Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

stage I and II

1st line – surgery

Back
ONGOING
|
stage I and II
|
suitable for surgery
1st line – 

surgery

Surgery is the standard treatment for early-stage NSCLC.[49]​​[65][113]​​​​​​​[114]​ Eligibility for surgery should be assessed by an expert multi-disciplinary team. Surgery is ideally performed by a thoracic surgical oncologist.[65][114]​​

For patients with sufficient pulmonary reserve, lobectomy (removal of an entire lung lobe) or pneumonectomy (removal of an entire lung) is preferred.

More limited surgery, such as a wedge resection or segmentectomy (removal of a segment of a lobe), is often necessary in older patients or those with comorbidities but is associated with a higher rate of recurrence.[115]

Access to the chest is achieved through a thoracotomy or minimally invasive techniques (e.g., video-assisted thoracic surgery); the latter is associated with shorter hospital stay.[116][117] Sampling or dissection of mediastinal lymph nodes is recommended.

Surgery provides the best chance of cure for early-stage NSCLC but can be associated with significant morbidity.[49]​​[114]​​[118][119]​​​​​​​​​ Intraoperative and postoperative complications include haemorrhage, infection, cardiac ischaemia, stroke, cardiac arrhythmia, pneumonia, prolonged air leak, chylothorax, pulmonary oedema, and bronchopleural fistula.

The 30-day mortality rate is approximately 1% to 3% after lobectomy and 3% to 7% after pneumonectomy.[120][121]​ The 30- and 90-day mortality are strongly influenced by age, performance status, and type of operation.[121] 

Plus – supportive care

Back
ONGOING
|
stage I and II
|
suitable for surgery
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All patients receive supportive care according to their needs. This will vary according to the intent of treatment (curative or palliative) and the progression of the disease.

For patients undergoing curative treatment, pulmonary rehabilitation may be appropriate, as well as optimisation of medical comorbidities. Patients with increasing symptoms may have a variety of interventions aimed at their individual needs, based on a holistic needs assessment.

A combination of physical interventions such as endobronchial treatment, treatment of pleural and other disease, and psychological and spiritual interventions and help may be indicated.[268]

Preoperative exercise may potentially reduce length of hospital stay and risk of postoperative complications.[129][130]​​​​​​​[131][132] [ Cochrane Clinical Answers logo ] ​​​​​​ Aerobic and resistance exercise during treatment with curative intent is recommended to reduce adverse effects of treatment.[129]

Consider – preoperative chemo-immunotherapy, chemotherapy, or chemoradiotherapy

Back
ONGOING
|
stage I and II
|
suitable for surgery
Consider – 

preoperative chemo-immunotherapy, chemotherapy, or chemoradiotherapy

Additional treatment recommended for SOME patients in selected patient group

All patients with resectable NSCLC should be evaluated for preoperative therapy. An immune checkpoint inhibitor combined with chemotherapy should be considered in patients with tumours ≥4 cm or node positive NSCLC (in the absence of contraindications to immune checkpoint inhibitor therapy).

Nivolumab (anti-programmed death receptor-1 [anti-PD-1] monoclonal antibody): recommended, in combination with platinum-based doublet chemotherapy, regardless of PD-L1 status.[65][77][122][123] Patients with resectable NSCLC treated with nivolumab plus chemotherapy prior to surgery experienced significantly longer event-free survival and improved pathological complete response compared with chemotherapy alone.​[122]​

Pembrolizumab (anti-PD-1 monoclonal antibody): recommended, in combination with cisplatin-based doublet chemotherapy.[65]​ Patients with early-stage NSCLC treated with preoperative pembrolizumab plus chemotherapy, followed by surgical resection experienced improved event-free survival and major pathological response compared with preoperative chemotherapy alone followed by surgery.[124]

Durvalumab (anti-PD-L1 monoclonal antibody): recommended, in combination with platinum-based doublet chemotherapy for adult patients with resectable NSCLC without EGFR mutations or anaplastic lymphoma kinase (ALK) rearrangements.[65][125]

Testing for PD-L1 status, epidermal growth factor receptor (EGFR) mutations, and ALK rearrangements can guide the use of induction chemotherapy combined with an immune checkpoint inhibitor.

Preoperative chemotherapy or chemoradiation regimens are recommended for patients not suitable for immune checkpoint inhibitors.[65] Preoperative chemotherapy significantly improves overall survival, time to distant recurrence, and recurrence-free survival in patients with resectable NSCLC.[126]​ Cisplatin-based chemotherapy regimens are recommended. Carboplatin-based regimens can be considered in selected patients who are not candidates for cisplatin. In early-stage patients, no statistically significant differences in disease-free survival were found between chemotherapy followed by surgery and surgery plus postoperative chemotherapy.[127]

All chemotherapy regimens have the potential to cause bone marrow suppression, nausea/vomiting, alopecia, and fatigue. Other adverse effects are specific to the particular agent.

For patients undergoing preoperative chemoradiotherapy, the mortality rate is higher than after pneumonectomy alone, especially right pneumonectomy.[128]​ Chemoradiation regimens include carboplatin plus pemetrexed or paclitaxel, and cisplatin plus pemetrexed or etoposide.[65]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

-- AND --

cisplatin

-- AND --

pemetrexed

or

gemcitabine

or

paclitaxel

OR

nivolumab

-- AND --

carboplatin

-- AND --

pemetrexed

or

gemcitabine

OR

pembrolizumab

-- AND --

cisplatin

-- AND --

gemcitabine

or

pemetrexed

OR

durvalumab

-- AND --

cisplatin

-- AND --

gemcitabine

or

pemetrexed

OR

durvalumab

-- AND --

carboplatin

-- AND --

paclitaxel

or

pemetrexed

or

gemcitabine

Secondary options

cisplatin

-- AND --

pemetrexed

or

gemcitabine

or

docetaxel

or

vinorelbine

or

etoposide

OR

carboplatin

-- AND --

paclitaxel

or

gemcitabine

or

pemetrexed

Consider – postoperative chemotherapy, chemo-immunotherapy, or immunotherapy

Back
ONGOING
|
stage I and II
|
suitable for surgery
Consider – 

postoperative chemotherapy, chemo-immunotherapy, or immunotherapy

Additional treatment recommended for SOME patients in selected patient group

Patients with completely resected NSCLC are at risk of developing metastatic disease. Postoperative chemotherapy has been shown to improve survival in patients with stage I to II disease (as well as stage III disease), and it is routinely offered to patients with stage IB disease, where the tumour is larger than 4 cm, up to stage IIIB disease.[133][134][135][136][137][138] [ Cochrane Clinical Answers logo ]

US guidelines recommend postoperative cisplatin-based chemotherapy for all patients with stage IIA and IIB completely resected NSCLC.[139] Postoperative cisplatin-based chemotherapy is not routinely recommended for patients with stage IB disease; the beneficial effect of postoperative chemotherapy appears to increase with disease stage.[139][140][141]​​​ Postoperative chemotherapy may be considered for high-risk stage IB disease. The optimal regimen is based on the individual patient characteristics including disease stage, previous regimens, and use of concomitant radiotherapy or surgical resection.

