Emerging treatments in ALK-positive NSCLC: new options, but also new challenges
Treatment with the ALK tyrosine kinase inhibitor (TKI) crizotinib has been established as a standard first-line option in patients with ALK-rearranged advanced NSCLC. Before the advent of crizotinib, a platinum–pemetrexed doublet followed by pemetrexed maintenance was standard of care in non-squamous NSCLC. However, after an initial response to crizotinib, acquired resistance invariably develops due to multiple mechanisms, which can include secondary mutations in the ALK tyrosine kinase domain. A range of newer-generation ALK inhibitors are now available or are currently under development. These include ceritinib, alectinib, brigatinib, ensartinib, entrectinib and lorlatinib. All of these have increased ALK-inhibition potencies and activities against the mutations that confer resistance to crizotinib. Also, many of these show improved CNS penetration over crizotinib.