First-in-human study of lomvastomig, a PD-1-TIM-3 bispecific antibody, in patients with advanced and/or metastatic solid tumors
Kristoffer Staal Rohrberg, Ignacio Melero, Miguel F Sanmamed, Eva Muñoz-Couselo, Andrés Cervantes, Valentina Gambardella, Laurent Greillier, Pilar Garrido, Hye Ryun Kim, Dae Ho Lee, Antoine Italiano, Philippe Alexandre Cassier, Sandrine Hiret, Sanjeev Deva, Tae Min Kim, George R Blumenschein, Rikke Løvendahl Eefsen, Brian S Henick, Mario Perro, Pablo Umaña, Antonio Peixoto, Laura Lauener, Patrick Weber, Stefan Seeber, Christian Klein, Brian Higgins, Micol Guidi, Dominik Kraus, Merlind Mücke, Christian Heichinger, Vu-Long Tran, Daniela Schmid, Francesca Michielin, Ting Liu, Christine McIntyre, Henry Kao, Laura Codarri Deak, Christoph Markert, Victor MorenoBackground
This first-in-human clinical study explored lomvastomig, an immunoglobulin G1-based Fc-silenced bispecific antibody that simultaneously blocks the immune checkpoint receptors programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain-3.
Methods
Lomvastomig was characterized in cell cultures and preclinically in cancer mouse models. The phase 1, open-label, multicenter clinical study of lomvastomig included a dose-escalation part in patients with advanced and/or metastatic solid tumors and an expansion part with four tumor-specific cohorts, which enrolled checkpoint inhibitor (CPI)-experienced patients with melanoma and non-small-cell lung cancer (NSCLC) and CPI-naïve patients with SCLC and esophageal squamous cell carcinoma (ESCC). Primary and secondary objectives included safety/tolerability, maximum tolerated dose (MTD)/recommended dose for expansion (RDE), pharmacokinetics, drug receptor occupancy, and antitumor activity.
Results
39 and 95 patients were enrolled in the dose-escalation and expansion parts, respectively. Lomvastomig was well tolerated up to the highest tested dose of 2,100 mg every 2 weeks (Q2W). One dose-limiting toxicity was reported at 1,200 mg (grade 3 troponin T increase). No MTD was reached, and 2,100 mg Q2W was established as the RDE. Linear pharmacokinetics across the studied dose range suggested target saturation. Peripheral blood drug receptor occupancy on CD3+ and CD8+ was saturated at >90% throughout treatment for doses ≥70 mg. Objective responses were observed at 2,100 mg lomvastomig during dose-escalation (21%; n=19), and in the CPI-experienced melanoma (8%, n=38) and CPI-naïve ESCC (20%, n=15) expansion cohorts.
Conclusions
Lomvastomig had a tolerable and manageable safety profile at 2,100 mg Q2W. Clinical activity was limited in CPI-experienced patients with melanoma and NSCLC, while an encouraging signal was observed in CPI-naïve patients with ESCC.
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