Postoperative targeted therapy options include anti-programmed death ligand-1 (anti-PD-L1) monoclonal antibodies, anti-programmed death receptor-1 (anti-PD-1) monoclonal antibodies, or tyrosine kinase inhibitor (TKI) therapy.[65]

Atezolizumab (anti-PD-L1 monoclonal antibody): recommended as monotherapy for postoperative treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA NSCLC whose tumours have PD-L1 expression on ≥1% of tumour cells.[65][139][142][143]​​​ Atezolizumab/hyaluronidase (a subcutaneous formulation of atezolizumab) may be substituted for atezolizumab.[65]​

Durvalumab (anti-PD-L1 monoclonal antibody): recommended as monotherapy for postoperative treatment for adult patients with resected tumours ≥4 cm and/or node positive NSCLC and no known EGFR mutations or ALK rearrangements who received preoperative durvalumab plus chemotherapy.[65]

Pembrolizumab (anti-PD-1 monoclonal antibody): recommended as monotherapy for postoperative treatment after tumour resection and platinum-based chemotherapy for adult patients with stage IB to IIIA NSCLC.[65][77]​​​​[144]

Nivolumab (anti-PD-1 monoclonal antibody): recommended, as postoperative treatment after tumour resection in adult patients with stage II to IIIB NSCLC and no known EGFR mutations or ALK rearrangements who received preoperative nivolumab plus chemotherapy.[65]​​​​​[123]​​

Alectinib (TKI): inhibits ALK tyrosine kinase. Alectinib is recommended as postoperative therapy after tumour resection in adult patients with stage II to IIIA ALK-positive NSCLC.[65][145]

Osimertinib (TKI): targets mutated forms of EGFRs. Osimertinib is recommended as postoperative therapy after tumour resection in adult patients with stage IB to IIIA NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations.[65][139][146]​​​​[147][148][149]

See local specialist protocol for dosing guidelines.

Primary options

cisplatin

-- AND --

pemetrexed

or

gemcitabine

or

docetaxel

or

vinorelbine

or

etoposide

OR

atezolizumab

OR

atezolizumab/hyaluronidase

OR

durvalumab

OR

pembrolizumab

OR

nivolumab

OR

alectinib

OR

osimertinib

Secondary options

carboplatin

-- AND --

paclitaxel

or

gemcitabine

or

pemetrexed

Consider – postoperative radiotherapy

Back
ONGOING
|
stage I and II
|
suitable for surgery
Consider – 

postoperative radiotherapy

Additional treatment recommended for SOME patients in selected patient group

Postoperative radiotherapy is associated with cardiopulmonary toxicity.[150]​ It may be considered for high-risk patients with stage II disease (those with positive or close margins or lymph node involvement in the mediastinum and/or extracapsular extension).[150][151] [ Cochrane Clinical Answers logo ] ​​​

Adverse effects depend on the size of the radiation field and the dose. Adjacent organs (e.g., lungs, esophagus) may unavoidably receive some radiation. The most common adverse effects are fatigue, skin erythema/desquamation, and esophagitis. Most patients develop some degree of esophagitis during treatment. The most common late complication is pneumonitis, which is characterised by dyspnoea, dry cough, and fever occurring 1-6 months after completing treatment.

Extranodal extensions (e.g., nodal metastases) seen on lung cancer resection specimens in stage I-III NSCLC may help radiotherapists decide whether or not to give postoperative radiotherapy.[152]

There is no evidence for the benefit of prophylactic cranial irradiation after potentially curative therapies in NSCLCs.[153]​ 

1st line – radiotherapy

Back
ONGOING
|
stage I and II
|
not suitable for surgery
1st line – 

radiotherapy

Patients with stage I to IIB NSCLC with no nodal disease who are medically inoperable, at high surgical risk, or who have declined surgery, should receive definitive radiotherapy (preferably stereotactic ablative radiation ([SABR]).[65][154][155]​​​ High-risk stage II patients should be considered for adjunct chemotherapy.[65]

SABR is a well-established technique that uses fewer fractions (3 to 8) with higher radiation doses per fraction (12-20 Gy each day, to a total of 48-60 Gy). There is good evidence for its safety and efficacy in patients with early-stage disease with significant respiratory comorbidity that precludes surgery.[155][156][157]

Adverse effects depend on the size of the radiation field and the dose. Adjacent organs (e.g., lungs, oesophagus) may unavoidably receive some radiation. The most common adverse effects are fatigue, skin erythema/desquamation, and esophagitis. Most patients develop some degree of esophagitis during treatment. The most common late complication is pneumonitis, which is characterised by dyspnoea, dry cough, and fever occurring 1-6 months after completing treatment.

Image-guided thermal ablation (e.g., radiofrequency ablation, cryoablation, microwave ablation) may be considered for selected patients who are medically inoperable.[65][158][159][160]

Plus – supportive care

Back
ONGOING
|
stage I and II
|
not suitable for surgery
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All patients receive supportive care according to their needs. This will vary according to the intent of treatment (curative or palliative) and the progression of the disease.

For patients undergoing curative treatment, pulmonary rehabilitation may be appropriate, as well as optimisation of medical comorbidities. Patients with increasing symptoms may have a variety of interventions aimed at their individual needs, based on a holistic needs assessment.

A combination of physical interventions such as endobronchial treatment, treatment of pleural and other disease, and psychological and spiritual interventions and help may be indicated.[268]

Consider – adjuvant chemotherapy

Back
ONGOING
|
stage I and II
|
not suitable for surgery
Consider – 

adjuvant chemotherapy

Additional treatment recommended for SOME patients in selected patient group

If adjuvant chemotherapy and radiotherapy is indicated, the chemotherapy is usually given first followed sequentially by radiotherapy.

The choice between the many chemotherapeutic regimens is complex and needs to be managed in a specialist oncology unit.

Cisplatin-based regimens are recommended. Carboplatin-based regimens can be considered in selected patients who are not felt to be appropriate candidates for cisplatin.

The optimal chemotherapeutic regimen is based on individual patient characteristics, including disease stage and previous treatment.

All chemotherapy regimens have the potential to cause bone marrow suppression, nausea/vomiting, alopecia, and fatigue. Other adverse effects are specific to the particular agent.

See local specialist protocol for dosing guidelines.

