Management of advanced/metastatic disease
The treatment strategy should consider the tumor histology and molecular pathology and the patient’s age, PS, comorbidities, and preferences.
Systemic therapy should be offered to all stage IV patients with PS 0–2.
In patients with any stage of NSCLC, smoking cessation should be highly encouraged because it improves outcome.
First-line treatment of EGFR- and ALK-negative NSCLC, PD-L1 ≥ 50%
Pembrolizumab is considered a standard first-line option for patients with advanced NSCLC and PD-L1 expression ≥ 50% who do not have contraindications to use of immunotherapy.
First-line treatment of NSCLC without actionable oncogenic driver, regardless of PD-L1 status
Chemotherapy with platinum doublets should be considered in all cases of stage IV NSCLC without an actionable oncogenic driver in patients without major comorbidities and PS 0–2.
Platinum-based doublets are the recommended chemotherapy option in all cases of stage IV NSCLC in patients with no contraindications to use of platinum compounds.
Four cycles of platinum-based doublets followed by less toxic maintenance monotherapy, or four cycles in patients not suitable for maintenance monotherapy, up to a maximum of six cycles, are currently recommended.
The albumin-bound paclitaxel/carboplatin (nab-PC) regimen could be considered a chemotherapeutic option in patients with advanced NSCLC, particularly those with greater risk of neurotoxicity, preexisting hypersensitivity to paclitaxel, or contraindications for standard paclitaxel premedication.
Combinations of platinum-based chemotherapy and anti-PD-(L1) inhibitors have reproducibly demonstrated superiority to standard platinum-based chemotherapy. In the absence of contraindications and conditioned by the registration and accessibility of anti-PD-(L)1 combinations with platinum-based chemotherapy, this strategy will be preferred to platinum-based chemotherapy in patients with PS 0-1 and PD-L1 < 50%.
Nivolumab plus ipilimumab represents an optional treatment regimen for patients with NSCLC with a high tumor mutational burden (TMB) (not European Medicines Agency [EMA] approved).
First-line treatment of squamous cell carcinoma
Platinum-based doublets with a third-generation cytotoxic agent (gemcitabine, vinorelbine, taxanes) are recommended in patients with advanced SCC who have no major comorbidities and PS 0–2.
The addition of necitumumab to cisplatin/gemcitabine has not been adopted as a standard in Europe for advanced SCC and its use should be carefully evaluated.
The combination of pembrolizumab and carboplatin with paclitaxel or albumin-bound paclitaxel is a standard choice in patients with metastatic squamous NSCLC (not EMA approved).
The use of atezolizumab with nab-PC represents an option in patients with metastatic squamous NSCLC (not EMA approved).
Other combinations of platinum-based chemotheraoy and anti-PD-(L1) inhibitors will demonstrate superiority to standard platinum-based chemotherapy. In the absence of contraindications and conditioned by the registration and accessibility of anti-PD-(L)1 combinations with platinum-based chemotherapy, this strategy should be preferred to platinum-based chemotherapy in patients with PS 0-1 and PD-L1 < 50%.
Nivolumab plus ipilimumab represents an optional treatment regimen for patients with SCC with a high TMB (not EMA-approved).
First-line treatment of non–squamous cell carcinoma (NSCC)
Pemetrexed-based combination chemotherapy is preferred to gemcitabine- or docetaxel-based combinations in patients with non-squamous tumors.
Pemetrexed use is restricted to NSCC in any line of treatment in advanced disease.
The combination of carboplatin with pemetrexed can be an option in patients with a contraindication to cisplatin.
Pembrolizumab in combination with pemetrexed and a platinum-based chemotherapy regimen should be considered a standard option in metastatic non-squamous NSCLC.
Atezolizumab in combination with pemetrexed and a platinum-based chemotherapy regimen is a therapeutic option in metastatic non-squamous NSCLC (not EMA-approved).
The combination of atezolizumab and bevacizumab with carboplatin and paclitaxel is a therapeutic option for metastatic non-squamous NSCLC in patients with PS 0-1 who do not have contraindications to use of immunotherapy (not EMA-approved).
