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J.R. Scranton

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    MINI 31 - ALK (ID 158)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI31.06 - Crizotinib and Interstitial Lung Disease: Systematic Review of Four Clinical Trials (ID 1580)

      18:30 - 20:00  |  Author(s): J.R. Scranton

      • Abstract
      • Presentation
      • Slides

      Tyrosine kinase inhibitors (TKIs) have been associated with the development of a rare but serious and potentially fatal lung injury syndrome referred to as drug-induced interstitial lung disease (ILD). This has been best characterized for the epidermal growth factor receptor (EGFR) TKIs, with a typical presentation of delayed but rapidly progressive dyspnea leading to respiratory failure and death in up to one third of cases. While case reports of crizotinib-associated ILD have been published, little is known regarding the incidence, clinical characteristics, and mortality of crizotinib-associated ILD. In an effort to better understand this adverse event (AE), we performed a systematic review of respiratory-related events in the four largest clinical trials with crizotinib.

      An independent three-person panel composed of a pulmonologist, radiologist, and oncologist, none of whom were associated with any of the clinical studies, was convened to analyze respiratory AEs of grade ≥3 and any-grade AEs reported by the investigator as pneumonitis, ILD, or radiation pneumonitis in four crizotinib studies (PROFILE 1001, 1005, 1007, and 1014). After review by each panel member individually followed by consensus review, the events were classified either as disease progression or true respiratory AEs. Respiratory AEs were then further sub-classified as due to: 1) de novo ILD, 2) exacerbation or recurrence of pre-existing ILD, 3) concurrent illness (recurrence or progression of pre-existing condition), or 4) other toxicity not thought to be related to ILD (e.g. bacterial pneumonia).

      There were a total of 1,669 patients in the four studies, among whom 446 events in 368 patients met the criteria for further analysis. Of these 446 events, 77 were attributed to progressive disease, 310 to other toxicity not thought related to ILD, 20 to de-novo ILD, 9 to concurrent illness, and 3 to exacerbation of underlying ILD. 27 cases (25 patients) were felt to have insufficient data to draw firm conclusions. Overall, the incidence of crizotinib-associated ILD was 1.2% (20/1,644) across the four studies, with no difference in incidence seen between Asian and Caucasian populations. The mean onset of ILD was 82 days. The mortality rate for patients identified with crizotinib-associated ILD was 50% (10/20). There was a trend towards improved survival if crizotinib was stopped rather than continued on presentation (64% [9/14] vs. 17% [1/6], P=0.065). Early administration of systemic corticosteroids did not seem to affect survival.

      This report represents the largest systematic review of TKI-associated ILD that has been performed by an independent multidisciplinary review panel. Crizotinib-associated ILD occurred in approximately 1.2% of patients who were administered crizotinib and displayed a characteristic pattern of delayed but rapidly progressive dyspnea and hypoxemia with a mortality of 50% (10/20). This pattern is similar to that seen with the EGFR TKIs, but appears to have a more delayed onset and a higher mortality rate. In contrast to EGFR TKI-associated ILD, which has a markedly higher incidence in the Asian population, there appears to be no such predilection for crizotinib-induced ILD. Immediate cessation of crizotinib may improve survival.

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