Primary options

cisplatin

-- AND --

pemetrexed

or

gemcitabine

or

docetaxel

or

vinorelbine

or

etoposide

Secondary options

carboplatin

-- AND --

paclitaxel

or

gemcitabine

or

pemetrexed

stage IIIA

1st line – surgery

Back
ONGOING
|
stage IIIA
|
suitable for surgery
1st line – 

surgery

Eligibility for surgery should be assessed by an expert multi-disciplinary team. Surgery is ideally performed by a thoracic surgical oncologist.[65][114]​​

There remains debate about the role of surgery, in the context of multimodality treatment, in N2 disease.[65] Several randomised trials evaluating treatment options for patients with N2 disease found no difference in overall mortality between definitive radical chemoradiotherapy and definitive chemoradiotherapy with surgical consolidation. Guidelines recommend consideration of surgery in selected patients (e.g., those with non-bulky single-zone N2 disease).[49][65]​​​[113][161][162][163]

For patients with sufficient pulmonary reserve, lobectomy or pneumonectomy is preferred. More limited surgery, such as a wedge resection or segmentectomy (removal of a segment of a lobe), is often necessary in older patients or those with comorbidities but is associated with a higher rate of recurrence.[115]

Access to the chest is achieved through a thoracotomy or minimally invasive techniques (e.g., video-assisted thoracic surgery); the latter is associated with shorter hospital stay.[116][117] Sampling or dissection of mediastinal lymph nodes is recommended.

Intraoperative and postoperative complications include haemorrhage, infection, cardiac ischaemia, stroke, cardiac arrhythmia, pneumonia, prolonged air leak, chylothorax, pulmonary oedema, and bronchopleural fistula.

The 30-day mortality rate is approximately 1% to 3% after lobectomy and 3% to 7% after pneumonectomy.[120][121]​ The 30- and 90-day mortality are strongly influenced by age, performance status, and type of operation.[121]

Patients with stage III NSCLC who are planned for surgical resection should receive either preoperative chemotherapy or chemoradiation.[149][164]​​​​​​​​​ Preoperative treatment is particularly important in patients planned for surgery in the N2 or superior sulcus settings.[164]​​

Plus – supportive care

Back
ONGOING
|
stage IIIA
|
suitable for surgery
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All patients receive supportive care according to their needs. This will vary according to the intent of treatment (curative or palliative) and the progression of the disease.

For patients undergoing curative treatment, pulmonary rehabilitation may be appropriate, as well as optimisation of medical comorbidities. Patients with increasing symptoms may have a variety of interventions aimed at their individual needs, based on a holistic needs assessment.

A combination of physical interventions such as endobronchial treatment, treatment of pleural and other disease, and psychological and spiritual interventions and help may be indicated.[268]

Preoperative exercise may potentially reduce length of hospital stay and risk of postoperative complications.[129][130]​​​​​​​​[131][132] [ Cochrane Clinical Answers logo ] ​​​​​​​ Aerobic and resistance exercise during treatment with curative intent is recommended to reduce adverse effects of treatment.[129]

Consider – preoperative chemotherapy, chemoradiotherapy, or chemo-immunotherapy

Back
ONGOING
|
stage IIIA
|
suitable for surgery
Consider – 

preoperative chemotherapy, chemoradiotherapy, or chemo-immunotherapy

Additional treatment recommended for SOME patients in selected patient group

In patients with stage IIIA disease who are medically suitable for surgery, preoperative chemotherapy, chemoradiotherapy, or chemo-immunotherapy should be considered.[65][133][134][135][149]​​​​​​​​​​[164]​​[165]​​​

Preoperative chemotherapy regimens are recommended for patients not suitable for immune checkpoint inhibitors.[65]​ Preoperative chemotherapy significantly improves overall survival, time to distant recurrence, and recurrence-free survival in patients with resectable NSCLC.[126]​ Pemetrexed plus cisplatin is preferred in patients with non-squamous disease; cisplatin plus gemcitabine or docetaxel is recommended for squamous disease.[65]

All chemotherapy regimens have the potential to cause bone marrow suppression, nausea/vomiting, alopecia, and fatigue. Other adverse effects are specific to the particular agent.

The addition of radiotherapy to preoperative chemotherapy (chemoradiotherapy) does not appear to improve survival outcomes compared with preoperative chemotherapy alone.[164][166]​​​​​​​ One study reported improved downstaging and pathological response in patients with stage IIIA-IIIB NSCLC who were randomised to preoperative chemoradiation followed by radiotherapy plus chemotherapy.[167] 

For patients undergoing preoperative chemoradiotherapy, the mortality rate is higher than after pneumonectomy alone, especially right pneumonectomy.[128]

Consideration should be given to preoperative nivolumab, pembrolizumab, or durvalumab plus chemotherapy for patients with potentially resectable stage III disease.[65]

See local specialist protocol for dosing guidelines.

Primary options

cisplatin

-- AND --

pemetrexed

or

gemcitabine

or

docetaxel

or

vinorelbine

or

etoposide

OR

nivolumab

-- AND --

cisplatin

-- AND --

pemetrexed

or

gemcitabine

or

paclitaxel

OR

nivolumab

-- AND --

carboplatin

-- AND --

pemetrexed

or

gemcitabine

OR

pembrolizumab

-- AND --

cisplatin

-- AND --

gemcitabine

or

pemetrexed

OR

durvalumab

-- AND --

cisplatin

-- AND --

gemcitabine

or

pemetrexed

OR

durvalumab

-- AND --

carboplatin

-- AND --

paclitaxel

or

pemetrexed

or

gemcitabine

Secondary options

carboplatin

-- AND --

paclitaxel

or

gemcitabine

or

pemetrexed

Consider – postoperative chemotherapy, chemo-immunotherapy, immunotherapy, radiotherapy, or chemoradiotherapy

Back
ONGOING
|
stage IIIA
|
suitable for surgery
Consider – 

postoperative chemotherapy, chemo-immunotherapy, immunotherapy, radiotherapy, or chemoradiotherapy

Additional treatment recommended for SOME patients in selected patient group

Postoperative chemotherapy, chemo-immunotherapy, immunotherapy, radiotherapy, or chemoradiotherapy should be considered, but is not required if administered preoperatively. Specialist advice must be sought.

Patients with resected stage III NSCLC who did not receive preoperative systemic therapy should receive platinum-based chemotherapy postoperatively.[162]

Postoperative targeted therapy options for resected stage IIIA NSCLC include the following options.

Anti-PD-1 monoclonal antibodies (pembrolizumab, nivolumab); as postoperative monotherapy after tumour resection and platinum-based chemotherapy for adult patients with stage IIIA NSCLC.[65][77][123]​​​[144]​​

Anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibodies (atezolizumab, durvalumab); as postoperative monotherapy after tumour resection and platinum-based chemotherapy for adult patients with stage IIIA NSCLC.[65][139][142][143]​​ Atezolizumab/hyaluronidase (a subcutaneous formulation of atezolizumab) may be substituted for atezolizumab.[65]

Tyrosine kinase inhibitor therapy; osimertinib as postoperative therapy after tumour resection in adult patients with stage IIIA NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations, or alectinib as postoperative therapy after tumour resection in adult patients with stage IIIA ALK-positive NSCLC.[65][139][145]​​​[146][147][148][149]​​​

See local specialist protocol for dosing guidelines.