Other combinations of platinum-based chemotherapy and anti-PD-(L1) inhibitors will demonstrate superiority to standard platinum-based chemotherapy. In the absence of contraindications and conditioned by the registration and accessibility of anti-PD-(L)1 combinations with platinum-based chemotherapy, this strategy should be preferred to platinum-based chemotherapy in patients with PS 0-1 and PD-L1 < 50%.
Nivolumab plus ipilimumab represents an optional treatment regimen for patients with NSCC with a high TMB (not EMA-approved).
If PD-(L)1 is not available for chemotherapy combinations, bevacizumab combined with paclitaxel/carboplatin may be offered in the absence of contraindications in patients with advanced NSCC and PS 0-1 (bevacizumab should be given until progression).
Bevacizumab might be considered with platinum-based regimens beyond paclitaxel/carboplatin, in the absence of contraindications.
Maintenance chemotherapy should be offered only to patients with PS 0–1 after first-line chemotherapy. Decisions about maintenance should consider histology, response to platinum-doublet chemotherapy, and remaining toxicity after first-line chemotherapy, PS, and patient preference.
In patients with NSCC and PS 0–1, pemetrexed switch maintenance should be considered in patients with disease control following four cycles of non-pemetrexed-containing platinum-based chemotherapy.
Pemetrexed continuation maintenance should be considered in patients with disease control following four cycles of cisplatin/pemetrexed.
Continuation maintenance with gemcitabine is an option in NSCLC patients treated with four cycles of cisplatin/gemcitabine.
Maintenance treatment with erlotinib is recommended only for patients with NSCC patients with an EGFR-sensitizing mutation.
Patients with performance status 2 and beyond
Chemotherapy prolongs survival and improves quality of life in NSCLC patients with PS 2 when compared with best supportive care.
Platinum-based (preferably carboplatin) combination chemotherapy should be considered in eligible PS 2 patients. Single-agent chemotherapy with gemcitabine, vinorelbine, docetaxel or pemetrexed (restricted to NSCC) is an alternative treatment option.
The use of checkpoint inhibitors for patients with advanced NSCLC and PS 2 can be considered.
Patients with poor PS (ie, PS 3–4) should be treated with best supportive care only in the absence of molecularly targetable alterations, such as EGFR mutations, ALK or ROS1 rearrangements, or BRAF V600 mutation.
Immunotherapy should be considered according to standard recommendations in elderly patients.
Carboplatin-based doublet chemotherapy is recommended in eligible elderly patients with PS 0–2 and with adequate organ function.
For patients not eligible for doublet chemotherapy, single-agent chemotherapy remains the standard of care.
Second-line treatment of NSCLC without an actionable oncogenic driver
PS 0–2 patients with clinical or radiological disease progression after first-line therapy should be offered second-line therapy irrespective of administration of maintenance treatment.
In patients with progression after first-line immunotherapy with pembrolizumab, platinum-based chemotherapy is recommended as a second-line treatment option.
Phase III studies of second-line therapy (nivolumab, pembrolizumab and atezolizumab versus docetaxel) have shown a general trend for enriched efficacy of anti-PD-1/PD-L1 agents in patients with higher PD-L1 expression compared with those with no/less PD-L1 expression. However, unselected patients may still have improved survival and tolerance with anti-PD-1/PD-L1 agents compared with docetaxel.
PD-L1 and PD-1 inhibitors (nivolumab, pembrolizumab and atezolizumab) are the treatment of choice for most patients with advanced, previously treated, PD-L1-naive NSCLC, irrespective of PD-L1 expression.
Nivolumab is recommended in both squamous and non-squamous NSCLC.
Pembrolizumab is recommended in patients with previously treated NSCLC with PD-L1 expression > 1%.
Atezolizumab is recommended in patients with advanced NSCLC previously treated with one or two prior lines of chemotherapy.
In patients not suited for immunotherapy, second-line chemotherapy is recommended. Comparable second-line therapy options are pemetrexed, for NSCC only, or docetaxel (pemetrexed has a more favorable tolerability profile).
Treatment may be prolonged if disease is controlled and toxicity acceptable.
