Interim results of a phase I clinical trial evaluating Fas ligand (FasL) blocking antibody M3T01 in adults with advanced treatment-refractory solid tumors

Background FasL expressed on tumor endothelial cells, macrophages, and activated T cells contributes to apoptosis of tumor-specific T cells and impaired tumor infiltration by T cells. In preclinical models, blockade of FasL/Fas signaling results in enhanced T cell infiltration of tumors and augments the antitumor efficacy of immune checkpoint inhibitors and adoptive cell therapies. M3T01 is a fully human IgG4/kappa monoclonal anti-FasL blocking antibody. M3T01 is being evaluated in an ongoing first-in-human phase I clinical trial (NCT06719362). Methods Dose escalation (3 + 3 design) of M3T01 as monotherapy (cohorts 1-5) and in combination with pembrolizumab (cohorts 6-8) is ongoing. Dose levels of M3T01 range from 100 to 800 mg intravenously every 3 weeks. Eligible patients have selected unresectable or metastatic solid tumors that have progressed through standard therapy. The primary objectives are to assess the safety/tolerability, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of M3T01. Secondary objectives include pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor efficacy of M3T01 as monotherapy and in combination with pembrolizumab. Results As of the data cutoff, 10 patients (4 women, 6 men) with a median age of 68 have been treated across 3 dose escalation cohorts (100 mg, 200 mg, 400 mg). Treatment-related adverse events (TRAE) of any grade (CTCAE v5.0) were reported in 5 of 10 patients (50%). Only one grade 3 TRAE was observed, immune thrombocytopenia (ITP), and there were no grade 4 or 5 TRAEs. The most common TRAEs included maculopapular rash (n=2, 20%), arthralgia (n=2, 20%), myalgia (n=1, 10%), chills (n=1, 10%), hypothyroidism (n=1, 10%), and ITP (n=1, 10%). No patients discontinued treatment due to TRAEs. No DLTs were observed and an MTD has not been reached. PK exposures increased approximately dose proportionally. Transient anti-drug antibodies (ADA) were observed without any impact on systemic exposure to M3T01. On-target pharmacodynamic potency of FasL inhibition was characterized, e.g. increased peripheral blood CD3 + /CD4 - /CD8 - (double-negative) T cells. The best objective response observed with escalating doses of M3T01 monotherapy was stable disease in 6 of 10 patients (60%). Three patients demonstrated tumor regression including a patient with treatment refractory gastroesophageal (GEJ) adenocarcinoma in which several liver metastases decreased in size. Conclusion Interim results of this first-in-human phase I clinical trial demonstrate that M3T01 has been well-tolerated and is showing approximately dose-proportional PK exposures. Preliminary signals of antitumor efficacy with M3T01 as monotherapy have been observed. These findings support the ongoing clinical development of this potent FasL inhibitor.