Background: The epidermal growth factor receptor (EGFR) and mesenchymal-epidermal transition tyrosine kinase receptor (c-MET) are expressed in diverse solid tumors, and function as driver genes in some types. Clinical benefit of bispecific monoclonal antibodies (Ab) targeting these receptors was demonstrated in pts with EGFR mutated (EGFRm) non-small-cell lung cancer (NSCLC), but an ADC targeting these receptors has not been developed. AZD9592 is an ADC with a bispecific Ab targeting EGFR and c-MET. When internalized, AZD9592 releases a topoisomerase 1 inhibitor (TOP1i) warhead that traps TOP1 on DNA, causing double-strand breaks and induction of apoptotic cell death. Preclinical data have demonstrated promising efficacy and safety of AZD9592 in tumors expressing EGFR and c-MET, including but not limited to adenocarcinoma and squamous NSCLC and head and neck squamous cell carcinoma (HNSCC). Methods: EGRET is a phase 1, open-label, multicenter, modular study in pts with advanced solid tumors (NCT05647122). Module 1 will evaluate AZD9592 monotherapy in pts with metastatic NSCLC (mNSCLC) with EGFRm (sensitizing L858R mutation or exon 19 deletions) or EGFR wild-type, or recurrent or metastatic HNSCC. Module 2 will evaluate AZD9592 in combination with osimertinib in pts with EGFRm mNSCLC. Each module will include dose escalation (Part A) and dose expansion (Part B) cohorts. Key inclusion criteria are age ≥18 years, ECOG performance status 0–1, life expectancy ≥12 weeks, measurable disease per RECIST v1.1, and adequate organ and bone marrow function. Key exclusion criteria for both modules include unresolved toxicities of Grade ≥2 (NCI CTCAE v5.0) from prior therapy, uncontrolled intercurrent illness, cardiovascular disorders, history of drug-induced interstitial lung disease or pneumonitis, and previous treatment with a TOP1i ADC or an EGFR- or MET-targeted ADC. Treatment continues until disease progression, initiation of alternative anticancer therapy or unacceptable toxicity. The primary objectives of Part A are to assess safety and tolerability, and to determine the maximum tolerated dose and/or the recommended phase 2 dose of AZD9592 as monotherapy or in combination with osimertinib. The primary objectives for Part B are to evaluate safety and tolerability, and antitumor activity by investigator-assessed objective response rate (ORR) according to RECIST v1.1. Secondary objectives for both Part A and B include assessing AZD9592, as monotherapy and in combination with osimertinib, for efficacy (by ORR, disease control rate, duration of response, and progression-free and overall survival), pharmacokinetics, and immunogenicity. Descriptive statistics will be used for all variables. The study will include sites across the EU, USA, and Asia Pacific; sites in USA and Australia are currently open for enrollment. Clinical trial information: NCT05647122.