Primary options

cisplatin

-- AND --

pemetrexed

or

gemcitabine

or

docetaxel

or

vinorelbine

or

etoposide

OR

pembrolizumab

OR

nivolumab

OR

atezolizumab/hyaluronidase

OR

durvalumab

OR

osimertinib

OR

alectinib

Secondary options

carboplatin

-- AND --

paclitaxel

or

gemcitabine

or

pemetrexed

1st line – radiotherapy or chemoradiotherapy

Back
ONGOING
|
stage IIIA
|
not suitable for surgery: candidate for treatment with curative intent
1st line – 

radiotherapy or chemoradiotherapy

Patients who have good performance status but are medically or surgically inoperable should be offered concurrent chemoradiotherapy instead of sequential chemotherapy and radiotherapy.[164] Concurrent chemoradiotherapy is modestly more effective than sequential chemoradiotherapy, but is more toxic.[168][169]​​​​ External beam radiotherapy should be given in conjunction with platinum-doublet chemotherapy to a radical dose, where patient fitness and tumour volume and distribution allows.[162][170]

Adverse effects depend on the size of the radiation field and the dose. Adjacent organs (e.g., lungs, oesophagus) may unavoidably receive some radiation. The most common adverse effects are fatigue, skin erythema/desquamation, and esophagitis. Most patients develop some degree of esophagitis during treatment. The most common late complication is pneumonitis, which is characterised by dyspnoea, dry cough, and fever occurring 1-6 months after completing treatment.

The optimal regimen is based on individual patient characteristics, including disease stage, previous regimens, and use of concomitant radiotherapy or surgical resection.

All chemotherapy regimens have the potential to cause bone marrow suppression, nausea/vomiting, alopecia, and fatigue. Other adverse effects are specific to the particular agent.

See local specialist protocol for dosing guidelines.

Primary options

cisplatin

-- AND --

pemetrexed

or

etoposide

OR

carboplatin

-- AND --

pemetrexed

or

paclitaxel

Plus – supportive care

Back
ONGOING
|
stage IIIA
|
not suitable for surgery: candidate for treatment with curative intent
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All patients receive supportive care according to their needs. This will vary according to the intent of treatment (curative or palliative) and the progression of the disease.

For patients undergoing curative treatment, pulmonary rehabilitation may be appropriate, as well as optimisation of medical comorbidities. Patients with increasing symptoms may have a variety of interventions aimed at their individual needs, based on a holistic needs assessment.

A combination of physical interventions such as endobronchial treatment, treatment of pleural and other disease, and psychological and spiritual interventions and help may be indicated.[268]

Consider – durvalumab or osimertinib

Back
ONGOING
|
stage IIIA
|
not suitable for surgery: candidate for treatment with curative intent
Consider – 

durvalumab or osimertinib

Additional treatment recommended for SOME patients in selected patient group

Durvalumab, an anti-PD-L1 monoclonal antibody, is recommended as consolidation therapy for 1 year for patients with unresectable stage III NSCLC whose disease has not progressed after concurrent platinum-based chemotherapy and radical radiotherapy.​[65]​​​[164][171][172]​ In Europe, durvalumab use is restricted to PD-L1 positive patients only (as there was no survival benefit in PD-L1 negative patients in an unplanned post hoc analysis).​[173]

Durvalumab can cause immune-related adverse events including pneumonitis and colitis.

Osimertinib, a tyrosine kinase inhibitor, is recommended as consolidation therapy until disease progression for patients with unresectable stage III NSCLC and EGFR exon 19 deletion or exon 21 L858R mutation whose disease has not progressed after concurrent platinum-based chemotherapy and radical radiotherapy.[65][174][175]

See local specialist protocol for dosing guidelines.

Primary options

durvalumab

OR

osimertinib

stage IIIB and IIIC

1st line – preoperative chemotherapy and/or preoperative radiotherapy

Back
ONGOING
|
stage IIIB and IIIC
|
resectable with no contralateral mediastinal adenopathy
1st line – 

preoperative chemotherapy and/or preoperative radiotherapy

Most of these patients (stage IIIB and IIIC NSCLC) will never be candidates for surgical resection or combination chemoradiotherapy.

A small proportion of patients with stage IIIB NSCLC without contralateral lymph node involvement (T4N2M0) may have resectable tumours if they can be down-staged. For patients who are fit enough, definitive chemotherapy and radiotherapy (60-66 Gy) should be offered. The choice of chemotherapeutic regimen is complex and should be managed by a specialist oncology unit.

Preoperative therapy should be followed by surgery. For patients with sufficient pulmonary reserve, lobectomy or pneumonectomy is preferred.[115]

Postoperative chemotherapy is recommended if not received preoperatively.

See local specialist protocol for dosing guidelines.

Primary options

cisplatin

-- AND --

pemetrexed

or

gemcitabine

or

docetaxel

or

vinorelbine

or

etoposide

Secondary options

carboplatin

-- AND --

paclitaxel

or

gemcitabine

or

pemetrexed

Plus – surgery

Back
ONGOING
|
stage IIIB and IIIC
|
resectable with no contralateral mediastinal adenopathy
Plus – 

surgery

Treatment recommended for ALL patients in selected patient group

A small proportion of patients with stage IIIB NSCLC without contralateral lymph node involvement (T4N2M0) may have resectable tumours if they can be down-staged. Patients with stage III NSCLC who are planned for surgical resection should receive either preoperative chemotherapy or chemoradiotherapy.[149][164]​​​

Surgery is ideally performed by a thoracic surgical oncologist.[65][114]​​ For patients with sufficient pulmonary reserve, lobectomy or pneumonectomy is preferred.[115]

Access to the chest is achieved through a thoracotomy or minimally invasive techniques (e.g., video-assisted thoracic surgery); the latter is associated with shorter hospital stay.[116][117]​​ Sampling or dissection of mediastinal lymph nodes is recommended.

Intraoperative and postoperative complications include haemorrhage, infection, cardiac ischaemia, stroke, cardiac arrhythmia, pneumonia, prolonged air leak, chylothorax, pulmonary oedema, and bronchopleural fistula.

The 30-day mortality rate is approximately 1% to 3% after lobectomy and 3% to 7% after pneumonectomy.[120][121] The 30- and 90-day mortality are strongly influenced by age, performance status, and type of operation.[121]

Plus – supportive care

Back
ONGOING
|
stage IIIB and IIIC
|
resectable with no contralateral mediastinal adenopathy
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All patients receive supportive care according to their needs. This will vary according to the intent of treatment (curative or palliative) and the progression of the disease.

For patients undergoing curative treatment, pulmonary rehabilitation may be appropriate, as well as optimisation of medical comorbidities. Patients with increasing symptoms may have a variety of interventions aimed at their individual needs, based on a holistic needs assessment.

