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

Clin Lung Cancer. 2017 Sep;18(5):472-479. doi: 10.1016/j.cllc.2017.03.004. Epub 2017 Mar 14.


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 ( 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.

Keywords: Adverse event; Anaplastic lymphoma kinase; Independent review; Pneumonitis; Tyrosine kinase inhibitor.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects*
  • Asian People / ethnology
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Crizotinib
  • Female
  • Humans
  • Incidence
  • Japan / ethnology
  • Lung Diseases, Interstitial / chemically induced*
  • Lung Diseases, Interstitial / epidemiology
  • Lung Diseases, Interstitial / mortality
  • Lung Neoplasms / drug therapy*
  • Male
  • Middle Aged
  • Pyrazoles / adverse effects*
  • Pyridines / adverse effects*
  • Randomized Controlled Trials as Topic
  • Retrospective Studies
  • White People / ethnology
  • Young Adult


  • Antineoplastic Agents
  • Pyrazoles
  • Pyridines
  • Crizotinib

Associated data