A Phase 1a/1b Of Zanidatamab In Combination With Zongertinib In HER2-Mutated Non-Small Cell Lung Cancer (NSCLC)

Primary Objectives: The primary objective of the study is to evaluate safety and tolerability of zongertinib in combination with zanidatamab in patients with HER2-mutant NSCLC. The co-primary endpoints will be the incidence of DLTs during the first 21 days in Part 1 (safety lead-in) to determine the recommended dose of zongertinib in combination with zanidatamab; and the incidence of Treatment-Emergent Adverse Events (TEAEs) during the entire treatment period of the study (part 1 and 2) Secondary Objectives: * Determine the confirmed objective response rate (ORR) as per RECIST v1.1 with zanidatamab and zongertinib combination with efficacy endpoint confirmed ORR * Determine the overall survival (OS) with zanidatamab and zongertinib combination with time to event endpoint OS * Determine the progression-free survival (PFS) as per RECIST v1.1 t with zanidatamab and zongertinib combination with time to event endpoint PFS * Determine the disease control rate (DCR) as per RECIST v1.1 t with zanidatamab and zongertinib combination with categorical efficacy endpoint DCR * Determine the Duration of response (DOR) with zanidatamab and zongertinib combination with durability endpoint DOR * Number of participants with adverse events (AEs) and serious adverse events (SAEs) categorized by severity with zanidatamab and zongertinib combination with endpoint AE/SAE frequency and severity * Number of participants with AEs leading to discontinuations and leading to dose reductions with endpoint tracking treatment modifications due to toxicity. EXploratory Objectives: * Explore the association of baseline comprehensive genomic profiling (MDA MAPP platform or other CLIA-certified next generation sequencing assays with complete coverage of all Erbb2 alterations) with clinical benefit in patients treated with zanidatamab and zongertinib combination * Explore resistance mechanisms to the zanidatamab and zongertinib combination. At the time of disease progression, patients will undergo plasma collection for circulating tumor DNA (ctDNA) testing and a tissue biopsy to perform genomic and transcriptomic analyses to provide additional insights into putative resistance mechanisms. * Correlate ctDNA clearance with treatment response. Serial ctDNA collections at baseline and during treatment will be analyzed to evaluate the relationship between ctDNA dynamics and therapeutic response. * Study the biology of drug-tolerant, persistent cancer cells. Tissue and plasma samples collected during treatment will be used to investigate the underlying biology of drugtolerant persistent cancer cells * Determine the immunomodulatory effects of zanidatamab and zongertinib combination in the tumor microenvironment.