Expanding anaplastic lymphoma kinase therapeutic indication to early stage non-small cell lung cancer

Fabrizio Tabbò, Silvia Novello


Oncogene-addicted non-small cell lung cancer (NSCLC) patients have been witnessing overwhelming therapeutic improvements, especially in advanced disease management, due to the advent of more potent tyrosine kinase inhibitors (TKIs). However, the concrete chance to cure anaplastic lymphoma kinase (ALK)-rearranged patients remains prerogative of surgical and peri-operative medical approaches to early disease stage. Clinical investigations in the adjuvant setting of genotype-restricted lung cancers (i.e., EGFR+, ALK+, etc.) are under-represented owing to the need of large patients’ enrollment and solid overall survival (OS) data, which solely can show real long-term impact of these therapeutic interventions. Current available radiological and molecular technologies will widely increase the number of surgical early stage patients, including ALK+, spurring the development of rational approaches aimed to prevent disease recurrence and prolong patients’ survival. Ongoing clinical trials, evaluating crizotinib and alectinib as adjuvant treatments, will gauge the real impact of TKIs in terms of patients’ disease free survival (DFS) and OS; other peri-operative investigations (e.g., neo-adjuvant strategies) will add information about ALK inhibitors’ tumor growth restraint capacities and early adaptation mechanisms to ALK targeting. Nevertheless, multiple questions are and will remain unanswered: if should be treated indifferently all ALK+ patients or, alternatively, should be stratified in different risk groups based on the detectable residual disease [i.e., minimal residual disease (MRD) after surgery]; whether ALK inhibitors administration could facilitate the accumulations of persister cells driving resistance mechanisms to targeted therapies; if alternative strategies, as combined treatments targeting different molecular hubs, could enhance disease control and cancer eradication.