A combination of physical interventions such as endobronchial treatment, treatment of pleural and other disease, and psychological and spiritual interventions and help may be indicated.[268]

Preoperative exercise may potentially reduce length of hospital stay and risk of postoperative complications.[129][130]​​​​​​​[131][132] [ Cochrane Clinical Answers logo ] ​​​​​​ Aerobic and resistance exercise during treatment with curative intent is recommended to reduce adverse effects of treatment.[129]

Consider – postoperative chemotherapy

Back
ONGOING
|
stage IIIB and IIIC
|
resectable with no contralateral mediastinal adenopathy
Consider – 

postoperative chemotherapy

Additional treatment recommended for SOME patients in selected patient group

Postoperative chemotherapy is recommended if not received preoperatively. Postoperative chemotherapy is not required if administered preoperatively.

The choice between the many chemotherapeutic regimens is complex and needs to be managed in a specialist oncology unit.

Patients with resected stage III NSCLC who did not receive preoperative systemic therapy should receive platinum-based chemotherapy postoperatively.[162] Specialist advice must be sought.

See local specialist protocol for dosing guidelines.

Primary options

cisplatin

-- AND --

pemetrexed

or

gemcitabine

or

docetaxel

or

vinorelbine

or

etoposide

Secondary options

carboplatin

-- AND --

paclitaxel

or

gemcitabine

or

pemetrexed

1st line – chemoradiotherapy

Back
ONGOING
|
stage IIIB and IIIC
|
unresectable or contralateral mediastinal adenopathy but suitable for radical treatment
1st line – 

chemoradiotherapy

For sufficiently fit patients with inoperable disease, consider concomitant radical chemoradiotherapy followed by durvalumab consolidation, or osimertinib consolidation if EGFR exon 19 deletion or exon 21 L858R mutation is present.[65][171]

Patients who have good performance status should be offered concurrent chemoradiotherapy instead of sequential chemotherapy and radiotherapy.[164] Concurrent chemoradiotherapy is modestly more effective than sequential chemoradiotherapy, but is more toxic.[168][169]​​​ External beam radiotherapy should be given in conjunction with platinum-doublet chemotherapy to a radical dose, where patient fitness and tumour volume and distribution allows.[162][170]

​See local specialist protocol for dosing guidelines.

Primary options

cisplatin

-- AND --

pemetrexed

or

etoposide

OR

carboplatin

-- AND --

pemetrexed

or

paclitaxel

Plus – supportive care

Back
ONGOING
|
stage IIIB and IIIC
|
unresectable or contralateral mediastinal adenopathy but suitable for radical treatment
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All patients receive supportive care according to their needs. This will vary according to the intent of treatment (curative or palliative) and the progression of the disease.

For patients undergoing curative treatment, pulmonary rehabilitation may be appropriate, as well as optimisation of medical comorbidities. Patients with increasing symptoms may have a variety of interventions aimed at their individual needs based on a holistic needs assessment.

A combination of physical interventions such as endobronchial treatment, treatment of pleural and other disease, and psychological and spiritual interventions and help may be indicated.[268]

Consider – durvalumab or osimertinib

Back
ONGOING
|
stage IIIB and IIIC
|
unresectable or contralateral mediastinal adenopathy but suitable for radical treatment
Consider – 

durvalumab or osimertinib

Additional treatment recommended for SOME patients in selected patient group

Durvalumab, an anti-PD-L1 monoclonal antibody, is recommended as consolidation therapy for 1 year for patients with unresectable stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radical radiotherapy.​[65]​​​[164][171][172]​ In Europe, durvalumab use is restricted to PD-L1 positive patients only, as there was no survival benefit in PD-L1 negative patients in an unplanned post hoc analysis.[171][173]

Durvalumab can cause immune-related adverse events, including pneumonitis and colitis.

Osimertinib, a tyrosine kinase inhibitor, is recommended as consolidation therapy until disease progression for patients with unresectable stage III NSCLC and EGFR exon 19 deletion or exon 21 L858R mutation whose disease has not progressed after concurrent platinum-based chemotherapy and radical radiotherapy.[65][174][175]

See local specialist protocol for dosing guidelines.

Primary options

durvalumab

OR

osimertinib

stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy

1st line – supportive care

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
1st line – 

supportive care

All patients receive supportive care according to their needs. This will vary according to the intent of treatment (curative or palliative) and the progression of the disease.

For patients undergoing curative treatment, pulmonary rehabilitation may be appropriate, as well as optimisation of medical comorbidities. Patients with increasing symptoms may have a variety of interventions aimed at their individual needs, based on a holistic needs assessment.

A combination of physical interventions such as endobronchial treatment, treatment of pleural and other disease, and psychological and spiritual interventions and help may be indicated.[268]

One study demonstrated that high-quality palliative care, instituted shortly after the time of diagnosis in parallel to standard care, can lead to improvements in both quality of life and survival in patients with advanced disease.[111] [ Cochrane Clinical Answers logo ]

Patients with ECOG performance status 3-4 (in bed >50% of the time) are treated with best supportive care, unless they are known to harbour activating epidermal growth factor receptor (EGFR) mutations, ALK fusions, ROS proto-oncogene 1 (ROS1) fusions, or the B-Raf proto-oncogene (BRAF) V600E mutation, in which case suitable therapy can be considered.[179]

Consider – treatment of brain metastases

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
Consider – 

treatment of brain metastases

Additional treatment recommended for SOME patients in selected patient group

A large proportion of patients with NSCLC have brain metastases (30% to 50%). Treatment options for limited brain metastases include stereotactic radiosurgery (SRS) alone, or, for selected patients, surgical resection followed by SRS or whole brain radiotherapy.[65][177]

Accumulating evidence supports the use of targeted agents for patients with NSCLC with brain metastases who have EGFR, ALK, ROS1, MET exon 14, or RET oncogenic driver alterations, and also the use of immunotherapy in those with PD-L1 expression.[47][178]​ 

Consider – palliative radiotherapy

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
Consider – 

palliative radiotherapy

Additional treatment recommended for SOME patients in selected patient group

Often effective in palliating symptoms of advanced intrathoracic disease (i.e., haemoptysis, chest pain, shortness of breath), and symptomatic metastatic sites (e.g., bone and diffuse brain metastases).

