AbstractPurpose:This phase 1 study (NCT03440437) evaluated the safety, tolerability, pharmacokinetics (PK), and activity of FS118, a bispecific antibody–targeting LAG-3 and PD-L1, in patients with advanced cancer resistant to anti–PD-(L)1 therapy.Patients and Methods:Patients with solid tumors, refractory to anti–PD-(L)1–based therapy, received intravenous FS118 weekly with an accelerated dose titration design (800 μg to 0.3 mg/kg) followed by 3+3 ascending dose expansion (1 to 20 mg/kg). Primary objectives were safety, tolerability, and PK. Additional endpoints included antitumor activity, immunogenicity, and pharmacodynamics.Results:Forty-three patients with a median of three prior regimens in the locally advanced/metastatic setting, including at least one anti–PD-(L)1 regimen, received FS118 monotherapy. FS118 was well tolerated, with no serious adverse events relating to FS118 reported. No dose-limiting toxicities (DLT) were observed, and an MTD was not reached. The recommended phase 2 dose of FS118 was established as 10 mg/kg weekly. The terminal half-life was 3.9 days. Immunogenicity was transient. Pharmacodynamic activity was prolonged throughout dosing as demonstrated by sustained elevation of soluble LAG-3 and increased peripheral effector cells. The overall disease control rate (DCR) was 46.5%; this disease control was observed as stable disease, except for one late partial response. Disease control of 54.8% was observed in patients receiving 1 mg/kg or greater who had acquired resistance to PD-(L)1–targeted therapy.Conclusions:FS118 was well tolerated with no DLTs observed up to and including 20 mg/kg QW. Further studies are warranted to determine clinical benefit in patients who have become refractory to anti–PD-(L)1 therapy.See related commentary by Karapetyan and Luke, p. 835