Introduction: Dacomitinib and gefitinib are irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) indicated for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) and EGFR-activating mutations. Pharmacokinetic (PK) studies in healthy volunteers suggested that acid-reducing drugs such as proton pump inhibitors (PPI) decreased dacomitinib and gefitinib exposure by limiting the pH-dependent absorption. This analysis retrospectively evaluates the effect of concomitant PPI use on dacomitinib exposure and on progression-free survival (PFS) and overall survival (OS) in patients treated with dacomitinib 45 mg QD or gefitinib 250 mg QD in a 1:1 randomized phase 3 study (ARCHER 1050). Methods: The analysis grouped all patients (n = 452) treated in each arm of the study as non-PPI users, PPI users, or extensive PPI users. PFS and OS data were presented by Kaplan--Meier plots and analyzed using Cox proportional hazards models. Dacomitinib exposure was compared using a linear mixed-effects model. Results: Results showed that dacomitinib PFS and OS did not differ significantly when comparing PPI users (N = 59) to non-PPI users (N = 152), while extensive PPI users (N = 24) had shorter PFS [hazard ratio (HR): 1.94, p = 0.011] and OS (HR: 1.77, p = 0.027) when compared to non-PPI users. For patients treated with gefitinib, PFS did not differ significantly when comparing PPI users (N = 51) and extensive PPI users (N = 19) to non-PPI users (N = 159); however, both PPI users (HR: 1.65, p = 0.007) and extensive PPI users (HR: 1.70, p = 0.050) had shorter OS when compared to non-PPI users. Further analysis by adjusting potential confounders indicated no statistically significant differences in PFS or OS between any PPI user vs. non-PPI user groups in the dacomitinib and gefitinib arms. PPI use did not appear to affect dacomitinib exposure. Conclusion:In conclusion, PPI use in patients with NSCLC likely has minimal impact on dacomitinib or gefitinib efficacy despite

Background and Objective Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the second-line treatment of patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. Lorlatinib is metabolized by cytochrome P450 (CYP) 3A and contraindicated with strong CYP3A inducers because of significant transaminase elevation. This phase I, open-label, two-period study evaluated the impact of a moderate CYP3A inducer, modafinil, on the safety and pharmacokinetics of lorlatinib. Methods Healthy participants received single-dose oral lorlatinib (50 mg [n = 2], 75 mg [n = 2], or 100 mg [n = 2 + 10 in an expanded cohort]) in Period 1 followed by modafinil 400 mg/day (days 1-19) and single-dose lorlatinib (day 15, same dose as previous) both orally in Period 2. Blood samples were collected for 120 h after each dose of lorlatinib. Results Of 16 participants, ten completed the study; six participants, all in the expanded 100-mg cohort, discontinued because of adverse events during the modafinil lead-in dosing period. Single doses of lorlatinib 50-100 mg were well tolerated when administered alone and in the presence of steady-state modafinil. Of the ten participants who completed the study, all had transaminase values within normal limits during the combination of lorlatinib with modafinil. The ratios of the adjusted geometric means (90% confidence interval) for lorlatinib area under the plasma concentration-time profile extrapolated to infinity and maximum plasma concentration were 76.69% (70.15-83.83%) and 77.78% (65.92-91.77), respectively, when lorlatinib 100 mg was co-administered with steady-state modafinil compared with lorlatinib administration alone. Conclusion Lorlatinib 100 mg may be safely co-administered with moderate CYP3A inducers. Clinical Trial Registration ClinicalTrials.gov NCT03961997; registered 23 May, 2019.

This phase I open‐label trial (NCT03627754) assessed glasdegib pharmacokinetics and safety in otherwise healthy participants with moderate (Child‐Pugh B) or severe (Child‐Pugh C) hepatic impairment. Participants with hepatic impairment and age/weight‐matched controls with normal hepatic function received a single oral 100‐mg glasdegib dose under fasted conditions. The primary end points were area under the plasma concentration–time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax). Twenty‐four participants (8/cohort) were enrolled. Glasdegib plasma exposures in moderate hepatic impairment were similar to controls, with adjusted geometric mean ratios (GMRs) of 110.8% (90% confidence interval [CI], 78.0–157.3) for AUCinf and 94.8% (69.9–128.4) for Cmax versus controls. In severe hepatic impairment, glasdegib plasma exposures were lower than controls (AUCinf GMR, 75.7%; 90%CI, 51.5–111.0; Cmax GMR, 58.0%; 90%CI, 37.8–89.0). Unbound glasdegib exposures were similar to controls for moderate (AUCinf,u GMR, 118.1%; 90%CI, 88.7–157.2; Cmax,u GMR, 101.1%; 90%CI, 78.4–130.3) and severe hepatic impairment (AUCinf,u GMR, 116.3%; 90%CI 81.8–165.5; Cmax,u GMR, 89.2%, 90%CI, 60.2–132.3). No treatment‐related adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiograms were observed. Together with previous findings, this suggests glasdegib dose modifications are not required based on hepatic impairment.

an indolent progress. In addition, although osimertinib showed good control of BM, local therapy although show be taken into consideration for patients with BM. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest. 124P The effect of proton pump inhibitors (PPI) on dacomitinib (DACO)pharmacokinetics and efficacy in non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutation