Clinical Experience With Crizotinib in Patients With Advanced <i>ALK</i>-Rearranged Non–Small-Cell Lung Cancer and Brain Metastases

TLDR

Crizotinib, an oral ALK‑kinase inhibitor approved for ALK‑rearranged non‑small‑cell lung cancer, had not previously been studied for efficacy in patients with brain metastases. This study aimed to evaluate the clinical benefits of crizotinib in patients with asymptomatic brain metastases enrolled in trials PROFILE 1005 and 1007. Patients with asymptomatic brain metastases were retrospectively analyzed, with tumor assessments every six weeks by RECIST 1.1, and baseline data showed 31 % had such metastases, 109 had none prior and 166 had prior radiotherapy. Crizotinib produced systemic and intracranial disease control rates of 63 %/56 % in untreated and 65 %/62 % in previously treated patients, median intracranial time to progression of 7 months and 13.2 months respectively, a 20 % incidence of new brain metastases in patients without baseline lesions, and frequent progression of existing or new intracranial lesions as a resistance mechanism.

Abstract

Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied.Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1).At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases.Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.