Background: Few treatment options have demonstrated therapeutic benefit in epidermal growth factor receptor–mutated (EGFRm) non–small cell lung cancer (NSCLC) that has progressed after treatment with EGFR tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy. HER3, a member of the human epidermal growth factor family, is detectable in most EGFRm NSCLC, and its expression has been linked to worse clinical outcomes. There are no approved HER3 directed therapies for the treatment of NSCLC. HER3-DXd is a novel, potentially first-in-class HER3 directed antibody drug conjugate that has demonstrated preliminary evidence of safety and antitumor activity in patients (pts) with EGFRm TKI–resistant NSCLC in an ongoing Phase 1 study, providing proof of concept of HER3-DXd. The Phase 2 study (HERTHENA-Lung01) is further evaluating HER3-DXd in pts with previously treated metastatic or locally advanced EGFRm NSCLC. Methods: This randomized, open-label Phase 2 study will enroll up to 420 pts at approximately 135 study sites in North America, Europe and the Asia-Pacific region. Eligible pts will have metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or L858R), progression during or after systemic treatment with ≥1 EGFR TKI and ≥1 platinum-based chemotherapy regimen, and ≥1 measurable lesion confirmed by blinded independent central review (BICR) per RECIST v1.1. Pts with an EGFR T790M mutation must have received and progressed on prior osimertinib. Pts with stable brain metastases are eligible. Exclusion criteria include evidence of previous small cell or combined small cell/non–small cell histology or any history of interstitial lung disease. Tumor tissue will be assessed retrospectively for HER3 expression and molecular mechanisms of TKI resistance. HER3 expression will not be used to select pts for enrollment. Pts will be randomized 1:1 to receive 1 of 2 HER3-DXd Q3W dose regimens that will be independently evaluated: a 5.6 mg/kg fixed-dose regimen (Arm 1) or an up-titration dose regimen (Arm 2: Cycle 1, 3.2 mg/kg; Cycle 2, 4.8 mg/kg; Cycle 3 and beyond, 6.4 mg/kg). After review of data from an ongoing Phase 1 study with similar patients treated with either of these dose regimens, a decision could be made to continue enrollment into 1 or both arms. The primary objective is to evaluate the efficacy of HER3-DXd as measured by objective response rate (ORR) by BICR. Secondary objectives are to evaluate the efficacy and safety/tolerability of HER3-DXd and to assess the relationship between efficacy and HER3 expression. Secondary endpoints include duration of response, progression-free survival, ORR by investigator, disease control rate, time to response, best percentage change in the sum of diameters of measurable tumors, and overall survival. The study is enrolling and is planned to finish in 2023. Clinical trial information: NCT04619004