Background: Effective treatment for patients with metastatic non-small cell lung cancer (mNSCLC) harboring EGFR or HER2 exon 20 insertion mutations (ex20) represents a significant unmet medical need. Poziotinib is a potent, irreversible, tyrosine kinase inhibitor (TKI) which has been shown to target both ex20 is currently being studied in a multi-cohort, Phase 2 study (ZENITH20, NCT03318939). Poziotinib has been extensively studied with once daily dosing and has demonstrated clinical activity in EGFR or HER2 ex20 NSCLC. Due to the relatively short half-life of 7.2 hours, pharmacokinetic simulation indicated that twice daily (BID) dosing schedule could reduce toxicity while preserving activity and is being evaluated in a randomized design. Here, we report preliminary poziotinib safety and tolerability data in patients treated for EGFR or HER2 ex20 NSCLC. Methods: ZENITH20-5 enrolled patients with locally advanced or mNSCLC and with EGFR or HER2 ex20. Patients were randomized to either 10, 12, 16 mg QD or to 6 and 8 mg BID arms of poziotinib. The endpoints were objective response rate (ORR per RECIST 1.1), duration of response (DOR), progression-free-survival (PFS) and safety and tolerability. Results: ZENITH20-5 enrolled 122 patients randomized into the QD (n of 26 at 16mg; 26 at 12mg; 37 at 10mg) and BID (n of 14 at 8mg; 19 at 6mg) arms and 62 are ongoing. 10mg QD dose cohort was terminated for suboptimal therapeutic effect. Demographics characteristics were representative of patient population with majority female (69%) and non-smokers (67%). Dose proportionality was observed. Comparison of QD vs BID dosing (16mg QD vs 8mg BID; 12mg QD vs and 6mg BID) showed relative reductions in dose interruptions of 38% and 52%. Time to first interruptions was substantially lower in BID dose schedule for 16mg and 12 mg arms (42% and 51%) respectively. The commonly expected treatment-related AE rate (rash, diarrhea, stomatitis) rate of Grade 3 or higher was lower for BID dosing (31% vs. 21% and 27% vs. 16%, respectively) in Cycle 1. Updated safety, tolerability and preliminary efficacy data will be presented at the meeting. Conclusions: Poziotinib demonstrated improved tolerability and safety with BID dosing. Additional efficacy data is required to make more definitive statement on efficacy with BID dosing.

Citation Format: Xiuning Le, Elaine Shum, Jennifer M. Suga, Julie R. Brahmer, Christophe Dooms, Hirva Mamdani, Hovav Nechushtan, Jonathan W. Riess, Alexander Spira, John A. Barrett, Lyndah K. Dreiling, Mark Socinski. Poziotinib administered twice daily improves safety and tolerability in patients with EGFR or HER2 exon 20 mutant NSCLC(ZENITH20-5) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT169.