Achievement of Dose-Dependent Peripheral T-Cell Proliferation Increase With MEDI5752 in Advanced Solid Tumors

Use of MEDI5752 in patients with advanced solid malignancies resulted in an boost in peripheral T-cell proliferation among those with, according to results from a first-in-human study.¹

In particular, this was observed at dose levels of 500 mg or higher, surpassing pharmacodynamic changes observed with 1 mg/kg to 3 mg/kg of tremelimumab, plus 10 mg/kg of durvalumab (Imfinzi).

“The total number of T-cell clones that expanded exhibits a dose-dependent increase before reaching a plateau from doses of 500 mg and beyond,” according to Ben Tran, MBBS, FRACP, lead genitourinary medical oncologist and associate professor at Peter MacCallum Cancer Centre. With regard to the proportion of newly expanded T-cell clones that weren’t present at baseline, he said, “Once again, there is a dose dependent increase before plateauing at 500 mg onwards. At that plateau, newly expanded clones represent 75% of all T-cell clones.”

MEDI5752 was designed to help boost CTLA-4 blockade on PD-1–positive activated T cells. The therapeutic preferentially binds to CTLA-4 on PD-1–positive T cells vs –negative T cells. MEDI5752 is able to induce comparable PD-1 binding on activated T cells, as well as yielding significantly greater CTLA-4 binding compared with co-administration.

Several doses of MEDI5752 were included in the dose-escalation portion of the trial, including 22.5 mg (n = 3), 75 mg (n = 3), 225 mg (n = 7), 500 mg (n = 3), 750 mg (n = 4), 1500 mg (n = 4), 2000 mg (n = 4), and 2500 mg (n = 7). In the immunotherapy-naïve dose expansion cohort (n = 25), patients received a 2000 mg dose intravenously every 3 weeks. The study’s primary objective was to assess the safety and efficacy of MEDI5752 and determine the maximum tolerated dose. Secondary outcomes included pharmacokinetics, immunogenicity, and preliminary anti-tumor activity.

To enroll on the study, patients were required to have measurable and histologically confirmed solid tumors, as well as disease that was refractory or not amenable to standard therapy. Patients also needed to be 18 years or older with an ECOG performance status of 0 or 1 and adequate organ function. Patients who received current or previous immunosuppressive therapy or who had active or prior autoimmune or inflammatory disorders were excluded from the study.

The median patient age was 60.5 years and the majority of patients were men (75.6%). The most common disease types were renal cell carcinoma (RCC; 22.1%) and non–small cell lung cancer (NSCLC; 16.3%). Most patients (61.6%) had a PD-1 expression of less than 1%.

Additional study findings indicated that MEDI5752 yielded dose proportional pharmacokinetics, with doses of over 225 mg providing sustained peripheral PD-1 receptor occupancy of over 90%.

In terms of safety, any grade and grade 3 or higher adverse events (AEs) related to treatment with MEDI5752 occurred in 85.0% and 38.4% of patients, respectively. Additionally, 31.0% of patients discontinued treatment due to AEs and 3 deaths, although only 1 was related to treatment with MEDI5752. Any grade AEs of special interest included dermatitis/rash (56%), hepatic events (27%), and diarrhea/colitis (11%). Grade 3 or higher AEs of special interest included hepatic events (17%), dermatitis/rash (6%), and diarrhea/ colitis (2%).

Doses of less than 1500 mg appeared to be better tolerated, according to Tran.

“The rate of discontinuation due to any grade AE were lower at 9% compared with 47%,” he explained. “Grade 3 to 4 related AEs were lower at 18% compared with 50%. This is also reflected in the grade 3/4 rates of hepatic events and grade 3/4 dermatitis or rash. The low rates of colitis remain consistent in both groups. One caveat of these data is that the low-dose group only includes 13 patients who received 500 mg and 700 mg MEGI5752. However, even when limiting the analysis to those 13 patients, the rates of discontinuation due to AEs remained lower at 23%—less than half that of the higher-dose group.”

Of the response evaluable patients (n = 86), investigators reported an overall response rate of 19.8% (95% CI, 12.0%-29.8%). One patient achieved a complete response, 16 had partial responses, 29 had stable disease, and 32 had progressive disease. The molecular response rate was 36.5% and the disease control rate was 53.5% (95% CI, 42.4%-64.3%). The median duration of response was 17.5 months.

In particular, robust responses were reported across different immunotherapy-naïve solid malignancies and with different doses, including RCC (multiple doses; n = 7), triple-negative breast cancer (2500 mg; n = 1), NSCLC (2000 mg; n = 2), mesothelioma (2000 mg; n = 1), thymic carcinoma (2000 mg; n = 1), colorectal cancer (1500 mg; n = 1), gastric cancer (500 mg, 2000 mg; n = 2), bladder cancer (500 mg; n = 1), Merkel cell carcinoma (225 mg; n = 1), and cervical cancer (22.5 mg; n = 1).

_Reference

_{Tran B, Voskoboynik M, Kim SW, et al. MEDI5752, a novel PD-1/CTLA-4 bispecific checkpoint inhibitor for advanced solid tumors: first-in-human study. Abstract CT016}