib
Evidence (afatinib):
EGFR-directed therapy (for patients with acquiredEGFRT790M mutations after previous EGFR-directed therapy)
Osimertinib
Evidence (osimertinib):
EGFR-directed therapy after first-line chemotherapy (for patients withEGFRexon 20 insertion mutations)
Amivantamab
Evidence (amivantamab):
The U.S. Food and Drug Administration (FDA) granted accelerated approval to amivantamab for the treatment of patients with EGFR exon 20 mutations whose disease has progressed on or after platinum-based therapy.
Mobocertinib
Evidence (mobocertinib):
The FDA granted accelerated approval to mobocertinib for the treatment of patients with EGFR exon 20 mutations whose disease has progressed on or after platinum-based therapy.
ALK-directed tyrosine kinase inhibitors (TKIs)
ALK-directed TKIs after first-line chemotherapy
Crizotinib
Evidence (crizotinib):
ALK-directed TKIs after prior ALK TKI therapy
Ceritinib
Evidence (ceritinib):
Alectinib
Evidence (alectinib):
Brigatinib
Evidence (brigatinib):
Lorlatinib
Evidence (lorlatinib):
BRAF V600E and MEK inhibitors (for patients withBRAFV600E mutations)
BRAF V600E mutations occur in 1% to 2% of lung adenocarcinomas.
Dabrafenib and trametinib
Evidence (dabrafenib and trametinib):
The FDA approved the combination of dabrafenib and trametinib for patients with NSCLC whose tumors harbor BRAF V600E mutations as detected by an FDA-approved test.
ROS1-directed therapy
ROS1 rearrangements occur in approximately 1% of patients with NSCLC.[
Entrectinib
The FDA approved entrectinib for treatment of patients with metastatic NSCLC whose tumors are ROS1-positive, regardless of the number of previous systemic therapies.
Evidence (entrectinib):
Seventeen (32%) patients had received no previous systemic therapy, 23 (43%) had received one previous therapy, and 13 (25%) had received two or more lines of treatment. CNS disease was present in 23 (43%) patients at baseline. Thirty-one (59%) patients were never smokers and 52 (98%) patients had adenocarcinoma histology.
Crizotinib
Crizotinib was approved for patients with metastatic NSCLC whose tumors are ROS1-positive, regardless of the number of previous systemic therapies.
Evidence (crizotinib):
NTRK inhibitors (for patients withNTRKfusions)
Somatic gene fusions in NTRK occur across a range of solid tumors including in fewer than 0.5% of NSCLC tumors.[
Larotrectinib
Evidence (larotrectinib):
The FDA
Entrectinib
The FDA granted accelerated approval to entrectinib for the treatment of solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic, have progressed after treatment, have no satisfactory alternative therapy, or for cases in which surgical resection is likely to result in severe morbidity.
Evidence (entrectinib):
Of 54 patients in the NTRK gene fusion-positive efficacy-evaluable population, 20 (37%) had received no previous systemic therapy, 11 (20%) had received one previous systemic therapy, and 23 (43%) had received two or more systemic therapies. Twelve (22%) patients had CNS disease at baseline. Ten (19%) patients had NSCLC. Fifty-two (96%) patients had an NTRK gene fusion detected by NGS and two (4%) had an NTRK gene fusion detected by other nucleic acid–based tests.
RET inhibitors (for patients withRETfusions)
Somatic gene fusions of RET occur in 1% to 2% of patients with NSCLC and in patients with thyroid cancer.[
Selpercatinib
Evidence (selpercatinib):
The FDA approved selpercatinib to treat adults with locally advanced or metastatic NSCLC with RET gene fusion, as detected by an FDA-approved test.