Plus – EGFR tyrosine kinase inhibitor

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
|
EGFR mutation positive
Plus – 

EGFR tyrosine kinase inhibitor

Treatment recommended for ALL patients in selected patient group

Patients with common sensitising epidermal growth factor receptor (EGFR) mutations (exon 19 deletion or L858R mutation positive) are optimally treated with an EGFR tyrosine kinase inhibitor (TKI). EGFR TKI therapy is associated with improved response rates, improved quality of life, improved progression-free and overall survival.[70][180][181][182]

First-line options for exon 19 deletion or L858R mutation positive disease are osimertinib, osimertinib plus pemetrexed plus cisplatin or carboplatin (non-squamous patients), or amivantamab plus lazertinib.[65][70]​​[183][184]​​​​​​​​[185][186][187][188]​​ Erlotinib (with or without bevacizumab or ramucirumab), afatinib, gefitinib, or dacomitinib are useful in certain circumstances.[65][70][189][190][191]​​​​​​​ [ Cochrane Clinical Answers logo ]

One systematic review reported significantly prolonged progression-free survival among EGFR mutation positive patients who were treated with NSCLC with erlotinib plus bevacizumab compared with erlotinib alone.[192]

Patients who cannot wait for results of EGFR molecular analyses may have to commence chemotherapy, but they should switch to an EGFR TKI as first-line maintenance therapy (or earlier if benefit from chemotherapy is poor), or on relapse in the second-line setting.[180][193][194]

For patients with less common EGFR mutations, such as S768I, L861Q, and G719X, afatinib and osimertinib are the preferred first-line options.[65][195][196]

Subsequent treatment for patients who experience progression on first-line therapy is complex and depends on many factors. Refer to local protocols for further guidance and dosing information.

Primary options

osimertinib

OR

osimertinib

-- AND --

pemetrexed

-- AND --

carboplatin

or

cisplatin

OR

amivantamab

and

lazertinib

OR

afatinib

OR

erlotinib

OR

dacomitinib

OR

gefitinib

OR

erlotinib

and

ramucirumab

OR

erlotinib

and

bevacizumab

Plus – ALK inhibitor

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
|
ALK re-arrangement positive
Plus – 

ALK inhibitor

Treatment recommended for ALL patients in selected patient group

For patients with ALK-positive tumours or who harbour ALK fusions, the following tyrosine kinase inhibitors (TKI) are recommended as initial treatment options: alectinib, brigatinib, or lorlatinib.[65][70]​​​[197][198][199]​​​​​​​​​​​​​​ Ceritinib is an alternative option, while crizotinib may be useful in some situations.[65][188]​​​

Subsequent treatment for patients who experience progression on first-line therapy is complex and depends on many factors. Refer to local protocols for further guidance and dosing information.

Primary options

alectinib

OR

brigatinib

OR

lorlatinib

OR

ceritinib

Secondary options

crizotinib

Plus – ROS1 inhibitor

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
|
ROS 1 re-arrangement positive
Plus – 

ROS1 inhibitor

Treatment recommended for ALL patients in selected patient group

In patients harbouring a ROS proto-oncogene 1 (ROS1) fusion, crizotinib, entrectinib, or repotrectinib are recommended in the first-line setting.[65][70][188]​​[200][201][202]​​​[203]​​​​ Ceritinib is an alternative first-line option for ROS1 rearrangements.[65]​​​​​​​

Subsequent treatment for patients who experience progression on first-line therapy is complex and depends on many factors. Refer to local protocols for further guidance and dosing information.

Primary options

crizotinib

OR

entrectinib

OR

repotrectinib

OR

ceritinib

Plus – BRAF inhibitor

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
|
BRAF V600E mutation positive
Plus – 

BRAF inhibitor

Treatment recommended for ALL patients in selected patient group

Dabrafenib and encorafenib are potent kinase inhibitors of the BRAF-associated kinase that is constitutionally activated through the somatic BRAF V600E mutation. Patients with BRAF V600E mutation-positive tumours should be treated with the synergistic combinations of dabrafenib plus trametinib, or encorafenib plus binimetinib.[65][70][188][204][205]​​

Trametinib and binimetinib are potent TKI of the mitogen-activated protein (MAP) kinase pathway, inhibiting MEK1 and MEK2 kinases, which are activated as a resistance mechanism for BRAF kinase inhibition.

Single-agent vemurafenib (a BRAF kinase inhibitor) or dabrafenib are options if dabrafenib plus trametinib or encorafenib plus binimetinib is not tolerated.[65]​​​​​[206]​​

Subsequent treatment for patients who experience progression on first-line therapy is complex and depends on many factors. Refer to local protocols for further guidance and dosing information.

Primary options

dabrafenib

and

trametinib

OR

encorafenib

and

binimetinib

OR

vemurafenib

OR

dabrafenib

Plus – c-MET inhibitor

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
|
MET exon 14 skipping mutation positive
Plus – 

c-MET inhibitor

Treatment recommended for ALL patients in selected patient group

Capmatinib, crizotinib, and tepotinib are TKI that target mesenchymal-epithelial transition factor (MET).​[65][70][207][208][209][210]

In Europe, capmatinib is recommended for patients with advanced NSCLC who have a MET exon 14 skipping mutation and who have had previous treatment with immunotherapy and/or platinum-based chemotherapy.

Subsequent treatment for patients who experience progression on first-line therapy is complex and depends on many factors. Refer to local protocols for further guidance and dosing information.

Primary options

capmatinib

OR

tepotinib

OR

crizotinib

Plus – RET kinase inhibitor

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
|
RET re-arrangement positive
Plus – 

RET kinase inhibitor

Treatment recommended for ALL patients in selected patient group

RET arrangement positive patients are treated with the RET kinase inhibitors, selpercatinib or pralsetinib.[65]​​[188]​ Another RET kinase inhibitor, cabozantinib, may be useful in certain circumstances.[65][70]​​[212][213]​​​​​​​​​​​​[214][215][216]​​​​​​ 

In an ongoing phase 3 trial, pralsetinib significantly increased the risk of severe and fatal infections including opportunistic infections.[217]​​

A post-marketing review of pralsetinib has reported a number of cases of tuberculosis (mostly extrapulmonary), the majority in TB-endemic regions.[218]​ Patients should be evaluated for active or latent TB and treated before initiating pralsetinib and monitored for signs of infection during treatment.[217][218]​​

Subsequent treatment for patients who experience progression on first-line therapy is complex and depends on many factors. Refer to local protocols for further guidance and dosing information.

Primary options

selpercatinib

OR

pralsetinib

Secondary options

cabozantinib

Plus – KRAS G12C inhibitor

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
|
KRAS G12C mutation positive
Plus – 

KRAS G12C inhibitor

Treatment recommended for ALL patients in selected patient group

Adagrasib and sotorasib are recommended for patients who have received at least one prior systemic therapy, but no previous KRAS G12C-targeted therapy.[65][188]​​​[219][220]​​​[221][222]​​

Subsequent treatment for patients who experience progression on first-line therapy is complex and depends on many factors. Refer to local protocols for further guidance and dosing information.

Primary options

sotorasib

OR

adagrasib

Plus – TRK inhibitor

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
|
NTRK gene fusion positive
Plus – 

TRK inhibitor

Treatment recommended for ALL patients in selected patient group

First-line option is larotrectinib, entrectinib, or repotrectinib.[65][188][202]​​​​[223]​​​[224]​​

Subsequent treatment for patients who experience progression on first-line therapy is complex and depends on many factors. Refer to local protocols for further guidance and dosing information.