Nintedanib/docetaxel is a treatment option in patients with adenocarcinoma progressing after previous chemotherapy or immunotherapy.
Ramucirumab/docetaxel is a treatment option in PS 0–2 patients with NSCLC that progresses after first-line chemotherapy or immunotherapy.
The combination of paclitaxel and bevacizumab is another treatment option but it is not EMA-approved.
Erlotinib represents a potential second/third-line treatment option in particular for patients who are not suited for immunotherapy or second-line chemotherapy and have tumors with unknown EGFR status or wild-type EGFR.
Afatinib is a potential option In patients with advanced SCC with PS 0–2 who are unfit for chemotherapy or immunotherapy and have tumors with unknown EGFR status or wild-type EGFR.
First-line treatment of EGFR-mutated NSCLC
Patients with a tumor that has a sensitizing EGFR mutation should receive first-line EGFR TKIs including erlotinib, gefitinib, or afatinib. None of those three EGFR TKIs is consensually considered a preferred option.
Dacomitinib will be added to the list when the drug has been approved by regulatory agencies (the US Food and Drug Administration [FDA] and the EMA).
First-line osimertinib is considered one of the options for patients with a tumor with sensitizing EGFR mutations.
All patients should be considered for EGFR TKIs irrespective of clinical parameters, including PS, gender, tobacco exposure, histology, and line of therapy.
Erlotinib/bevacizumab represents a front-line treatment option in patients with EGFR-mutated tumors.
The addition of carboplatin and pemetrexed to gefitinib represents a first-line option in patients with EGFR-mutated tumors (not EMA-approved).
Patients who have radiological progression with ongoing clinical benefit may continue with EGFR TKI treatment.
In EGFR-mutated NSCLC patients with localized distant progression and ongoing systemic control, continuation of treatment with an EGFR TKI in combination with local treatment of progressing metastatic sites may be considered.
Second-line treatment of EGFR-mutated NSCLC
EGFR TKI should be stopped when the patient starts chemotherapy for treatment of TKI resistance.
All tumors demonstrating clinical evidence of EGFR TKI resistance, in patients not previously treated with osimertinib, should be tested for presence of EGFR exon 20 T790M mutation.
Liquid biopsy can be used as the initial test for detection of T790M mutation, and if the test is negative, re-biopsy should be attempted if feasible.
Osimertinib is the standard therapy for patients whose tumors test positive for T790M, either on liquid biopsy or re-biopsy, and who have not received osimertinib previously.
In EGFR-mutated NSCLC with CNS disease, osimertinib is highly active.
Platinum-based doublet is the standard therapy for patients whose tumor is negative for T790M, either on re-biopsy or liquid biopsy (only when re-biopsy is not feasible).
After targeted therapies have been exploited, the combination of atezolizumab and bevacizumab with carboplatin and paclitaxel should be considered as a therapeutic option in patients with an EGFR-mutated tumor who have PS 0–1 and no contraindications to use of immunotherapy (not EMA-approved).
First-line treatment of ALK-rearranged NSCLC
Patients with ALK-rearranged NSCLC should receive first-line ALK TKI treatment including crizotinib, ceritinib, alectinib, or brigatinib (not EMA-approved).
Alectinib is associated with longer progression-free survival (PFS) and lower toxicity than crizotinib and showed activity against CNS disease in patients previously untreated with ALK-positive NSCLC.
Brigatinib is associated with longer PFS than crizotinib at the first interim analysis and showed activity against CNS disease in previously untreated patients with ALK-positive NSCLC (not EMA approved).
In patients with CNS involvement, front-line use of ALK TKIs is effective, and alectinib, brigatinib, or ceritinib are recommended. Ceritinib represents a better treatment strategy than chemotherapy and presumably than crizotinib; alectinib represents a better treatment option than crizotinib; brigatinib represents a better treatment option than crizotinib (not EMA-approved).
In patients who have ALK-rearranged NSCLC with localized distant progression and ongoing systemic control, continuation of treatment with an ALK TKI in combination with local treatment of progressing metastatic sites may be considered.
