MEDI5752, a Novel PD-1/CTLA-4 Bispecific Checkpoint Inhibitor for Advanced Solid Tumors: First-in-Human Study

MEDI5752 is a novel monovalent bispecific antibody designed to target PD-1 and CTLA-4.^1,2 The unique bispecific structure allows for preferential inhibition of these 2 checkpoints on activated T-cells in tumors, where co-expression is usually abundant.^1,2 This results in improved anticancer immune response and reduced peripheral toxicity that is common when targeting these checkpoints independently.² The results of the dose-escalation study for MEDI5752 from a phase 1, open-label, multicenter study in advanced solid tumors (NCT03530397) were recently reported at the American Association for Cancer Research 2022 annual meeting.²

The study enrolled patients with an Eastern Cooperative Oncology Group performance status of 0 or 1.² Patients were treated with MEDI5752 at 10 dose levels ranging from 2.25 mg to 2500 mg intravenously every 3 weeks until progression or unacceptable toxicity. The primary objectives were safety and identification of maximum tolerated dose. Secondary objectives included preliminary antitumor activity by RECIST version 1.1, pharmacokinetics, and immunogenicity. Exploratory objectives included the evaluation of pharmacodynamic biomarkers.²

By the cutoff date of September 30, 2021, 86 patients were enrolled. The most common tumor types were renal-cell carcinoma (22.1%), non–small-cell lung cancer (16.3%), and head and neck cancer (8.1%).² Of these patients, 95.2% had received prior systemic therapy, and 90.7% were immunotherapy naïve.²

MEDI5752 showed dose-dependent pharmacokinetics and sustained peripheral PD-1 receptor occupancy (>90%) at doses >225 mg. Dose-dependent increases in peripheral T-cell proliferation (Ki67+) and activation (ICOS+) plateaued at doses ≥500 mg and demonstrated CTLA-4–specific blockade in the range that is achieved with tremelimumab 6 mg/kg to 10 mg/kg.²

At doses ≥500 mg, MEDI5752 resulted in a significant expansion of new and existing T-cell clones.² Across all doses, objective responses were observed in 19.8% of patients (n = 17; 1 complete response and 16 partial responses).² Median duration of response was 17.5 months. Molecular response (defined as ≥50% reduction in ctDNA) was observed in 36.5% of participants. Doses ≥1500 mg (n = 53) were poorly tolerated and were associated with grade 3/4 treatment-related adverse events (TRAEs) in 50.9% of patients. Discontinuation due to TRAEs occurred in 45.3% of patients, and death occurred in 1 patient (at 2000 mg). However, doses <1500 mg (n = 33) were better tolerated, with grade 3/4 TRAEs occurring in 18.2% of patients, and discontinuations due to TRAEs occurring in 9.1%. A maximum tolerated dose was not reached based on the protocol-defined dose-limiting toxicity criteria. Immune-related adverse events were also less common at doses <1500 mg than doses >1500 mg (grade 3/4 rates of 18.2% vs 49.1%, respectively).²

MEDI5752 showed promising antitumor activity with durable clinical benefit and was well-tolerated at doses <1500 mg. In addition, MEDI5752 resulted in robust dual checkpoint blockade, T-cell activation, and expansion of new and existing T-cell clones.

References

1. Dovedi SJ, Elder MJ, Yang C, et al. Design and efficacy of a monovalent bispecific PD-1/CTLA4 antibody that enhances CTLA4 blockade on PD-1+ activated T cells. Cancer Discov. 2021;11:1100-1117.
2. Tran B, Voskoboynik M, Kim SW, et al. CT016 - MEDI5752, a novel PD-1/CTLA-4 bispecific checkpoint inhibitor for advanced solid tumors: first-in-human study. Presented at: American Association for Cancer Research Annual Meeting (hybrid meeting); April 8-13, 2022; New Orleans, LA. Abstract CT016.