Background: Epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-MET) are dysregulated in many tumors, including NSCLC. In particular, splice-site alterations resulting in the loss of transcription of exon 14 in the oncogenic driver c-MET (METex14 skipping mutations) occur in ~3% of NSCLC and lead to oncogenic MET activation. MCLA-129 is a bispecific antibody that targets EGFR and c-MET with multiple mechanisms of action, including inhibition of EGFR and c-MET signaling, antibody-dependent cellular phagocytosis and enhanced antibody-dependent cellular cytotoxicity. In the dose escalation part of a phase 1/2 trial (NCT04868877), the initial recommended phase 2 dose of MCLA-129 monotherapy was determined to be 1500 mg every 2 weeks (Q2W) with 28-day cycles. Significant tumor shrinkage was observed in one patient with METex14 NSCLC previously treated with multiple chemotherapy agents and the c-MET tyrosine kinase inhibitor (TKI) capmatinib. Preliminary data are presented of patients (pts) with advanced or metastatic METex14 NSCLC treated with MCLA-129 in the dose expansion phase of the trial. Methods: Pts with advanced/metastatic METex14 NSCLC Pts received MCLA-129 1500 mg IV Q2W, until disease progression or unacceptable toxicity. Tumor imaging was conducted every 8 weeks. Primary endpoint: investigator-assessed ORR (RECIST v1.1), in pts with measurable disease, ≥2 MCLA-129 cycles, and ≥1 post-baseline scan. Secondary endpoints: DCR and safety. Biomarker analyses of EGFR/c-MET expression and ctDNA mutation status are planned. Results: As of December 1, 2023, 15 pts were dosed. The median age was 72 years (range 61-83), 40% were male, and 13%/87% of pts had ECOG performance status 0/1 respectively. The trial is ongoing; further analysis of safety and efficacy is planned with a later data cutoff date and will be presented at the meeting. Conclusions: MCLA-129 is being evaluated as monotherapy for the treatment of patients with locally advanced/metastatic c-MET exon 14 skipping NSCLC. Clinical trial information: NCT04868877.