FS118, an investigational bispecific antibody targeting LAG-3 and PD-L1, demonstrated a modest overall response rate (ORR) of 20% in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in a phase 2 trial. The findings, presented at the 2024 American Society of Hematology (ASH) Annual Meeting, suggest that FS118 could offer a potential treatment option for patients with limited alternatives, particularly those who have relapsed following CAR T-cell therapy.
The phase 2 trial (EudraCT 2021-003406-47) included a cohort of 10 patients with relapsed/refractory DLBCL who had previously received at least two systemic regimens, including anti-CD20 chemoimmunotherapy and, if standard of care at their institution, CD19-directed CAR T-cell therapy. The primary endpoint was ORR per Lugano criteria, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
Efficacy and Outcomes
The study revealed that 2 out of 10 patients achieved a complete response (CR), resulting in an ORR of 20% (95% CI, 2.5%-55.6%). Notably, one of the responding patients had previously been treated with CAR T-cell therapy and experienced a DOR longer than 64.9 weeks. The other patient had a DOR of 8.1 weeks. Six patients experienced progressive disease, and data were not available for the remaining two patients.
The median PFS was 7.1 weeks (range, 0.0-72.9), and the median OS was 32.9 weeks (range, 6.3-NA).
Safety Profile
FS118 demonstrated a manageable safety profile. There were no dose-limiting toxicities, and no patients discontinued treatment due to toxicity or treatment-emergent adverse events (TEAEs) related to FS118. Eight patients experienced any-grade TEAEs, and three patients had any-grade drug-related TEAEs. Four patients experienced at least one serious TEAE, with one being drug-related (pulmonary embolism). Three immune-related, drug-related TEAEs occurred, and one TEAE led to treatment discontinuation but was not treatment-related. No grade 4 or 5 drug-related TEAEs were reported.
Mechanism of Action and Rationale
FS118 is a tetravalent bispecific antibody designed to target both LAG-3 and PD-L1, aiming to overcome immune suppressive signals. Preclinical data suggest that FS118 has greater activity than a monoclonal antibody combination. Patients with relapsed/refractory DLBCL after multiple lines of therapy, including CAR T-cell therapy, face poor prognoses, highlighting an unmet need for new treatment options. DLBCL tumors often exhibit high levels of PD-L1 and LAG-3, making them potential targets for immunotherapy.
Investigator Commentary
Lead study author Dr. Jean-Marie Michot, from the Department of Hematology and Innovative Drugs at Gustave Roussy in Villejuif, France, emphasized the potential of FS118 as a new immune checkpoint blocker. "FS118 is a new potential immune checkpoint blocker showing meaningful efficacy with durable responses achieved in patients with relapsed/refractory DLBCL," Dr. Michot noted in the poster presentation. "These results support the potential use of FS118 as an off-the-shelf treatment option in relapsed/refractory DLBCL in the post-CAR T patient population, who typically have dismal outcomes."
Dr. Michot also highlighted the importance of further investigation into activity biomarkers to understand the varying efficacy observed among patients.
