Petosemtamab plus pembrolizumab as first-line (1L) treatment of PD-L1 high metastatic non-small cell lung cancer (NSCLC): Global phase 2 trial.

TPS8662 Background: NSCLC has a heterogeneous biology frequently including high mutational burden, high EGFR expression and upregulated EGFR signaling that is associated with poor prognosis. In the first-line metastatic setting, combination regimens pairing platinum-based chemotherapy with immune checkpoint blockade are standard of care; however, most patients experience disease progression within the first year. Petosemtamab is a low-fucose human common light chain, IgG1 bispecific antibody targeting EGFR and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5). Petosemtamab mechanism of action includes inhibition of EGFR ligand binding and downstream signaling, degradation of EGFR via LGR5 internalization in EGFR/LGR5-expressing cells, and immune system activation via enhanced ADCC (Herpers et al. Nat Cancer 2022; Lundberg et al. Cancers 2025). Petosemtamab plus pembrolizumab has previously demonstrated clinically meaningful efficacy and a manageable safety profile in 1L PD-L1-positive recurrent/metastatic head and neck squamous cell carcinoma (van Herpen et al. ASCO 2025). Methods: MCLA-158-CL04 (NCT07353957) is an open-label, multicenter, phase 2 trial to investigate petosemtamab in combination with pembrolizumab in squamous (Sq) and non-SqNSCLC. Two cohorts will be evaluated in patients with PD-L1 high (TPS ≥50%) metastatic sqNSCLC and non-sqNSCLC, respectively, with no prior systemic treatment for metastatic disease. Patients will be treated with petosemtamab 1500 mg IV Q2W in combination with pembrolizumab 400 mg IV Q6W. The primary objective is investigator-assessed objective response rate. Enrollment of approximately 80 patients in North America, EU, and Asia-Pacific is planned. Clinical trial information: NCT07353957 .