Approach

Treatment regimens vary depending on the stage of cancer. Stage I to IIIA lung cancer is potentially curable. For patients with stage IIIB or IV disease, the goal of treatment is to reverse, delay, or prevent symptoms due to the local or metastatic tumour as well as to prolong survival. With all treatments, the fitness of the patient can be a major factor in the decision-making process.

Care of patients with lung cancer should be undertaken by a multi-disciplinary team in a specialist oncology centre. Good palliative and supportive care is important at all stages of non-small cell lung cancer (NSCLC) and has been shown to confer advantages of both quality of life and survival in advanced disease.[111][112]​​​ [ Cochrane Clinical Answers logo ]

Early-stage NSCLC (stage I-II), suitable for 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] 

Early-stage NSCLC (stage I-II), suitable for surgery: preoperative (neoadjuvant) treatment

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 programmed death-ligand 1 (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 epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.[65][125]

Testing for PD-L1 status, 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]

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]

Early-stage NSCLC (stage I-II), suitable for surgery: preoperative exercise

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]

Early-stage NSCLC (stage I-II), suitable for surgery: postoperative (adjuvant) treatment

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-PD-L1 monoclonal antibodies or tyrosine kinase inhibitor (TKI) therapy.

  • 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]

Early-stage NSCLC (stage I-II), suitable for surgery: postoperative radiotherapy

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, 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.

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]​ 

Early-stage NSCLC (stage I-II), not suitable for surgery: candidate for non-surgical treatment with curative intent

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]

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]

Stage IIIA NSCLC, suitable for surgery

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, is often necessary in older patients or those with comorbidities, but it 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 the lymph nodes is strongly recommended. 

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]

Stage IIIA NSCLC, suitable for surgery: preoperative (neoadjuvant) treatment

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]

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] 

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

Stage IIIA NSCLC, suitable for surgery: postoperative (adjuvant) treatment

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:[65][77][123][139]​​​​​​​​[142][143][144]​​[145][146][147][148]​​​[149]

  • Anti-PD-1 monoclonal antibodies (pembrolizumab, nivolumab) as postoperative monotherapy after tumour resection and platinum-based chemotherapy for adult patients with stage IIIA NSCLC.

  • Anti-PD-L1 monoclonal antibodies (atezolizumab, durvalumab) as postoperative monotherapy after tumour resection and platinum-based chemotherapy for adult patients with stage IIIA NSCLC.

  • Osimertinib (TKI) 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.

  • Alectinib (TKI) as postoperative therapy after tumour resection in adult patients with stage IIIA ALK-positive NSCLC.

Stage IIIA NSCLC, not suitable for surgery: candidate for treatment with curative intent

Patients who have good performance status but are medically or surgically inoperable should be offered concurrent chemoradiation instead of sequential chemotherapy and radiotherapy.[164] Concurrent chemoradiation is modestly more effective than sequential chemoradiation, 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]

Patients not suitable for concurrent chemoradiation, but who are candidates for chemotherapy, should be offered sequential chemotherapy and radiotherapy over radiation alone.

Patients receiving chemoradiation should be treated to 60 Gy (higher doses of 60-70 Gy in selected patients).

Stage IIIA NSCLC, not suitable for surgery: durvalumab

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]

Stage IIIA NSCLC, not suitable for surgery: osimertinib

Osimertinib 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]

Stage IIIB and IIIC NSCLC

The management of stage IIIB and IIIC NSCLC is similar to stage IV disease. Most of these patients 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.

For sufficiently fit patients with inoperable disease consider:[65][171]

  • concomitant radical chemoradiotherapy followed by durvalumab consolidation, or

  • osimertinib consolidation if EGFR exon 19 deletion or exon 21 L858R mutation is present.

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease)

These patients are generally treated with palliative intent, and according to histological NSCLC subtype and biomarker status (molecular genotype and PD-L1 status).

The following tests are recommended, or should be considered, in patients with non-squamous and selected squamous subtype NSCLC (e.g., especially never smokers):[65][70][77]​​​​​​​​​​​​​​[176]​​

  • EGFR mutations

  • ALK gene rearrangements

  • ROS proto-oncogene 1 (ROS1) gene fusions

  • B-Raf proto-oncogene (BRAF) point mutations

  • Neurotrophin tyrosine receptor kinase (NTRK) gene fusions

  • Mesenchymal-epithelial transition factor (MET) exon 14 (METex14) skipping mutations

  • Re-arranged during transfection (RET) gene mutations

  • KRAS proto-oncogene (KRAS) point mutations

  • Erb-B2 receptor tyrosine kinase 2 (ERBB2 [HER2]) gene mutations

  • PD-L1 expression

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): brain metastases

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]

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): palliative radiotherapy and supportive care

Radiotherapy is 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).

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 EGFR mutations, ALK fusions, ROS1 fusions, or the BRAF V600E mutation, in which case suitable therapy can be considered.[179]

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): common sensitising EGFR mutation positive

Patients with common sensitising 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:[65][70]​​[183][184]​​[185]​​​​[186][187][188]​​​

  • osimertinib

  • osimertinib plus pemetrexed plus cisplatin or carboplatin (non-squamous patients), or

  • amivantamab plus lazertinib.​​​​​​​​​​

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 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]

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): ALK rearrangement positive

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

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): ROS1 rearrangement positive

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

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): BRAF V600E mutation positive

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 tyrosine kinase inhibitors 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]​​

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): MET exon 14 skipping mutation positive

Capmatinib, crizotinib, and tepotinib are tyrosine kinase inhibitors 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.

