Open-Label Phase 2 Study Results of FS118, a LAG-3/PD-L1 Bispecific Antibody, in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Introduction

Patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) after two lines of systemic therapy and after CD19 CAR-T cells have poor prognosis and new therapies are needed. There are no approved immune checkpoint blockers (ICB) for DLBCL. Immune checkpoint blockers anti-PD1 have demonstrated modest activity in R/R DLBCL and new optimized immunotherapies are required. DLBCL are tumors known to express high levels of immune checkpoints PD-L1 and LAG-3.

FS118 is a novel ICB, tetravalent bispecific IgG1 antibody, which consists of an anti-PD-L1 IgG1 with a distinct LAG-3 binding capability with a terminal half-life of ~4 days. In a Phase 1, previously conducted in both US (IND Number:137281) and Europe (EudraCT Number: 2021-002946-33), FS118, was well tolerated up to dosage 20 mg/kg intravenously (IV) QW with no dose limiting toxicities (DLT) observed and demonstrated antitumor activity. Established recommended Phase 2 dose was 10 mg/kg IV QW and was investigated in FS118-21201 study (EudraCT 2021-003406-47) enrolling non-small cell lung cancer patients (Cohort A, n=21) and DLBCL patients (Cohort C, n=10).

Methods

FS118-21201 is a Phase 2 open-label basket study of FS118 in adult patients. The study design consists of multiple single-arm tumor-specific cohorts and is primarily designed to assess efficacy. Secondary objectives were assessment of tolerability of FS118 and PK parameters.

Key inclusion criteria for cohort C were patients with measurable R/R DLBCL who previously received at least 2 systemic regimens, where one therapy line must have included anti-CD20 immuno-chemotherapy regimen and one therapy line must have included CD19 CAR-T cells where this is the institution’s standard of care, unless contraindicated.

Patients received FS118 IV, 10 mg/kg QW, until disease progression or unacceptable toxicity, for a maximum of 24 months. Patients achieving a durable complete response (CR) could discontinue the treatment after at least 24 QW administrations and 8 QW administrations after CR.

Results.

In cohort C, as of 23 Jun 2024, 10 patients with R/R DLBCL were treated. Median (range) age of 5 males and 5 females (6 patients of white race and 4 unknown) was 58.5 years (36-65 years). Median number of previous lines of therapy was 3.5 (range 2-7). Four (4/10, 40%) patients previously received CD19 CAR-T cells therapy. The overall response rate was 20% (2/10 evaluable patients), and both were complete responses. Responders (n=2) included one patient previously treated with CD19 CAR-T cells therapy. One of the responders (CD19 CAR-T cells pre-treated) had a duration of response for >64.9 weeks and other had a duration of response for 8.1 weeks. All patients have discontinued the study. Two patients discontinued due to confirmed CR and eight patients discontinued treatment due to progressive disease. There were no dose-limiting toxicities (DLTs) observed. No patients discontinued the treatment due to toxicity. Eight patients (8/10, 80% patients) experienced any grade treatment-emergent adverse event (TEAE). Three patients (3/10, 30% patients) experienced any grade drug-related TEAE. One patient experienced grade 3 drug related TEAE of pulmonary embolism. There were no grades 4 or 5 drug-related TEAE. Four (4/10, 40%) Patients experienced at least one serious TEAE (3 unrelated and 1 drug-related (pulmonary embolism).

Conclusions

In this phase 2 study, FS118 was well tolerated in patients with R/R DLBCL with no DLTs reported. FS118 is a new potential immune checkpoint blocker showing meaningful efficacy with durable responses achieved in patients with R/R DLBCL.