Independent review of fatal interstitial lung disease (ILD) in TRIBUTE: paclitaxel + carboplatin ± erlotinib in advanced non-small cell lung cancer (NSCLC)

7071 Background: ILD is a rare but serious complication of EGFR tyrosine kinase inhibitor (TKI) therapy, fatal in about 1/3 of cases. The incidence, severity & risk factors for ILD remain poorly understood, but it is reported to be more common in Asian patients receiving gefitinib. Whether the risk of ILD with gefitinib exceeds that of erlotinib is unclear. Whether concurrent chemotherapy increases the risk of ILD is also unclear. Methods: This study was designed to determine the incidence of ILD leading to death in 1,059 TRIBUTE patients randomized to chemotherapy plus erlotinib or placebo (Herbst: JCO, 2005). A blinded review of fatal SAEs was performed by an independent 3 person panel comprised of a medical oncologist (DRG), radiologist (DS), and pulmonologist (KY) unassociated with the study. Fatal respiratory SAEs (41 met criteria) were assigned to 1 of 4 potential attributions: progressive NSCLC; concurrent illness; toxicities not related to study drug; or ILD. Each panel member first made an independent assignation based on case report forms/source documents; then each case was discussed jointly. If needed, consensus was reached by vote. Results: Fatal SAEs were reported in 80/1059 patients (7.6%): 53/526 patients on erlotinib (10.1%) & 27/533 on placebo (5.1%) (p = 0.002). Consensus assignation for 41 respiratory SAEs was as follows: NSCLC: 18 (44%), concurrent illness: 15 (37%), toxicities not related to study drug: 5 (12%), ILD: 3 (7%). There were no statistical differences in assignation by study arm. However, all 3 ILD cases occurred in the erlotinib arm (3/523; overall incidence 0.6%). Case details will be provided. Conclusions: 1) To our knowledge, this analysis of TRIBUTE is the only independent blinded assessment of respiratory SAEs & ILD related to an EGFR TKI (erlotinib) + chemotherapy. 2) Overall, there were 41 fatal respiratory SAEs (3.9%). Fatal ILD occurred in 0.6% of cases treated with the combination. Using estimates that 1/3 of EGFR TKI-induced ILD cases are fatal, the overall incidence in this study arm was likely around 1.5–2%, not inconsistent with prior reports of TKIs alone. 3) Further studies designed to better define the underlying pathophysiology and risk factors for ILD are needed. [Table: see text]