Abstract
Non-small-cell lung cancer is still considered a difficult disease to manage because of its aggressiveness and resistance to common therapies. Chemotherapy remains the gold standard in nearly 80% of lung cancers, but clinical outcomes are discouraging, and the impact on median overall survival (OS) barely reaches 12 months.At the end of the last century, the discovery of oncogene-driven tumours completely changed the therapeutic landscape in lung cancers, harbouring specific gene mutations/translocations. Epidermal growth factors receptor (EGFR) common mutations first and anaplastic lymphoma kinase (ALK) translocations later led new insights in lung cancer biology knowledge. The use of specific tyrosine kinases inhibitors overturned the biological behaviour of EGFR mutation positive tumours and became a preclinical model to understand the heterogeneity of lung cancers and the mechanisms of drug resistance. In this review, we summarise the employment of targeted agents against the most representative biomolecular alterations and provide some criticisms of the therapeutic strategies.
Highlights
Lung cancer is still considered an aggressive disease and worldwide as a big-killer disease
This trial demonstrated a statistically significant improvement of both median progression-free survival (PFS) (16.8 months versus 6.9 months, HR 0.25 [0.16–0.39]; p < 0.0001) and median overall survival (OS) (31.4 versus 20.6 months, HR 0.48 [0.27–0.84]; p = 0.0092), in patients with Epidermal growth factors receptor (EGFR) activating mutations treated with chemotherapy plus erlotinib followed by erlotinib until progression, compared to those treated with chemotherapy plus placebo followed by erlotinib until progression [19]
It is undebatable that testing the ‘mutational status’ of lung cancer could be useful in most patients suffering from inoperable non-small-cell lung cancer (NSCLC), and it should be done at first diagnosis in order to put together the best therapeutic strategy
Summary
Lung cancer is still considered an aggressive disease and worldwide as a big-killer disease. A phase III trial comparing dacomitinib to gefitinib in first-line patients with EGFR-activating mutations is ongoing (ARCHER 1050) Awaiting these results, clinicians should consider higher incidence of adverse events, mostly diarrhoea, rash, and mucositis, associated with second-generation EGFR TKIs, probably because of inhibition of wild-type EGFR. In the population with CNS involvement, 75% of patients achieved a prolonged objective response Thanks to these latter two phase II studies, the FDA approved alectinib for advanced ALK positive NSCLC patients resistant or intolerant to crizotinib [82]. Among 13 patients with a CNS involvement, 69% had an objective response Given these promising results, this drug is studied in a phase II trial (ALTA) in advanced crizotinib-pretreated ALK positive NSCLC population. Generation sequencing techniques applied to tissue or plasma sample may guide clinicians to choose the right generation ALK TKI to specific resistance mutation (Figure 5)
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