MT-8421 Displays Acceptable Safety Profile in First-in-Human Trial for Advanced Solid Tumors

Treatment with the novel CTLA-4–targeted engineered toxin body MT-8421 was safe and produced no grade 4 or 5 toxicities in patients with select advanced solid tumors, according to findings from the dose-escalation portion of a first-in-human phase 1 trial (NCT06034860), which were presented at the 2025 ESMO Targeted Anticancer Therapies Congress.1

The maximum tolerated dose (MTD) was not reached. Across all treated patients (n = 15), the most frequently reported treatment-emergent adverse effects (TEAEs), including immune-mediated AEs, were pyrexia/chills (40%; n = 6), infusion-related reactions (IRRs; 33%; n = 5), fatigue (27%; n = 4), pruritus (27%; n = 4), rash (20%; n = 3), nausea (20%; n = 3), and muscle/joint pain (20%; n = 3). Grade 3 TEAEs were infrequent. No grade 4 or 5 TEAEs were reported. Notably, grade 1/2 cytokine release syndrome (CRS) was observed in 7% of patients (n = 1); no grade 3 CRS occurred.

The best overall responses per RECIST 1.1 criteria included stable disease (SD) in 33% of patients (n = 3) and progressive disease in 66% of patients (n = 6). No patients achieved a partial or complete response.

“MT-8421 reduced T-cell regulation, which may allow for immune re-invigoration. Further investigation of CTLA-4 as a target for an engineered toxin body is warranted to determine whether combination treatment with approved checkpoints may enhance effects,” explained lead study author Justin T. Moyers, MD, in the presentation.

Moyers is a medical oncologist and hematologist at The Angeles Clinic and Research Institute in Los Angeles, California.

Study Design

To be eligible for enrollment in this trial, patients must have had histologically confirmed, unresectable, locally advanced or metastatic solid tumors, including: melanoma, hepatocellular carcinoma (HCC), non–small cell lung cancer (NSCLC), renal cell carcinoma (RCC), microsatellite instability–high or mismatch repair-deficient malignancies, urothelial carcinoma, esophageal squamous cell carcinoma, mesothelioma, head and neck squamous cell carcinoma (HNSCC), or cervical carcinoma. Patients in the dose-escalation portion must have had measurable or evaluable disease per RECIST 1.1 criteria. Patients needed to have received prior treatment with a PD-1 or PD-L1 inhibitor. Prior therapy with a CTLA-4 inhibitor was not required.

Additional key inclusion criteria included adequate bone marrow function, defined as an absolute neutrophil count of at least 1500/µL, a platelet count of at least 75,000/µL, and hemoglobin levels of at least 8.0 g/dL. Patients must have also demonstrated adequate renal function, defined as an estimated creatinine clearance of at least 50 mL/min; and adequate hepatic function, defined as a total bilirubin level of no more than 1.5 times the upper limit of normal (ULN) and AST/ALT levels no greater than 3 times the ULN.

Patients enrolled in this phase 1 study received intravenous infusion of MT-8421 monotherapy over 30 minutes on days 1, 8, 15, and 22 of each 28-day cycle. The study followed a dose-escalation design using a Modified Toxicity Probability Interval model to determine the MTD and recommended phase 2 dose. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, death, study termination by the sponsor, or fulfillment of another discontinuation criterion.2

The primary objective of the study was to assess the safety and tolerability of MT-8421 per the incidence of AEs, including dose-limiting toxicities; and to estimate the MTD.1

Secondary objectives included evaluating the efficacy of MT-8421 in terms of objective response rate, duration of response, and disease control rate; as well as characterizing the pharmacokinetics and immunogenicity of the agent.

Baseline Patient Characteristics

Among the enrolled patients, the median patient age was 63 years (range, 32-75). In total, 53% of patients (n = 8) were female, 87% of patients (n = 13) were White, and 13% of patients (n = 2) were Asian. Melanoma was the most common tumor type, present in 53% of patients (n = 8). NSCLC and HNSCC each accounted for 13% of patients (n = 2 each), whereas 1 patient each had cervical cancer, RCC, and HCC. Most patients (93%; n = 14) had received prior anti–PD-1 therapy, and 53% of patients (n = 8) had been previously treated with an anti–CTLA-4 agent.

Safety Data Stratified by Cohort

Patients in cohort 1 (n = 3) received MT-8421 at 32 µg/kg. The most common grade 1/2 TEAEs in this cohort included pyrexia/chills and IRRs (n = 2 each); as well as fatigue, pruritus, rash, muscle/joint pain, nasal congestion/drip, hemorrhage, and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) level increases (n = 1 each). One patient experienced a grade 3 thromboembolic effect, and 1 patient had grade 3 anemia.

The most commonly reported grade 1/2 TEAEs in cohort 2 (n = 7) included fatigue, pruritus, and muscle/joint pain (n = 2 each); as well as pyrexia/chills, IRRs, nausea, diarrhea, thromboembolic event, nasal congestion/drip, CRS, and rash (n = 1 each). One patient had a grade 3 anemia effect, and another patient had grade 3 hemorrhage.

The most common grade 1/2 TEAEs in cohort 3 (n = 5) were pyrexia/chills (n = 3); IRRs, nausea, and cough (n = 2 each); and fatigue, rash, diarrhea, AST/ALT level increases, and myalgia (n = 1 each). No grade 3 TEAEs were reported in this cohort.

Pharmacokinetics Findings

MT-8421 was shown to deplete T-regulatory cells that are known to express high levels of CTLA-4. Treatment with this agent also led to an increase in the ratio of CD8 cells to CD4 cells from baseline and induced a T-cell effector phenotype.

Case Study Findings

In the presentation, Moyers presented a case study of a 63-year-old male with stage IIIA BRAF V600E-positive cutaneous melanoma of the left shoulder, with disease sites in the bilateral lung nodules and subcarinal lymph nodes, as well as a boney lesion in the left humerus. This patient received MT-8421 in cohort 1 and had a best response of SD.

Notably, this study was terminated by Molecular Templates, Inc., the study sponsor.2

References

1. Moyers JT, Singh S, Spira A, et al. First-in-human, dose escalation of MT-8421: a novel engineered toxin body (ETB) targeting CTLA-4, in patients with select advanced solid tumors. ESMO Open. 2025;10(suppl 2):104166. doi:10.1016/j.esmoop.2025.104166
2. Study of MT-8421 as monotherapy and in combination with nivolumab in patients with selected advanced solid cancer types. ClinicalTrials.gov. Updated November 1, 2024. Accessed March 11, 2025. https://clinicaltrials.gov/study/NCT06034860