ESMO E-Learning: Important Pathways to Target in (Advanced) NSCLC: A Focus on ALK Inhibition in Non-Small-Cell Lung Cancer (NSCLC)

This E-Learning module is an update of a previous module focusing on anaplastic lymphoma kinase (ALK) inhibition and implications for the treatment of patients with advanced non-small cell lung cancer (NSCLC). The authors elaborate on the diagnosis and ALK testing, prognostic impact of ALK rearrangement, and detail the results of clinical trials with crizotinib, a first in class ALK inhibitor, patterns of progression and mechanisms of resistance to crizotinib. They summarise the results from the clinical trials with next-generation ALK inhibitors, ceritinib, alectinib, brigatinib and lorlatinib Furthermore, they elaborate brain efficacy of ALK inhibitors and other upfront and as next-line treatment options discussing the present situation  in terms of optimal sequence determination.

ALK rearrangement frequency is reported in 2-5% of all patients with NSCLC, and 33% in EGFR negative never smokers. At least 28 different EML4-ALK variants have been identified in NSCLC, but clinical significance of each variant is unknown. Patients with ALK-positive disease tend to be younger, never-light smokers, presenting with adenocarcinoma, adenosquamous carcinoma, and rarely squamous cell carcinoma (SCC). Pleural and pericardial effusion and brain metastases are more common among patients with ALK-positive tumours.

ALK testing should be carried out simultaneously with EGFR at diagnosis of advanced NSCLC. ALK mutation testing is recommended in all patients with advanced NSCLC of a non-squamous subtype, regardless of smoking history. Testing is not recommended in patients with an unequivocal diagnosis of SCC, except in never/former light smokers.

This E-Learning module elaborates clinical characteristics of patients with ALK-positive NSCLC and provides evidence from clinical trials with ALK inhibitors. Crizotinib was the first in class ALK inhibitor registered for the treatment of patients with ALK-positive NSCLC. By elaborating the mechanisms of resistance and providing an overview of clinical trials with next-generation ALK inhibitors, the authors underline the intense drug developments in that setting and emphasize on the need for establishing the most appropriate treatment sequence.