Correlation of extent of ALK FISH positivity and crizotinib efficacy in three prospective studies of ALK-positive patients with non-small cell lung cancer

Abstract

Background

In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)—particularly near the cutoff defining positive status—and clinical outcomes have been limited by small sample sizes.

Patients and methods

Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cutoff of ≥ 15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively.

Results

Of 11 081 screened patients, 1958 (18%) were ALK-positive, 7512 (68%) were ALK-negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15–19% ALK-positive cells; of ALK-negative patients, 2% had 10 − 14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n=700/1246), 55% (n=725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15–19% ALK-positive cells (n=25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P=0.054; PFS, P=0.17).

Conclusions

Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cutoff. The small number of patients with scores near the cutoff warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.