Primary options

larotrectinib

OR

entrectinib

OR

repotrectinib

Plus – HER2 inhibitor

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
|
ERBB2 (HER2) mutation positive
Plus – 

HER2 inhibitor

Treatment recommended for ALL patients in selected patient group

ERBB2 (HER2) mutation testing is recommended in all patients with metastatic non-squamous NSCLC. Testing can be considered in patients with metastatic squamous cell carcinoma.[65]

Trastuzumab deruxtecan (a monoclonal antibody targeting ERBB2 [HER2]) is indicated as preferred monotherapy for patients with metastatic NSCLC and ERBB2 (HER2) mutations who have received at least one prior systemic therapy.[65][188]​​[225]​​

Trastuzumab emtansine (a HER2-targeted monoclonal antibody-drug conjugate) is recommended as an alternative option.[65][226]

Platinum-based chemotherapy with or without immunotherapy is first-line therapy for metastatic NSCLC in patients with ERBB2 (HER2) exon 20 insertion mutations.[65]

Subsequent treatment for patients who experience progression on first-line therapy is complex and depends on many factors. Refer to local protocols for further guidance and dosing information. Trastuzumab deruxtecan and trastuzumab emtansine should not be substituted for other trastuzumab-based products.

Primary options

trastuzumab deruxtecan

OR

trastuzumab emtansine

Plus – immune checkpoint inhibitor ± chemotherapy

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and suitable for immunotherapy or targeted therapy
|
no mutation/fusion but suitable for immune checkpoint inhibitor
Plus – 

immune checkpoint inhibitor ± chemotherapy

Treatment recommended for ALL patients in selected patient group

In patients who are negative for the oncogenic driver gene mutations (e.g., ALK, BRAF V600E, EGFR), programmed death-ligand 1 (PD-L1) status assists in decision-making for treatment with immune checkpoint inhibitors. The level of expression of PD-L1 on tumour cells is usually classed as low (PD-L1 <1%), intermediate (PD-L1 ≥1% to 49%), or high (PD-L1 ≥50%). The higher the PD-L1 expression on the cancer cells, the more likely a patient is to respond to immune checkpoint inhibitor therapy.[227]

The immune checkpoint inhibitors for NSCLC include: anti-PD-1 inhibitors (cemiplimab, nivolumab, pembrolizumab); anti-PD-L1 inhibitors (atezolizumab, durvalumab); and anti-CTLA inhibitors (ipilimumab, tremelimumab).

Adverse effects of immunotherapy differ from those of cytotoxic chemotherapy. Guidelines can assist with the recognition and management of immune-mediated toxicities.[228][229]​​​​​​​ The American Heart Association has published a scientific statement regarding potential cardio-oncology drug interactions, including those involving immunomodulatory agents.[230][231]

Immunohistochemistry testing for PD-L1 expression is recommended ideally before first-line treatment in all patients with metastatic NSCLC.[65]​ PD-L1 testing is not required for certain immune checkpoint inhibitor first-line therapy options as they are recommended regardless of PD-L1 expression (e.g., cemiplimab monotherapy, atezolizumab with or without chemotherapy).[65]

Single-agent pembrolizumab, atezolizumab, or cemiplimab are recommended as preferred first-line therapy options for patients with metastatic NSCLC regardless of histology, with PD-L1 ≥50%, and negative test results for oncogenic driver gene mutations.[65][232][233][234][235][236][237][238]

Atezolizumab/hyaluronidase (a subcutaneous formulation of hyaluronidase) may be substituted for atezolizumab.[65]​ Systematic reviews and meta-analyses report immune checkpoint inhibitors improved overall survival and reduced the incidence of treatment-related adverse effects compared with platinum-based chemotherapy.[239][240][241]

An alternative for patients with non-squamous NSCLC (any PD-L1 status) is combination carboplatin plus paclitaxel plus bevacizumab plus atezolizumab quadruple therapy.[65][242]​ However, this presents toxicity challenges. This regimen is approved by the EMA for non-squamous subtype NSCLC and by the FDA in the same population, but excluding patients with sensitising EGFR mutations and ALK fusions.[243]

Atezolizumab plus carboplatin plus nanoparticle albumin-bound (nab)-paclitaxel is recommended as an alternative first-line therapy regardless of PD-L1 levels, in patients with metastatic non-squamous NSCLC with no EGFR mutations or ALK rearrangements.[65]

For any PD-L1 status or histology, cemiplimab plus platinum-based chemotherapy is recommended as an alternative option.[65][238][244]

Nivolumab plus ipilimumab is recommended for first-line therapy for patients with PD-L1 expression ≥50% in certain circumstances (e.g., renal impairment and as an alternative option for PD-L1 <50%). Nivolumab plus ipilimumab can be considered, with or without platinum-based chemotherapy, for squamous or non-sqamous patients.[65][77][245]

Pembrolizumab monotherapy is recommended as first-line therapy for patients with PD-L1 expression ≥1% to 49% when there are contradictions to combination therapy. Pembrolizumab plus chemotherapy is recommended if tolerated by the patient. Pembrolizumab chemotherapy regimens are preferred first-line therapies for squamous patients of any PD-L1 status.[65]

Tremelimumab plus durvalumab plus platinum-based chemotherapy regimens are recommended as first-line therapy regardless of histology or PD-L1 levels.[65][77][238]​ Tremelimumab is approved in combination with durvalumab and platinum-based chemotherapy for the treatment of adult patients with metastatic NSCLC with no sensitising EGFR mutations or ALK genomic tumour aberrations.[238][246]

Subsequent treatment for patients who experience progression on first-line therapy is complex and depends on many factors. Refer to local protocols for further guidance and dosing information.

Primary options

pembrolizumab

OR

atezolizumab

OR

atezolizumab/hyaluronidase

OR

cemiplimab

OR

carboplatin

or

cisplatin

-- AND --

pemetrexed

-- AND --

pembrolizumab

OR

carboplatin

-- AND --

paclitaxel

-- AND --

bevacizumab

-- AND --

atezolizumab

or

atezolizumab/hyaluronidase

OR

carboplatin

-- AND --

paclitaxel nanoparticle albumin-bound

-- AND --

atezolizumab

or

atezolizumab/hyaluronidase

OR

cemiplimab

-- AND --

paclitaxel

or

pemetrexed

-- AND --

carboplatin

or

cisplatin

OR

tremelimumab

and

durvalumab

and

carboplatin

and

paclitaxel nanoparticle albumin-bound

OR

tremelimumab

-- AND --

durvalumab

-- AND --

carboplatin

or

cisplatin

-- AND --

pemetrexed

or

gemcitabine

OR

carboplatin

-- AND --

paclitaxel

or

paclitaxel nanoparticle albumin-bound

-- AND --

pembrolizumab

OR

nivolumab

and

ipilimumab

OR

nivolumab

-- AND --

ipilimumab

-- AND --

pemetrexed

-- AND --

cisplatin

or

carboplatin

OR

nivolumab

and

ipilimumab

and

paclitaxel

and

carboplatin

stage III with tumours too extensive for combination chemoradiotherapy or stage IV and unsuitable for immunotherapy or targeted therapy (ECOG performance 0-2)

