LAG-3/PD-L1 Bispecific Shows Response After CAR T in DLBCL

Diffuse Large B-cell Lymphoma |
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Treatment with the investigational LAG-3/PD-L1 bispecific antibody FS118 yielded complete responses (CRs) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to results from a phase 2 trial (EudraCT 2021-003406-47) that were presented during the 2024 ASH Annual Meeting & Exposition.¹

The ORR was 20% (n = 2; 95% CI, 2.5%-55.6%) in the cohort of 10 patients, and both patients had CRs. One of the responders was previously treated with chimeric antigen receptor (CAR) T-cell therapy and had a duration of response (DOR) longer than 64.9 weeks; the other patient experienced a DOR of 8.1 weeks. Six patients had progressive disease (PD), and 2 patients did not have these data available (NA).

“FS118 is a new potential immune checkpoint blocker showing meaningful efficacy with durable responses achieved in patients with relapsed/refractory DLBCL,” lead study author Jean-Marie Michot, MD, of the Department of Hematology and Innovative Drugs at Gustave Roussy in Villejuif, France, and coinvestigators, wrote in the poster presented during the conference. “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.”

Patients with relapsed/refractory DLBCL after 2 lines of systemic therapy and following CD19-directed CAR T-cell therapy have poor prognoses and represent an unmet need. There are currently no FDA-approved immune checkpoint inhibitors for this patient population; however, patients with DLBCL have been known to have high levels of PD-L1 and LAG-3.

FS118 is a tetravalent bispecific antibody that targets both LAG-3 and PD-L1 with the ability to overcome immune suppressive signals; it is designed to have more preclinical activity compared with a monoclonal antibody combination.² FS118 surrogate downregulates LAG-3 in vivo on tumor-infiltrating lymphocytes and also increases soluble LAG-3 in mice serum. Prior phase 1 data showed that treatment with FS118 led to a dose-dependent increase in soluble LAG-3 in serum of patients with advanced cancers.³

At the 2024 ASH Annual Meeting, investigators reported on the primary analysis from the phase 2 trial in patients with relapsed/refractory DLBCL. The recommended phase 2 dose of FS118 was 10 mg/kg weekly given intravenously and the study comprised 2 cohorts: patients with non–small cell lung cancer (cohort A; n = 21) and those with DLBCL (cohort C; n = 10).

To be eligible for enrollment in cohort C, patients had to have histologically confirmed relapsed/refractory DLBCL, measurable disease, an ECOG performance status of 0 or 1, and adequate organ function. Moreover, patients must have previously received at least 2 systemic regimens; one prior therapy must have included an anti-CD20 chemoimmunotherapy regimen and another must have comprised CD19-directed CAR T-cell therapy, where this is the institution’s standard therapy unless contraindicated.

Investigators noted that a minimal washout period was required from CAR T cells within 60 days to the planned FS118 dosing.

FS118 was given at the recommended dosing until disease progression or unacceptable toxicity for up to 24 months. Additionally, patients who achieved a durable CR were permitted to discontinue therapy after at least 24 weekly administrations and 8 weekly administrations after achieving a CR.

The primary end point was ORR per Lugano criteria; key secondary end points included DOR, progression-free survival (PFS), overall survival (OS), and safety. Immune biomarkers served as an exploratory end point.

As of the data cutoff date of June 23, 2024, of the 10 patients with DLBCL, the median age was 58.5 years (range, 36-65); half of patients were male. Six patients were White and 4 had an unknown race. Four patients had an ECOG performance status of 1. Moreover, patients had the activated B-cell subtype (n = 2), germinal center B-cell (n = 2), or unknown DLBCL subtype (n = 6). All 10 patients had Ann Arbor stage III to IV disease at study entry. The median number of prior lines of therapy was 3.5 years (range, 2-7); 4 patients had been previously treated with CD19-targeted CAR T-cell therapy.

All patients had discontinued study treatment, due to progressive disease (n = 6), confirmed CR (n = 2), or clinical progression (n = 2).

Further findings showed that the median PFS was 7.1 weeks (range, 0.0-72.9) and the median OS was 32.9 weeks (range, 6.3-NA).

Regarding safety, investigators noted no dose-limiting toxicities, and no patients discontinued treatment due to toxicity or treatment-emergent adverse effects (TEAEs) related to FS118. Eight patients had any-grade TEAEs, and 3 patients had any-grade drug-related TEAEs; 4 patients experienced at least 1 serious TEAE, 3 of which were unrelated, and 1 that was drug-related in the form of a pulmonary embolism. Three immune-related, drug-related TEAEs occurred and 1 TEAE led to treatment discontinuation but was not found to be treatment related. No grade 4 or 5 drug-related TEAEs were reported.

TEAEs were examined by system organ class and included blood and lymphatic system disorders (grades 1 2, n = 1; grades 3-4, n = 1), cardiac disorders (grades 1-2, n = 1), endocrine disorders (grades 1-2, n = 1), gastrointestinal disorders (grades 1-2, n = 1), general disorders (grades 1-2, n= 2; grades 3-4, n = 1), hepatobiliary disorder (grades 1-2, n = 1), infections (grades 1-2, n = 3; grades 3-4, n =2), investigations (grades 1-2, n = 2), metabolism and nutrition disorders (grades 1-2, n = 1; grades 3-4, n = 1), psychiatric disorders (grades 1-2, n = 1), renal and urinary disorders (grades 1-2, n = 1; grades 3-4, n = 1), respiratory disorders (grades 1-2, n = 1; grades 3-4, n = 1), and skin and subcutaneous disorders (grades 1-2, n = 1).

Michot concluded that an investigation of the activity of biomarkers “seems important at this stage, particularly to understand the rather spectacular efficacy of therapy in certain patients.”

_References

_{1. Michot J-M, Patki A, Maglakelidze M, et al. 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. Blood. 2024;144(suppl 1):1731. doi:10.1182/blood-2024-202538}

_{2. Kraman M, Faroudi M, Allen NL, et al. FS118, a bispecific antibody targeting LAG-3 and PD-L1, enhances T-cell activation resulting in potent antitumor activity. Clin Cancer Res. 2020;26(13):3333-3344. doi:10.1158/1078-0432.CCR-19-3548}

_{3. Yap T, Wong D, Hu-Lieskovan S, et al. A first-in-human study of FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, in patients with advanced cancer and resistance to PD-(L)1 therapy. J Immunotherapy Cancer. 2020;8(3). doi:10.1136/jitc-2020-SITC2020.0395}