Identifying risk factors for refractory tyrosine kinase inhibitor-induced interstitial lung disease in patients with non-small cell lung cancer.

[BACKGROUND] Tyrosine kinase inhibitors (TKIs) are crucial targeted therapies for non-small cell lung cancer (NSCLC) patients harboring driver gene mutations. TKI-induced interstitial lung disease (TKI-ILD) is uncommon but potentially life-threatening, particularly when there is a poor response to initial corticosteroid treatment. Early identification of patients with refractory TKI-ILD is pivotal for effective management and prognosis. This study aimed to identify risk factors for refractory TKI-ILD.

[METHODS] We conducted a retrospective analysis of clinical records from 71 patients with TKI-ILD at our institution. Refractory TKI-ILD was defined as ILD unresponsive to initial steroid therapy as per therapeutic consensus. We evaluated clinical characteristics, peripheral blood biomarkers, radiological features, and treatment outcomes in both non-refractory and refractory TKI-ILD cases. Risk factors associated with refractory TKI-ILD were examined.

[RESULTS] Among 71 patients diagnosed with TKI-ILD, 10 (14.1%) developed refractory TKI-ILD. There was a significant disparity in gene mutations (P=0.02) between the two groups. Specifically, anaplastic lymphoma kinase (ALK) rearrangement was more prevalent in the refractory group than in the non-refractory group (40.0% vs. 9.8%). Shortness of breath (100% vs. 55.7%, P=0.02) and dyspnea (60% vs. 11.5%, P=0.001) were more frequent in the refractory group. At TKI-ILD onset, white blood cell count (WBC) [10.58 (8.21-15.38) vs. 6.94 (5.06-10.29) ×109/L, P=0.04] and absolute neutrophil count (ANC) [9.67 (5.71-13.36) vs. 4.53 (3.13-7.85) ×109/L, P=0.04] were significantly high in the refractory TKI-ILD group. Additionally, lactate dehydrogenase (LDH) levels in the refractory group were significantly elevated compared to those in the non-refractory group [422.00 (311.50-518.50) vs. 279.00 (206.00-332.00) U/L, P=0.03]. Radiographic patterns also differed significantly between the two groups (P<0.001), with diffuse alveolar damage (DAD)-like patterns being most prevalent in refractory TKI-ILD patients (80%). Multivariable logistic analysis identified dyspnea, LDH >420 U/L at TKI-ILD onset, and DAD radiographic pattern as independent risk factors for refractory TKI-ILD. The mortality rate of refractory TKI-ILD was 50% (5/10).

[CONCLUSIONS] The mortality rate associated with refractory TKI-ILD is substantial. Dyspnea, LDH >420 U/L at TKI-ILD onset, and DAD radiographic pattern are independent risk factors that may aid in identifying refractory TKI-ILD cases.