1st line – histology-specific platinum doublet chemotherapy

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and unsuitable for immunotherapy or targeted therapy (ECOG performance 0-2)
1st line – 

histology-specific platinum doublet chemotherapy

Histology-specific chemotherapy is recommended first-line for patients (ECOG performance status 0-2) with stage IV squamous and non-squamous subtype NSCLC, and patients who are negative for oncogenic driver gene mutations. Platinum-doublet therapy, as first-line treatment for patients with advanced NSCLC with performance status 2, improved response, progression free survival, and overall survival rates.[247]

Histology-specific chemotherapy (for patients not suitable for immune checkpoint inhibitor therapy) should be considered for those with:[65][70][180][248][249][250][251][252]​​​​[253][254]​​​​​[255]

contraindications to immune checkpoint inhibitors (e.g., solid organ transplant, ongoing corticosteroid requirement, uncontrolled CNS metastases, or active autoimmune disease requiring disease-modifying therapy);

squamous NSCLC; usually a combination of a platinum agent (e.g., cisplatin, carboplatin) with a third-generation cytotoxic agent (e.g., gemcitabine, paclitaxel, docetaxel, vinorelbine). An alternative is to combine carboplatin with nanoparticle albumin bound (nab)-paclitaxel. Between 4 and 6 cycles of a platinum-based regimen typically consisting of two agents is usually recommended. One meta-analysis found no survival benefit with 6 cycles compared with 3 or 4 cycles. Regimens containing pemetrexed or bevacizumab are not recommended for squamous cell carcinoma;

non-squamous NSCLCs; chemotherapy usually consists of a combination of a platinum agent (e.g., cisplatin, carboplatin) with another cytotoxic agent (e.g., pemetrexed, gemcitabine, paclitaxel, docetaxel). For non-squamous tumours (predominantly adenocarcinomas), pemetrexed plus cisplatin combination chemotherapy for up to 6 cycles has demonstrated a superior survival over a non-pemetrexed containing platinum-doublet (e.g., cisplatin plus gemcitabine). Maintenance pemetrexed chemotherapy after 4 cycles of platinum-doublet chemotherapy may be preferred for patients due to improved overall survival and quality of life. Patients who did not receive pemetrexed as part of a platinum-doublet chemotherapy regimen may switch to maintenance pemetrexed after 4 cycles of platinum-doublet chemotherapy. An alternative is to combine platinum-doublet chemotherapy with or without maintenance chemotherapy with the anti-angiogenic monoclonal antibody bevacizumab.

Subsequent treatment for patients who experience progression on first-line therapy is complex and depends on many factors. Refer to local protocols for further guidance and dosing information.

Primary options

bevacizumab

-- AND --

carboplatin

-- AND --

pemetrexed

or

paclitaxel

OR

bevacizumab

and

cisplatin

and

pemetrexed

OR

carboplatin

-- AND --

paclitaxel nanoparticle albumin-bound

or

docetaxel

or

etoposide

or

gemcitabine

or

paclitaxel

or

pemetrexed

OR

cisplatin

-- AND --

docetaxel

or

etoposide

or

gemcitabine

or

paclitaxel

or

pemetrexed

OR

gemcitabine

-- AND --

docetaxel

or

vinorelbine

Plus – supportive care

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and unsuitable for immunotherapy or targeted therapy (ECOG performance 0-2)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All patients receive supportive care according to their needs. This will vary according to the intent of treatment (curative or palliative) and the progression of the disease. For patients undergoing curative treatment, pulmonary rehabilitation may be appropriate, as well as optimisation of medical comorbidities. Patients with increasing symptoms may have a variety of interventions aimed at their individual needs, based on a holistic needs assessment.

A combination of physical interventions such as endobronchial treatment, treatment of pleural and other disease, and psychological and spiritual interventions and help may be indicated.[268]

One study demonstrated that high-quality palliative care, instituted shortly after the time of diagnosis in parallel to standard care, can lead to improvements in both quality of life and survival in patients with advanced disease.[111] [ Cochrane Clinical Answers logo ]

Patients with ECOG performance status 3-4 (in bed >50% of the time) are treated with best supportive care, unless they are known to harbour activating epidermal growth factor receptor (EGFR) mutations, ALK fusions, ROS proto-oncogene 1 (ROS1) fusions, or the B-Raf proto-oncogene (BRAF) V600E mutation, in which case suitable therapy can be considered.[179]

Consider – treatment of brain metastases

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and unsuitable for immunotherapy or targeted therapy (ECOG performance 0-2)
Consider – 

treatment of brain metastases

Additional treatment recommended for SOME patients in selected patient group

A large proportion of patients with NSCLC have brain metastases (30% to 50%). Treatment options for limited brain metastases include stereotactic radiosurgery (SRS) alone, or, for selected patients, surgical resection followed by SRS or whole brain radiotherapy.[65][177]

Accumulating evidence supports the use of targeted agents for patients with NSCLC with brain metastases who have EGFR, ALK, ROS1, MET exon 14, or RET oncogenic driver alterations, and the use of immunotherapy in those with PD-L1 expression.[47][178]​ 

Consider – palliative radiotherapy

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and unsuitable for immunotherapy or targeted therapy (ECOG performance 0-2)
Consider – 

palliative radiotherapy

Additional treatment recommended for SOME patients in selected patient group

Often effective in palliating symptoms of advanced intrathoracic disease (i.e., haemoptysis, chest pain, shortness of breath), and symptomatic metastatic sites (e.g., bone and diffuse brain metastases).

stage III with tumours too extensive for combination chemoradiotherapy or stage IV and unsuitable for immunotherapy or targeted therapy (ECOG performance 3-4)

1st line – supportive care

Back
ONGOING
|
stage III with tumours too extensive for combination chemoradiotherapy or stage IV and unsuitable for immunotherapy or targeted therapy (ECOG performance 3-4)
1st line – 

supportive care

All patients receive supportive care according to their needs. This will vary according to the intent of treatment (curative or palliative) and the progression of the disease.

For patients undergoing curative treatment, pulmonary rehabilitation may be appropriate, as well as optimisation of medical comorbidities. Patients with increasing symptoms may have a variety of interventions aimed at their individual needs, based on a holistic needs assessment.

A combination of physical interventions such as endobronchial treatment, treatment of pleural and other disease, and psychological and spiritual interventions and help may be indicated.[268]

back arrow

Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

Use of this content is subject to our disclaimer