Phase 1 PF-08046033 GPNMB-targeted antibody-drug conjugate delivers auristatin tubulin payload.

This first-in-human, open-label Phase 1 trial from Pfizer tests PF-08046033 as IV monotherapy in adults with metastatic/unresectable, progressive solid tumors, starting with dose escalation (multiple ascending dose levels) and moving into tumor-specific expansion cohorts. PF-08046033 is an antibody-drug conjugate directed at GPNMB (glycoprotein NMB) on tumor cells; after binding and internalization, the auristatin payload disrupts microtubules (tubulin inhibitor) to drive cell-cycle arrest and cell death, aiming to improve the therapeutic window versus earlier GPNMB ADC efforts by using a distinct auristatin (auristatin S). Part 2 focuses on previously treated (2nd–3rd line) non-small cell lung cancer, esophageal squamous cell carcinoma, and cutaneous melanoma, where today’s care is sequential systemic therapy—NSCLC often chemo-immunotherapy then targeted/chemo options as appropriate, ESCC typically platinum/fluoropyrimidine-based chemo ± immunotherapy, and melanoma usually immune checkpoint inhibitors and/or BRAF/MEK targeted therapy when BRAF V600–mutant—so the key angle is whether a GPNMB-directed ADC can add a biomarker-defined cytotoxic option across multiple tumor types.