Second and further lines of treatment of ALK-rearranged NSCLC
Any patient with NSCLC that harbors an ALK fusion should receive crizotinib as next-line therapy, if not received previously.
Ceritinib and alectinib are recommended in patients with ALK-positive advanced NSCLC that progresses on treatment with criotinib or who are intolerant to crizotinib.
In patients with ALK-positive NSCLC that progresses on crizotinib with CNS progression, treatment should be a next-generation ALK TKI such as alectinib or ceritinib. In patients whose disease progresses after a second-generation ALK TKI, a next-generation ALK inhibitor such as brigatinib or lorlatinib is an option if available; these agents are currently not approved by the EMA.
Treatment of ROS1-rearranged NSCLC
Crizotinib is recommended in the first-line setting in patients with stage IV NSCLC with ROS1 rearrangement.
In patients with ROS1-positive NSCLC who have not received crizotinib in the first-line setting, single-agent crizotinib may be offered as second-line therapy.
Ceritinib might be considered in crizotinib-naive patients but is currently not approved by the EMA.
Patients who received crizotinib in the first-line setting may be offered platinum-based chemotherapy in the second-line setting.
Treatment of BRAF-mutated NSCLC
Patients with stage IV NSCLC with BRAF V600 mutation should be exposed in first- or second-line to therapy BRAF/MEK inhibition using dabrafenib/trametinib.
If patients have received BRAF/MEK inhibition in the first-line setting, then they may be offered platinum-based chemotherapy in the second-line setting.
Patients with NSCLC with other actionable oncogenic driver
Targeting RET, MET amplification, HER2 dysregulation, or NRTK fusions is not currently routinely recommended. Recruitment into open trials is encouraged.
Targeting METex14 variants (while evidence of benefit is stronger) is not currently routinely recommended and recruitment into open trials is encouraged. Crizotinib has demonstrated potential clinical efficacy for METex14 variant NSCLC; this needs to be confirmed.
Role of radiotherapy (RT) in stage IV NSCLC
External beam radiotherapy (EBRT) is indicated in cases of hemoptysis and symptomatic airway obstruction.
RT can achieve symptom control for a variety of clinical scenarios including hemoptysis, symptomatic airway obstruction, painful chest wall disease and bone metastasis, superior vena cava syndrome, and soft tissue or neural invasion.
Administration of high-dose RT does not result in greater levels of palliation.
EBRT alone is more effective for palliation than endobronchial brachytherapy (EBB) alone.
For patients previously treated with EBRT who have symptomatic recurrent endobronchial central obstruction, EBB may be considered in selected cases.
Neurological symptoms from spinal cord compression can be relieved by early RT.
Whole-brain radiotherapy (WBRT) can be considered in selected patients, contingent on prognostic factors of better survival. WBRT should not be offered to recursive partitioning analysis (RPA) class III patients, in view of their dismal prognosis; only best supportive care is recommended.
The most frequently used WBRT schedules are 20 Gy in 5 fractions or 30 Gy in 10 fractions, with no difference in outcome.
For most patients with symptomatic brain metastases and/or significant edema, dexamethasone or equivalent corticosteroid is recommended.
Neuroprotective agents are not recommended for routine use.
Hippocampus-avoidance WBRT is not currently recommended as a standard treatment.
In cases of a single brain metastasis, surgical resection can be considered.
Postoperative WBRT or stereotactic radiosurgery (SRS) is recommended after surgical resection.
In patients with RPA class I–II who have a limited number of metastases, SRS alone is the recommended treatment.
SRS alone, without WBRT but with close MRI brain imaging follow-up, is an alternative strategy.
The indication for SRS is based on total tumor volume rather than numbers of metastases, as the risk of radionecrosis increases with tumor volume.
In patients with asymptomatically detected CNS metastases at presentation, systemic therapy with deferred RT should be considered due to similar intra-cranial and extra-cranial response.
In patients with an actionable oncogenic driver (eg, EGFR, ALK) and clinically asymptomatic brain metastases, next-generation TKIs may restore control of brain disease and delay cranial RT.
