A Phase 1 First-in-Human Study of FS118, a Tetravalent Bispecific Antibody Targeting LAG-3 and PD-L1 in Patients with Advanced Cancer and PD-L1 Resistance

Abstract

Purpose: This Phase 1 study (NCT03440437) evaluated the safety, tolerability, pharmacokinetics 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. Experimental Design: 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 mg/kg to 20 mg/kg). Primary objectives were safety, tolerability, and pharmacokinetics. 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 (DLTs) were observed, and a maximum tolerated dose (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. Conclusion: 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.

Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy

“…FS118 binds both LAG-3 and PD-L1, blocking PD-1/PD-L1, CD80/PD-L1, and LAG-3/MHC-II interactions, thereby reversing T cell suppression and promoting the production of cytokines by CD4 + and CD8 + T cells [ 187 ]. A Phase I clinical trial (NCT03440437) for patients with advanced cancers and PD-L1 drug resistance initially showed that FS118 was well tolerated, but further studies are needed to determine the clinical benefit for patients refractory to anti-PD-(L)1 therapy [ 188 ]. IBI323 demonstrated similar potency in blocking the interactions of PD-1/PD-L1, CD80/PD-L1, and LAG-3/MHC-II.…”

The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling

“…Moreover, binding of the surrogate mLAG-3/PD-L1 antibody resulted in the rapid shedding of mouse LAG-3 into the blood [ 130 ]. In clinical studies, a phase 1 trial (NCT03440437) demonstrated the safety and tolerability of FS118 in patients with advanced, anti-PD-1/PD-L1-resistant cancers [ 131 ]. FS118 showed a recommended phase 2 dose of 10 mg/kg weekly, sustained pharmacodynamic activity, and an overall disease control rate of 46.5%, particularly notable in patients with acquired resistance to PD-1/PD-L1-targeted therapy [ 131 ].…”

“…In clinical studies, a phase 1 trial (NCT03440437) demonstrated the safety and tolerability of FS118 in patients with advanced, anti-PD-1/PD-L1-resistant cancers [ 131 ]. FS118 showed a recommended phase 2 dose of 10 mg/kg weekly, sustained pharmacodynamic activity, and an overall disease control rate of 46.5%, particularly notable in patients with acquired resistance to PD-1/PD-L1-targeted therapy [ 131 ]. This study supports the continued investigation of FS118 for patients with refractory cancers, highlighting its potential as an effective dual PD-L1 × LAG-3 blockade strategy.…”

A Comprehensive Review of Immunotherapy Clinical Trials for Metastatic Urothelial Carcinoma: Immune Checkpoint Inhibitors Alone or in Combination, Novel Antibodies, Cellular Therapies, and Vaccines

“…The following supporting information can be downloaded at https:// www.mdpi.com/article/10.3390/cancers16020335/s1, Table S1: Clinical trials of bispecific antibodies for advanced solid tumors including metastatic urothelial carcinoma; Table S2: Clinical trials of cellular therapies in advanced solid tumors including metastatic urothelial carcinoma; Table S3: Clinical trials of vaccines and oncolytic viruses in advanced solid tumors including metastatic urothelial carcinoma. References [124,[147][148][149][150][151][152][153][154][155][156][157][158][159][160] are cited in the supplementary materials.…”