Pralsetinib
Evidence (pralsetinib):
MET inhibitors (for patients withMETexon 14 skipping mutations)
Dysregulation of the MET proto-oncogene resulting from disruption of distinct splice sites leads to loss of MET exon 14 and enhanced MET signaling. These MET alterations drive tumor proliferation, survival, invasion, and metastasis, and occur in 3% to 4% of patients with NSCLC.[
Tepotinib
Evidence (tepotinib):
Capmatinib
Evidence (capmatinib):
KRAS G12C inhibitors (for patients withKRASG12C mutations)
Activating mutations in KRAS are found in 25% to 30% of nonsquamous NSCLC, resulting in activation of downstream oncogenic pathways and uncontrolled growth. The G12C single-nucleotide variant, with glycine substituted by cysteine at codon 12, is the most frequent variant in NSCLC, occurring in approximately 13% of lung adenocarcinomas.[
Adagrasib
Evidence (adagrasib):
The FDA approved adagrasib for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who received at least one prior systemic therapy.[
Sotorasib
Evidence (sotorasib):
The FDA approved sotorasib for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy.
HER2-targeted therapy (for patients withHER2-mutations)
Mutations in the human epidermal growth factor receptor 2 (HER2) gene are found in 1% to 4% of patients with nonsquamous NSCLC. These mutations are associated with female sex, Asian ethnicity, never-smoking status, a higher incidence of brain metastasis, moderate to poorly differentiated adenocarcinoma histology, and poor prognosis.[
Trastuzumab deruxtecan
Trastuzumab deruxtecan is an antibody-drug conjugate consisting of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor.
Evidence (trastuzumab deruxtecan):
The FDA granted accelerated approval to trastuzumab deruxtecan for patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This approval was based on objective response rate and DOR.
Immunotherapy
Nivolumab is a fully human monoclonal antibody that inhibits the PD-1 coinhibitory immune checkpoint expressed on tumor cells and infiltrating immune cells.[
Nivolumab
Evidence (nivolumab):
In two phase III clinical trials, one conducted in patients with advanced platinum-pretreated squamous NSCLC and the other trial conducted in patients with nonsquamous NSCLC, nivolumab demonstrated a significant improvement in OS compared with the previous standard treatment of docetaxel chemotherapy.[
Both of these trials demonstrated long-term clinical benefit at the 2-year outcomes. The OS rates for nivolumab at 2 years compared with docetaxel in squamous NSCLC were 23% (95% CI, 16%–30%) versus 8% (95% CI, 4%–13%), and OS rates in nonsquamous NSCLC were 29% (95% CI, 24%–34%) versus 16% (95% CI, 12%–20%).[
Nivolumab is now considered a standard second-line therapy for patients with metastatic NSCLC with progression on or after first-line platinum-based chemotherapy and is associated with improved survival and lower rates of toxicity than docetaxel. However, clinical trials of nivolumab to date have not enrolled patients with a history of autoimmune disease, interstitial lung disease, or an ECOG performance status higher than 1. Patients with active autoimmune conditions cannot be treated with nivolumab. Closely monitoring all patients for autoimmune toxicities from treatment is required. Specific algorithms for the management of autoimmune toxicity are included in the FDA label for
Pembrolizumab
Evidence (pembrolizumab):
The FDA granted accelerated approval to pembrolizumab as a second-line therapy for patients with NSCLC whose tumors express PD-L1 (>50% staining as determined by an FDA-approved test) with progression on or after first-line chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapies before receiving pembrolizumab (see the FDA label for
Atezolizumab
Evidence (atezolizumab):
mTOR inhibitors
Everolimus
Everolimus is used for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors.
Everolimus, an oral mTOR inhibitor, is clinically active against advanced pancreatic and nonpancreatic neuroendocrine tumors.[
Evidence (everolimus):
Current Clinical Trials
Use our
References:
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Treatment of Stage IIIA Non-Small Cell Lung Cancer (NSCLC)
Added Osimertinib (for patients with EGFR mutations) as a new subsection.
Treatment of Stages IIIB and IIIC NSCLC
Added Osimertinib (for patients with EGFR mutations) as a new subsection.
This summary is written and maintained by the
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of non-small cell lung cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Non-Small Cell Lung Cancer Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Non-Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at:
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Last Revised: 2024-08-30
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