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): RET rearrangement positive

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][211][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]

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): KRAS G12C mutation positive

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]​​

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): NTRK gene fusion positive

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

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): Erb-B2 receptor tyrosine kinase 2 (ERBB2 [HER2]) gene mutation positive

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 recommended 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 for metastatic NSCLC in patients with ERBB2 (HER2) exon 20 insertion mutations.[65]

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): candidate for immune checkpoint inhibitor therapy

In patients who are negative for the oncogenic driver gene mutations (e.g., ALK, BRAF V600E, EGFR), 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-cytotoxic T-lymphocyte-associated antigen-4 (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 found that 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 a combination of carboplatin plus paclitaxel plus bevacizumab plus atezolizumab (quadruple therapy).[65][242]​​​ However, this presents toxicity challenges. This regimen is approved in Europe for non-squamous subtype NSCLC and in the US 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 and non-squamous 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 cell carcinoma 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]

Stage III (unsuitable for radical therapy) and IV NSCLC (metastatic disease): patients not suitable for immune checkpoint inhibitor therapy

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:

  • Contraindications to immune checkpoint inhibitors (e.g., solid organ transplant, ongoing corticosteroid requirement, uncontrolled CNS metastases, or active autoimmune disease requiring disease-modifying therapy).[248]

  • Squamous-subtype NSCLC; usually a combination of a platinum agent (e.g., cisplatin, carboplatin) with a third-generation cytotoxic agent (e.g., gemcitabine, paclitaxel, docetaxel, vinorelbine).[249][250]​ An alternative is to combine carboplatin with 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.[251]​ Regimens containing pemetrexed or bevacizumab are not recommended for squamous cell carcinoma.[65]

  • 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).[250][252]​​ Maintenance pemetrexed chemotherapy after 4 cycles of platinum-doublet chemotherapy may be preferred for patients due to improved overall survival and quality of life.[65]​​[253][254]​​ 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.[253] An alternative is to combine platinum-doublet chemotherapy with or without maintenance chemotherapy with the anti-angiogenic monoclonal antibody bevacizumab.[70][180][255]​​​

Failure of radical treatment at stage III or failure of first-line treatment for stage IV disease

Recurrence after definitive (radical) lung cancer treatment typically leads to poor prognosis. Relapsed therapy aims for palliative survival, but long-term survival is now possible with immune checkpoint inhibitors and genomic medicine. Patients should be evaluated based on new presentations and treated radically if possible.

Immune checkpoint inhibitor monotherapy (if not given as first-line treatment) is the most effective intervention for relapsed NSCLC. Long-term control in small subsets of patients is observed.

In squamous sub-type NSCLC, nivolumab demonstrated a 41% relative survival benefit (related to tumour PD-L1 expression level) compared with docetaxel monotherapy.[256][257]​

In non-squamous NSCLC, nivolumab was associated with a relative 27% survival benefit compared with docetaxel monotherapy, with magnitude of benefit increasing with the extent of tumour PD-L1 expression.[257][258]​ Five-year pooled trial data showed overall survival rates of 13.4% for nivolumab versus 2.6% for docetaxel; progression free survival rates were 8.0% for nivolumab versus 0% for docetaxel.[259]

Pembrolizumab is recommended for relapsed NSCLC (any histology). In patients with previously treated NSCLC non-small-cell lung cancer with PD-L1 expression, pembrolizumab prolonged survival compared with docetaxel.[260] In this setting, pembrolizumab is approved only in patients with PD-L1 ≥1%.

Atezolizumab, a PD-L1 inhibitor, improved overall survival compared with docetaxel in previously treated non-small-cell lung cancer.[261] Superior activity was observed regardless of PD-L1 status. However, in this study, PD-L1 status was determined using the SP142 anti-PDL1 assay, which tends to under-report PD-L1 expression.[76][261]​​

For patients without oncogenic driver mutations who relapse after first-line palliative systemic therapy, cytotoxic chemotherapy may be considered. It is superior to best supportive care, and is indicated in patients with good performance status (ECOG PS 0-2).[180] The addition of nintedanib, a triple angiokinase TKI, to standard docetaxel chemotherapy in adenocarcinomas modestly improves survival by approximately 2 months, potentially more so in patients progressing on, or relapsing shortly after, platinum-doublet chemotherapy.[262] Weekly paclitaxel plus bevacizumab as a second- or third-line option improved progression free survival compared with docetaxel.[263] The VEGFR-R2-directed monoclonal antibody improved survival by 1.4 months in combination with docetaxel in NSCLC not restricted to histological subtype.[264]

For patients that receive first-line chemotherapy and are subsequently identified to be ALK-positive, crizotinib can be considered in the second-line (relapsed) setting where it is markedly superior to second-line docetaxel or pemetrexed chemotherapy with improved responses, quality of life, and progression-free survival.[265]

Insertion of intercostal drain, Seldinger technique: animated demonstration
Insertion of intercostal drain, Seldinger technique: animated demonstration

How to insert an intercostal (chest) drain using the Seldinger technique. Video demonstrates: how to identify a safe site for insertion; use of an introducer needle, guidewire, dilators, and intercostal drain; how to confirm drain position; and post-procedure care.

Insertion of intercostal drain, open technique: animated demonstration
Insertion of intercostal drain, open technique: animated demonstration

How to insert an intercostal (chest) drain using the open technique. Video demonstrates: tube selection, how to identify the site for drain insertion, how to make the correct incision, how to insert the intercostal drain, how to secure the drain, and post-procedure care.

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