Abstract Background: Despite targeted agents recently approved for treating patients with advanced NSCLC harboring EGFR exon 20 insertion (ex20ins) mutations, there is still a high unmet need for more effective agents with good tolerability. BAY2927088 is an oral, reversible, highly potent TKI targeting EGFR and HER2 driver mutations with high selectivity for ex20ins vs wild-type EGFR. In addition, BAY2927088 retains potent antiproliferative activity in the presence of EGFR C797S acquired resistance (AR) mutation due to its non-covalent binding mode. In preclinical studies, BAY2927088 demonstrated strong dose-dependent in vivo tumor growth inhibition in NSCLC EGFR ex20ins mutant patient-derived xenograft models and models carrying the AR mutation C797S (Siegel et al, ENA 2022). The strong potency and high selectivity of BAY2927088 for mutant vs wild-type EGFR offers the prospect of an improved therapeutic window in the clinical setting vs available EGFR TKIs. Methods: 21607 is an open-label, multicenter, first-in-human Phase I study of BAY2927088 in patients with advanced NSCLC harboring EGFR or HER2 mutations. The study comprises dose escalation, backfill, and dose expansion. The dose escalation is enrolling patients with EGFR or HER2 driver mutations and follows a modified continual reassessment method, allowing for concurrent backfill to previously cleared dose levels that demonstrated therapeutically relevant exposures or direct evidence of clinical activity in patients harboring ex20ins or EGFR C797S mutations. Dose-limiting toxicities are evaluated for 21 days. The primary objective of dose escalation is to determine BAY2927088 safety, tolerability, PK, and maximum tolerated dose. Dose expansion will enroll patients based on specific EGFR/HER2 mutations and previous treatment, including those with ex20ins mutation either naïve or pretreated with ex20ins-targeted agents and those with AR EGFR C797S mutation. Key objectives of dose expansion are to further characterize BAY2927088 safety, tolerability, and to characterize PK of the optimal dose(s) selected during dose escalation and backfill. Key secondary objectives include determining antitumor activity based on overall response rate per RECIST v1.1 and the recommended Phase II dose of BAY2927088. Eligible patients must have measurable disease per RECIST v1.1, have a documented EGFR or HER2 mutation in tumor tissue or plasma, have disease progression after treatment with ≥1 systemic therapy for advanced disease, be appropriate candidates for experimental therapy, be aged ≥18 years, have ECOG PS of 0 or 1, and have adequate organ function. Key exclusion criteria include presence of serious cardiac conditions, interstitial lung disease, active CNS metastasis, or leptomeningeal disease. The trial is currently enrolling patients in dose-escalation and backfill parts (NCT05099172). Citation Format: Daniel Tan, Koichi Goto, Herbert HF Loong, Tsung-Ying Yang, Shirish Gadgeel, Erminia Massarelli, Gennaro Daniele, Xiuning Le, Yuki Shinno, Haruyasu Murakami, Tomohiro Sakamoto, Jose C. Ruffinelli, Shun Lu, Yiping Zhang, Tae Min Kim, Barbara J. Brennan, Chunlin Chen, Miranda Joosten, Zebin Wang, Su-Fen Pu, Weichao Bao, Martin Kornacker, Roberta Ferraldeschi, Paolo Grassi, Boon Cher Goh. An open-label, first-in-human study of BAY2927088 in patients with advanced non-small cell lung cancer (NSCLC) harboring an EGFR and/or HER2 mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT126.