Guideline: Patients with advanced NSCLC harbouring an ALK rearrangement should receive an ALK TKI at some point in their systemic therapy.

Level of Evidence: I

A small proportion of NSCLC have a novel fusion oncogene called EML4-ALK. The EML4 portion mediates ligand-independent dimerization and/or oligomerization of the tyrosine kinase containing ALK portion of this chimeric protein resulting in constitutive TK activity-a potent oncogenic driver of these cancers. Small molecule inhibitors of the ALK tyrosine kinase have been found to inhibit the growth of these cancers in cell lines and animal models. The EML4-ALK fusion protein, which almost always occurs independent of EGFR and KRAS mutations, can be detected by IHC, FISH and RT-PCR.

EML4-ALK rearrangements (ALKr+) occur in about 4% of unselected cases.¹³ Clinicopathologic features that increase the likelihood of finding an ALK-fusion oncogene include: younger age, light/never smoking status, adenocarcinoma histology.¹⁷

Crizotinib is a small molecule TKI originally developed to inhibit c-MET but was also found to be a potent inhibitor of the ALK tyrosine kinase. This drug has been shown to induce significant tumour responses in patients whose cancers are ALKr+ in nonrandomized studies.^14-15

A phase III clinical trial demonstrated the value of crizotinib over appropriate single agent chemotherapy in 347 patients with ALKr+ NSCLC who had received prior platin-doublet chemotherapy. The primary endpoint of median PFS was statistically superior for the crizotinib (7.7 months versus 3.0 months with pemetrexed or docetaxel). 112 patients (64%) who received initial chemotherapy crossed over to crizotinib and subsequently the median OS was similar between the 2 groups (20.3 months for the crizotinib and 22 months for the chemotherapy arms). Symptom and quality of life improvements were greater on the crizotinib arm.¹⁶ This study would support the use of crizotinib in the second or third line setting in ALKr+ patients previously receiving platin-based doublet chemotherapy with or without second line chemotherapy.

There are two phase III trials exploring the value of crizotinib over first line platin doublet chemotherapy in ALKr+ NSCLC. At least one of these studies may have results available by ASCO 2014. Until then, the current evidence best supports crizotinib in the second or third line setting.

Patients with a known ALK rearrangement and no EGFR mutation do not likely respond to EGFR TKIs and thus erlotinib should not be used in this setting.¹⁷