P3.01-100 Risk of Gastrointestinal and Hepatic Toxicities in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Osimertinib

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line therapy in patients with advanced non-small-cell lung cancer (NSCLC) who harbors EGFR mutation. The presence of T790M point mutation, later, mediates the resistance to first-generation and second-generation EGFR-TKIs. Osimertinib, an oral third-generation EGFR-TKI, targets both EGFR-TKI sensitizing and EGFR T790M resistance mutations. We undertook a systematic review and combined analysis of two phase III randomized controlled trials (RCT) to determine the risk of gastrointestinal and hepatic toxicities among patients with advanced NSCLC treated with osimertinib. We conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through March 2018. Phase III RCTs that mention diarrhea, nausea, vomiting, stomatitis and elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Fixed effects model was applied. Two phase III RCTs with a total of 971 patients with advanced NSCLC were included in the analysis. Studies compared osimertinib vs carboplatin/cisplatin + pemetrexed and osimertinib vs gefitinib/erlotinib. The randomization ratio was 1:1 in the FLAURA study and 2:1 in the AURA3 study. Osimertinib was utilized in T790M-positive advanced NSCLC after prior first-line EGFR-TKIs in the AURA3 study (n= 556) and as first-line treatment in the FLAURA study (n= 415). The RR of all-grade side effects were as follows: diarrhea, 1.305 (95% CI: 1.128 – 1.509, p < 0.0001); nausea, 0.480 (95% CI: 0.378–0.611; p < 0.0001); vomiting, 0.783 (95% CI: 0.561–1.092; p = 0.149); stomatitis, 1.262 (95% CI: 0.980 – 1.626, p = 0.071); elevated AST, 0.397 (95% CI: 0.277–0.569; p < 0.0001); and elevated ALT, 0.312 (95% CI: 0.212–0.458; p < 0.0001). The RR of high-grade side effects were as follows: diarrhea, 0.912 (95% CI: 0.354 – 2.347, p = 0.849); vomiting, 0.135 (95% CI: 0.022 – 0.831; p = 0.031); stomatitis, 0.532 (95% CI: 0.124 – 2.293, p = 0.397); elevated AST, 0.296 (95% CI: 0.096 – 0.907; p = 0.033); and elevated ALT, 0.112 (95% CI: 0.034 – 0.372; p < 0.0001). Patients on osimertinib noted a significant increase in the risk of all-grade diarrhea. Nevertheless, the risk of developing any-grade nausea, all grades of elevated AST/ALT and high-grade vomiting, was significantly reduced in osimertinib arm, favoring osimertinib.