Currently, limited trial data demonstrate the safety and efficacy of immunotherapy in patients with small-volume untreated CNS metastases.
Leptomeningeal (LM) carcinomatosis
A high index of suspicion should be borne for LM involvement especially in patients with actionable oncogenic drivers having TKI treatment. CSF sampling is diagnostic of LM disease but limited by low sensitivity, albeit with high specificity.
Patients with actionable oncogenic drivers and LM disease can be treated with CNS-penetrant next-generation TKIs.
Chemotherapy and bevacizumab may have activity both extra-cranially and intra-cranially, and also in the context of LM disease.
Intra–cerebrospinal fluid pharmacotherapy can be considered, contingent on clinical factors.
In exceptional cases, focal RT can be considered for circumscribed, notably symptomatic, lesions.
Surgery in stage IV NSCLC
Surgery may be indicated for diagnosis, evaluation of response to systemic therapy, and palliation.
Highly selected patients may be considered for lung resection with therapeutic intent or even for a salvage procedure.
When metastatic disease is suspected on PET scanning, invasive surgical procedures such as incisional biopsies, mediastinoscopy, thoracoscopy (VATS), or laparoscopy may be required to obtain relevant biopsy samples. Adequate samples should be provided to the pathologist for detailed routine staining, IHC, and molecular genetic testing.
Persisting or recurrent pleural effusions are usually managed by pleurodesis to improve dyspnea. Talc is the preferred agent and thoracoscopic poudrage may be better than injection of talc slurry in patients with primary lung cancer.
In cases of a trapped lung from thickened visceral pleural peel, indwelling pleural catheters or pleuroperitoneal shunts provide symptomatic relief.
Treatment of oligometastatic disease
Stage IV patients with one to three synchronous metastases at diagnosis may experience long-term disease-free survival (DFS) following systemic therapy and local consolidative therapy (high-dose RT or surgery). Because of the limited evidence, these cases should be discussed by a multidisciplinary tumor board, and inclusion in clinical trials is preferred.
Although operative risk is low and long-term survival may be achieved, current evidence for surgery in oligometastatic disease is limited, and the relative contribution of surgery versus RT as a local treatment modality has not been established yet.
Patients with stage IV NSCLC with limited metachronous metastases may be treated with a radical local therapy (high-dose RT or surgery) and may experience long-term DFS. However, this is based mainly on retrospective data and inclusion in clinical trials is preferred.
Patients with stage IV NSCLC with driver mutations, with oligoprogression while on molecular-targeted therapy, may be treated with a radical local treatment (high-dose RT or surgery) and may experience long-term DFS. However, this recommendation is based mainly on retrospective data and inclusion in clinical trials is preferred.
Solitary lesions in the contralateral lung should, in most cases, be considered as synchronous secondary primary tumors and, if possible, treated with curative-intent therapy.
Zoledronic acid reduces skeletal-related events (pathological fracture, radiation/surgery to bone or spinal cord compression) and is recommended in stage IV bone metastatic disease.
Denosumab shows a trend towards superiority to zoledronic acid for prevention of skeletal-related events in patients with lung cancer and is recommended in selected patients with advanced lung cancer with bone metastases.
In patients with uncomplicated painful bone metastases, single-fraction EBRT is the recommended treatment, on the basis of non-inferiority to multiple-fraction RT.
Role of minimally invasive procedures in stage IV NSCLC
In patients with symptomatic major airway obstruction or post-obstructive infection, endoscopic debulking by laser, cryotherapy, or stent placement may be helpful.
Endoscopy is useful in the diagnosis and treatment (endobronchial or by guiding endovascular embolization) of hemoptysis.
Vascular stenting might be useful in NSCLC-related superior vena cava compression.
Palliative care in stage IV NSCLC
Early palliative care intervention is recommended, in parallel with standard oncological care.
Close follow-up, at least every 6–12 weeks after first-line therapy, is advised to allow for early initiation of second-line therapy but should depend on individual retreatment options.
Medscape © 2018 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Metastatic Non–Small Cell Lung Cancer Clinical Practice Guidelines (2018) - Medscape - Nov 02, 2018.