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Advanced/metastatic non-small cell lung cancer in focus

This section considers advances made in the treatment of advanced/metastatic non-small cell lung cancer (NSCLC) in recent years and how these changes may affect treatment decisions in the clinical management of this disease.

Despite the recent increase in the number of treatment options, lung cancer remains the most common cause of cancer deaths worldwide for men, and the second most common for women.1 It is estimated that in 2020 there will be 2.3 million new lung cancer cases and 2.0 million resulting deaths worldwide.2 Although patient outcomes are better if the disease is diagnosed in its early stages, the 5-year survival rate for metastatic disease remains less than 5%.3 NSCLC is the most common tumour type, accounting for approximately 85% of lung cancers.3

What recent advances have been made in the treatment of advanced/metastatic non-small cell lung cancer (NSCLC)?

One of the most significant advances in the treatment of advanced/metastatic NSCLC has been the introduction of personalised medicine through the identification and targeting of driver mutations, primarily epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangement,4,5 while the rarer ROS-1 rearrangement is also targetable.6 RET rearrangement, found in 1–2% of NSCLC tumours of adenocarcinoma histology, is also a potential target.5 Tyrosine kinase inhibitors (TKIs) that target EGFR mutations or ALK rearrangement are considered the standard of care in the first-line treatment of patients whose tumours bear these mutations, which occur most frequently in non-squamous NSCLC.6 As such, EGFR and ALK testing is recommended for all patients with advanced non-squamous NSCLC.6  Acquired resistance to EGFR TKIs has been reported, of which the most common mechanism is T790M mutation.4

For patients with NSCLC tumours that do not exhibit driver mutations, recent advances in various treatment lines have included agents that inhibit angiogenesis and immunotherapies targeting the programmed cell death receptor 1 (PD-1) or programmed cell death ligand 1 (PD-L1).6

What have these recent advances meant for patients with non-small cell lung cancer (NSCLC)?

The number of treatment options for patients with advanced/metastatic NSCLC has increased, and patients may now receive multiple lines of therapy at this stage of disease.7

With the increasing number of treatment options has come the need to tailor treatment to ensure that the best therapy is chosen for each individual patient at the right time.8 As well as the genetic profile of the tumour, many other factors need to be considered, such as the patient’s age, his or her overall health status, the presence or absence of brain metastases, and the patient’s preference. An increasing amount of evidence in subgroups of patients with NSCLC, such as elderly patients6,9,10 and patients with brain metastases,11-13 is now available to support clinical decision-making.

With regard to a patient’s overall health status, for those with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2, chemotherapy increases survival and improves health-related quality of life compared with best supportive care (BSC).6 Poor ECOG PS (3 or 4) can be caused by high tumour burden and may improve with treatment, or be a result of comorbidities.6 For these patients, BSC is the preferred first-line option.

Despite the advances in treatment options and the fact that treatment can to some extent be tailored to the individual patient in advanced/metastatic NSCLC, there is still much room for improvement. Although EGFR- and ALK-targeted therapies are effective, a proportion of patients with adenocarcinoma and the large majority of patients with squamous disease do not have tumours that bear these driver mutations.6 In addition, while immunotherapies have been hailed as practice changing, not all tumours respond to this class of treatment, and data are still too immature to ascertain their impact on long-term survival.14 Further research is needed to clearly identify which patient subgroups will benefit most from novel treatments such as immunotherapies.

Which are the key factors in clinical decision-making in non-small cell lung cancer (NSCLC)?

Histology and biomarkers

Decisions on the treatment of patients with NSCLC should be based on tumour histology and the presence or absence of key genetic alterations.6 EGFR mutations are found in 10–15% of lung cancers in Caucasian patients and 30–40% of East Asian patients.4 Most NSCLC tumours with these mutations are of adenocarcinoma histology.6 ALK rearrangement occurs in 2–7% of NSCLC tumours and is more common in younger patients, never or light smokers, and adenocarcinoma NSCLC.15 Although EGFR testing is required for patients with adenocarcinoma, it is not considered beneficial for patients with squamous cell carcinoma of the lung unless they are never smokers or former light smokers.6 Similarly, testing for ALK rearrangements is only recommended for patients with non-squamous NSCLC.6 Testing for ROS1 rearrangements is recommended based upon lower-level evidence.16

With regard to immunotherapy, since not all patients respond to PD-1/PD-L1 inhibitors, the use of a validated predictive biomarker would be invaluable to aid treatment decisions.17 A universal PD-L1 immunohistochemistry (IHC) test for selecting patients for PD-1/PD-L1 therapy is not yet available,3 and negative test results are not always considered to be sufficient for excluding patients from immunotherapies.6 Levels of PD-L1 expression associated with clinical benefit vary amongst different immune checkpoint inhibitors that have been approved, and within different treatment lines; different IHC antibody clones, staining protocols, scoring systems and cutoff values have been used.3 It is possible that the timing and frequency of measurements may also be important – PD‑L1 expression may vary over time due to tumours’ adapting their immune response, and the level of PD‑L1 expressed at tissue sampling may not be indicative of PD‑L1 levels as the disease progresses.16 Questions remain on how to select patients who would derive the most benefit from immunotherapy and how to accurately and consistently assess response.3

Importantly, further research on biomarkers will also help clinicians establish the optimal sequence of therapies in the advanced/metastatic setting.

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*Afatinib is approved in more than 80 markets including the EU, Japan, Taiwan, and Canada under the brand name GIOTRIF®, in the US under the brand name GILOTRIF® and in India under the brand name Xovoltib®; for the full list please see here. Registration conditions differ internationally; please refer to locally approved prescribing information.