Tyrosine Kinase Inhibitor-Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic Dilemmas

Since the approval of the first molecularly targeted tyrosine kinase inhibitor (TKI), imatinib, in 2001, TKIs have heralded a new era in the treatment of many cancers. Among their innumerable adverse effects, interstitial lung disease (ILD) is one of the most serious, presenting most frequently with dyspnea, cough, fever, and hypoxemia, and often treated with steroids. Of the 28 currently approved TKIs, 16 (57 %) are reported to induce ILD with varying frequency and/or severity. The interval from drug administration to onset of ILD varies between patients and between TKIs, with no predictable time course. Its incidence is variously reported to be approximately 1.6-4.3% in Japanese populations and 0.3-1.0 % in non-Japanese populations. The mortality rate is in the range of 20-50 %. Available evidence (primarily following the use of erlotinib and gefitinib in Japan because of the unique susceptibility of that population) has identified a number of susceptibility and prognostic risk factors (male sex, a history of smoking, and pre-existing pulmonary fibrosis being the main ones). Although the precise mechanism is not understood, collective evidence suggests that immune factors may be involved. If TKI-induced ILD is confirmed by thorough evaluation of the patient and exclusion of other causes, management is supportive, and includes discontinuation of the culprit TKI and administration of steroids. Discontinuing the culprit TKI presents a clinical dilemma because the diagnosis of TKI-induced ILD in a patient with pre-existing pulmonary fibrosis can be challenging, the patient may have TKI-responsive cancer with no suitable alternative, and switching to an alternative agent, even if available, carries the risk of the patient experiencing other toxic effects. Preliminary evidence suggests that therapy with the culprit TKI may be continued under steroid cover and/or at a reduced dose. However, this approach requires careful individualized risk-benefit analysis and further clinical experience.