First-in-human study of lomvastomig, a PD-1-TIM-3 bispecific antibody, in patients with advanced and/or metastatic solid tumors
Rohrberg KS., Melero I., F Sanmamed M., Muñoz-Couselo E., Cervantes A., Gambardella V., Greillier L., Garrido P., Kim HR., Lee DH., Italiano A., Cassier PA., Hiret S., Deva S., Kim TM., Blumenschein GR., Løvendahl Eefsen R., Henick BS., Perro M., Umaña P., Peixoto A., Lauener L., Weber P., Seeber S., Klein C., Higgins B., Guidi M., Kraus D., Mücke M., Heichinger C., Tran V-L., Schmid D., Michielin F., Liu T., McIntyre C., Kao H., Codarri Deak L., Markert C., Moreno V.
Background 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. Trial registration number NCT03708328 (registration date: 2018–10-09).