Interstitial Lung Disease Onset and Its Risk Factors in Japanese Patients With ALK-Positive NSCLC After Treatment With Crizotinib

Abstract

Introduction:The study objective was to determine the incidence and characteristics of drug-induced interstitial lung disease (ILD) associated with an orally available small-molecule tyrosine kinase inhibitor, crizotinib, in a real-world clinical setting.Methods: Post-marketing surveillance was performed in Japan to obtain information on the safety and efficacy of crizotinib. Target patients included all patients with anaplastic lymphoma kinase-positive NSCLC who received crizotinib during the enrollment period between May 2012 and December 2014. The observation period was 52 weeks. Expert analysis of the ILD incidence was performed by an ILD independent review committee composed of five medical specialists. Results:The safety analysis set included 2028 patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of ILD associated with crizotinib therapy was 5.77%; and 3.45% patients showed grade 3 or greater. Pulmonary edema-like shadows with or without diffuse alveolar damage pattern were observed in crizotinib-associated ILD (incidence: 0.39%), but a causal relationship with the prognosis could not be identified. ILD developed within 4 weeks from initiation of crizotinib administration in 41.9% and within 8 weeks in 69.2% of the patients. Age 55 years or older, Eastern Cooperative Oncology Group performance status 2-4, smoking history, previous or concomitant ILD, and comorbid pleural effusion were statistically determined as significant risk factors for crizotinib-induced ILD.Conclusions: Crizotinib therapy should be applied to the NSCLC patients with any of above risk factors under a cautious monitoring for ILD occurrence, and clinicians should pay attention to the risks of severe ILD.

A Targeted Approach to the Complications of Targeted Therapy

“…Without the benefit of the expert panel, this might have occurred in one in six events. The ability to make a diagnosis of ILD in the ever-changing landscape of cancer therapies is dependent on the data provided in large postmarketing cohorts such as that presented both here and previously by Gemma et al 6,8 A clinician's individual experience is likely to be littered with the odd case of drug-induced ILD, and therefore, developing a true feel for what is and is not ILD through experience alone is likely to be insufficient. A watch and wait approach to management with broad-spectrum therapies (e.g., antibiotics, diuretics, corticosteroids) may be all-encompassing; however, each treatment is not without harm and the complications of targeted therapies should be met with a similarly targeted therapeutic approach.…”

“…Gemma et al are to be congratulated for detailing the occurrence of ILD as a complication of the targeted NSCLC therapeutic agent crizotinib in a large cohort of consecutive patients, which is a necessity given the relative rarity of ALK receptor tyrosine kinase gene (ALK) mutations. 6 The incidence of crizotinib-induced ILD was 5.77%, with a mortality of 20%. The incidence of ILD as a complication of targeted cancer therapy appears to be more common in Japanese cohorts.…”

“…A total of 140 suspected cases (7%) were reported and assessed by an expert study panel consisting of medical oncologists, radiologists, and a pulmonologist. Gemma et al 6 highlight the diagnostic challenge of pulmonary opacities in the oncologic patient: 23 patients (16%) in whom ILD was suspected were deemed by the expert panel to not have ILD. An additional 31 patients could not be evaluated by the panel owing to missing data, but those patients were assumed to have ILD for the purpose of this study.…”

“…Gemma et al 6 present data for a number of factors that may adjust the pretest probability of an ILD event. The timing of the event appears to be an important factor, with most fatal ILD events occurring within the first 10 weeks of treatment.…”

“…This and previous cohorts have demonstrated that smoking and the presence of known ILD are factors that should be thoroughly assessed before embarking on targeted therapy. 5,8 Missing from the article by Gemma et al 6 are the other historical, physical, and biochemical features that might be useful to a diagnostic algorithm. A history of orthopnea or paroxysmal nocturnal dyspnea and a raised B-type natriuretic peptide level might clinch a diagnosis of congestive cardiac failure to explain bilateral pulmonary opacities.…”