Interstitial Lung Disease Associated With Crizotinib in Patients With Advanced Non-Small Cell Lung Cancer: Independent Review of Four PROFILE Trials

Abstract Introduction Interstitial lung disease (ILD) is a rare, but potentially serious, side effect associated with crizotinib, a tyrosine kinase inhibitor for anaplastic lymphoma kinase-positive ( ALK + ) advanced non–small cell lung cancer. Our objective was to determine the incidence and nature of ILD associated with crizotinib in 4 PROFILE trials ( ClinicalTrials.gov identifiers, NCT00585195 , NCT00932451 , NCT00932893 , and NCT01154140 ). Materials and Methods Grade ≥ 3 respiratory adverse events (AEs) and serious AEs (SAEs) and any grade AEs/SAEs reported as pneumonitis, ILD, or radiation pneumonitis in trials PROFILE 1001, PROFILE 1005, PROFILE 1007, and PROFILE 1014 were evaluated by an expert independent review committee that included a pulmonologist, medical oncologist, and radiologist. Events were designated as disease progression, de novo ILD possibly or probably related to crizotinib, exacerbation or recurrence of pre-existing ILD, concurrent illness, other toxicity not thought to be related to ILD, or inconclusive. Results The independent review committee evaluated 446 events (in 368 of 1669 patients who had received crizotinib therapy). They classified these events as follows: progressive disease, 77; de novo ILD, 20; pre-existing ILD, 3; concurrent illness, 9; other toxicities, 310; and inconclusive, 27. The incidence of de novo ILD was 1.2% overall, 1.3% in whites, and 1.2% overall in Asians, but greater at 3.7% in Japanese patients. The median onset of ILD from the initiation of crizotinib therapy was 23 days (range, 3-763 days). The mortality rate due to ILD was 50%. Survival was improved if crizotinib was discontinued on presentation of ILD (9 of 14 patients) compared with discontinued later or continued (1 of 6 patients). Conclusion ILD associated with crizotinib, although rare, can occur at any time and requires close monitoring.