First-In-Human Study For Bispecific Checkpoint Inhibitor Shows ‘Encouraging Activity'

Author: By Lynda Williams, medwireNews Reporter 

medwireNews: The PD-1/CTLA-4 bispecific checkpoint inhibitor MEDI5752 increases peripheral T-cell proliferation and has shown encouraging activity across a range of advanced solid tumours, indicates research presented at the 2022 AACR Annual Meeting in New Orleans, Louisiana, USA. 

The first-in-human study findings were presented by Ben Tran, from the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia, who said that MEDI5752 is now being tested in expansion cohorts of patients with renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC). 

The investigator explained that serious toxicity has prevented use of CTLA-4 monotherapy at the high doses shown to improve survival and increase T-cell proliferation and activation. 

To overcome this toxicity issue, the researchers designed the MEDI5752 monovalent antibody, which has affinity to both PD-1 and CTLA-4 and therefore enhances CTLA-4 blockade on PD-1-positive activated T cells. 

Ben Tran said that “by using PD-1 as an anchor MEDI5752 is able to saturate the CTLA-4 receptor at much lower concentrations on PD-1-positive T cells compared to the PD-1-negative resting T cells”. 

And when compared with co-administration of both PD-1 and CTLA-4 inhibitors, MEDI5752 achieved “preferential inhibition of CTLA-4 on PD-1-positive activated T cells and comparable inhibition of PD-1”, he reported. 

The study design included acceleration and dose-escalation phases, increasing the dose from 2.25 mg to 2500 mg given at 3-week intervals, followed by a dose-expansion phase using a 2000 mg dose. 

The 86 patients in the current analysis include 61 from the dose-expansion phase and 25 from the 2000 mg expansion cohort; participants were aged a median 60.5 years and the most common diagnoses were RCC (22.1%) and NSCLC (16.3%). The majority of patients were PD-L1-negative (61.6%) and immunotherapy-naïve (90.7%), and the median number of prior treatments was one. 

Pharmacokinetic analysis demonstrated that MEDI5752 doses over 225 mg gave “sustained peripheral PD-1 receptor occupancy of greater than 90%”, the presenter said. And for doses of 500 mg and higher, there was a dose-dependent increase in peripheral T-cell proliferation that “approaches” the 1000–2000-fold increase achieved by tremelimumab 10 mg/kg plus durvalumab associated with dose-limiting toxicity, he continued. 

Grade 3–4 treatment-related adverse events (TRAEs) occurred in 38.4% of patients and 31.0% discontinued treatment because of TRAEs. TRAEs of special interest included rash, hepatic events and hypothyroidism, but rates of diarrhoea/colitis and infusion-related reactions were low grade and/or “uncommon”. 

Although a maximum tolerated dose was not reached, two patients developed dose-limiting toxicities. These included grade 3 pneumonitis and grade 1 myocarditis in one patient while on a dose of 2000 mg, and grade 3 maculopapular rash in the second patient on a dose of 2500 mg. 

There was one death related to MEDI5752 treatment in a patient with type 2 diabetes who was given the 2000 mg dose and developed diabetic ketoacidosis and hyperthyroidism during cycle 1. 

The presenter emphasized that treatment was “better tolerated” at a dose below 1500 mg than at higher doses, as demonstrated by lower rates of TRAEs leading to discontinuation (9 vs 47%) and grade 3–4 TRAEs (18 vs 51%), including both hepatic events and dermatitis/rash. 

Turning to the efficacy analysis, Ben Tram said that “MEDI5752 demonstrates encouraging anti-tumour activity”, with an objective response rate of 19.8% that included one complete response in a patient with Merkel cell carcinoma treated with the 225 mg dose.  

There were also partial responses achieved at a range of different doses in 18.6% of patients with nine other types of tumour including RCC, triple-negative breast cancer, NSCLC, mesothelioma, thymic carcinoma, colorectal and gastric cancer, bladder cancer and cervical cancer. The disease control rate was 53.5%. 

Furthermore, there was “durable” clinical benefit across a range of dose levels with a median duration of response of 17.5 months, the investigator said, adding that a molecular response, defined as a 50% or greater decrease in circulating tumour DNA by week 6, occurred in 36.5% of 63 evaluable patients. 

Ben Tram concluded that MEDI5752 has achieved “deep and durable responses” across a “diverse” range of tumours, leading to further exploration at 500–750 mg doses in RCC and NSCLC expansion cohorts. 

Session discussant Jason Luke, from the UPMC Hillman Cancer Center in Pittsburgh, Pennsylvania, USA, noted that a raft of other bivalent and tetravalent bispecific PD-1/PD-L1 and CTLA-4 antibodies are now in development, including lorigerlimab, but that as all have been largely assessed in single-arm studies, it is difficult to compare the agents or determine if they are more active than an anti-PD-1 inhibitor given alone. 

He observed that, as found with CTLA-4 inhibitors, there is a “plateau effect” for dosing with MEDI5752 on T-cell proliferation and T-cell clone expansion, “indicating that a modest amount of CTLA-4 blockade may be enough to maximise the effect without going too far to cause toxicity.” 

Jason Luke concluded that both prostate and ovarian cancer have shown response to PD-1–CTLA-4 agents but have been limited by toxicity and therefore may be suitable targets for bispecific antibody treatment. He added that there is also the potential with bispecific antibodies to introduce CTLA-4 targeting in combinations with current treatments for melanoma, RCC and NSCLC. 

Reference 

Tran B, Voskoboynik M, Kim S-W, et al. MEDI5752, a novel PD-1/CTLA-4 bispecific checkpoint inhibitor for advanced solid tumors: First-in-human study. AACR Annual Meeting 2022; New Orleans, Louisiana, USA: 8–13 April.