The development of ALK inhibitors for non–small cell lung cancer (NSCLC) is rapidly progressing, yet acquired treatment resistance remains a key issue for a majority of patients.1

ALK as a Target in NSCLC

ALK gene fusions in NSCLC were first reported in 2007, and it was since determined that 3% to 7% of NSCLC tumors harbor an ALK rearrangement. These aberrations occur more frequently among younger patients with adenocarcinoma histology who never smoked or were low-level smokers.

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The EML4-ALK fusion is the most common, though all fusions contain the preserved ALK tyrosine kinase domain, an N-terminal promoter from the partner gene, and an N-terminal oligomerization domain of the partner, resulting in constitutive activation. ALK fusion proteins promote signaling pathways important for cell growth and survival.

Four years since the discovery of ALK fusions in NSCLC, the US Food and Drug Administration (FDA) approved the first ALK inhibitor, crizotinib. Second- and third-generation ALK inhibitors were since developed.

First-generation ALK Inhibitors

Crizotinib is a first-generation ALK inhibitor, which also targets MET and ROS1, that can result in impressive response rates compared with chemotherapy. In 2 phase 3 trials, crizotinib yielded an overall response rate (ORR) of 65% and 74% compared with 20% with pemetrexed or docetaxel (P < .001), or 45% with pemetrexed plus cisplatin or carboplatin (P < .001), respectively.

Progression-free survival (PFS) was also significantly improved in both trials, at 7.7 months and 10.9 months with crizotinib compared with 3.0 months with pemetrexed or docetaxel (P < .001) or 7.0 months with pemetrexed plus cisplatin or carboplatin (P < .001).

Overall survival (OS), however, was not significantly different with crizotinib compared with chemotherapy in either trial. This could be because of crossover after progression during chemotherapy, or due to acquired resistance.

Crizotinib also lacks efficacy against central nervous system (CNS) metastases, and 20% of patients will develop CNS metastases during crizotinib treatment. Another issue is serious adverse events (AEs) not reported in initial trials, including erythema multiforme, acute interstitial lung disease, renal polycytosis, contact esophagitis, decreased glomerular filtration rate, and hypersensitivity.2

A major challenge with crizotinib, as with all targeted therapies, is treatment resistance. Secondary resistance to crizotinib typically occurs within 1 year due to several known mechanisms. ALK gene amplifications or mutations within the kinase domain can occur, resulting in continued activity despite ALK inhibition. Activation of other components of the signaling pathways, such as EGFR, HSP90, PI3K/AKT/mTOR, can also overcome ALK inhibition by providing the tumor alternate oncogenic drivers.2