ALK Mutation Variant May Affect Response to Targeted Agents

Anaplastic lymphoma kinase (ALK)-targeting agents such as crizotinib may work most effectively in non–small-cell lung cancer (NSCLC) patients with ALK variant 1, according to a recent study published in the Journal of Clinical Oncology.

Because the magnitude of response as well as durations of response to tyrosine kinase inhibitors (TKIs) that target ALK varies among ALK-positive NSCLC patients, Tatsuya Yoshida, MD, PhD, of the Aichi Cancer Center Hospital in Japan, and colleagues assessed the efficacy of crizotinib among 35 patients whose ALK variant could be determined and who received the treatment as their initial ALK-TKI.

Ten of the patients received crizotinib as a first-line treatment, while the majority, 18 patients, received the oral drug as a second-line therapy. The median progression-free survival (PFS) among patients in the study was 9.7 months.

Patients with ALK variant 1 were more likely to have disease control compared to patients with other variants (95% vs 63%; P = .0318), and median PFS was significantly longer in patients with variant 1 (11 months vs 4.2 months; P = .05).

The overall response rates were 74% in the variant 1 group and 63% in the non–variant 1 group (P = .7160).

ALK variant 1 (in which exon 13 of EML4 is fused to exon 20 of ALK), makes up approximately one-third of all ALK mutated tumors in NSCLC patients. Other variants include variant 2 (exon 20 of EML4 fused to exon 20 of ALK), which is present in about 10% of patients, and variant 3a/b (exon 6a or 6b of EML4 is fused to exon 20 of ALK), which is present in about 29% of patients.

Among the retrospective cohort, variant 1 was most frequent (19 patients), followed by variant 2 (5 patients), and variant 3a/3b (4 patients). Other variants were present in 7 patients.

Nine patients required dose reductions, but there were no differences between variant 1 and non–variant 1 patients (P = .167).

In their discussion, the authors noted that in the phase I crizotinib trial, there was no difference in response between those with ALK variant 1 (13 patients) and those with other variants (7 patients).

According to the authors, the treatment strategy for ALK-positive NSCLC “should be determined on the basis of the ALK variant status of the patient,” but that prospective studies are needed to validate the association between ALK variants and agents that target the mutation.