Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and potent topoisomerase I inhibitor. In a phase II trial in patients (pts) with heavily pretreated, metastatic HER2+ breast cancer (BC), T-DXd had a confirmed objective response rate (cORR) of 60.9% (112/184) and median progression-free survival (PFS) of 16.4 mo (Modi N Engl J Med 2019); these results led to the recent FDA approval for HER2+ unresectable or metastatic BC after ≥ 2 prior anti-HER2 based regimens. For HER2-low BC and HER2-expressing/mutated NSCLC, no HER2-directed therapies have been approved. In a phase I trial of T-DXd in pts with HER2-low BC or HER2-expressing/mutated NSCLC, cORR was 44.2% (19/43) (Modi SABCS 2018), and 55.6% (10/18) (Tsurutani Thorac Oncol 2018), respectively. In preclinical models, T-DXd combined with an anti–PD-1 antibody was more effective than monotherapy with either agent (Iwata Mol Cancer Ther 2018). Here we describe a phase Ib study of T-DXd in combination with pembrolizumab in pts with locally advanced/metastatic HER2-expressing BC or HER2-expressing/mutated NSCLC (DS8201-A-U106; NCT04042701). Methods: This is an open-label, multicenter, nonrandomized, multidose, 2-part study in adult (aged ≥18 y) pts in the United States and Europe. In part 1 (dose escalation), pts received T-DXd 3.2 or 5.4 mg/kg IV q3w and pembrolizumab 200 mg IV q3w to determine the recommended dose for expansion (RDE). The RDE will be given to 4 cohorts (part 2): 2 cohorts with BC (HER2+ [IHC 3+ or IHC 2+/ISH+] with progression on prior T-DM1; and HER2-low [IHC 1+ or IHC2+/ISH-] with progression on prior standard treatments) and 2 cohorts with NSCLC (anti–PD-1, –PD-L1, and -HER2 treatment naive either HER2-expressing [IHC ≥ 1+] or HER2-mutated). Enrollment began in February 2020 with approximately 115 to 133 pts planned to be enrolled at 5 sites for part 1 and expanding to 25 sites for part 2. The primary endpoint in part 1 is dose-limiting toxicities. The part 2 primary efficacy endpoint is cORR by independent central review (ICR) per RECIST 1.1. Additional endpoints include duration of response, disease control rate, and progression-free survival by ICR, overall survival, safety, and pharmacokinetics. Clinical trial information: NCT04042701.