Bispecific antibody shows durable benefit in advanced solid tumors
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A novel PD-1/CTLA-4 bispecific checkpoint inhibitor demonstrated antitumor activity and tolerability among patients with advanced solid tumors, according to study results.
Preliminary data from the first-in-human study of MEDI5752, presented at American Association for Cancer Research Annual Meeting, showed evidence of T-cell activation and clonal expansion at higher phamacodynamic levels than clinically feasible with dosing of conventional anti-PD-1 plus anti-CTLA-4 therapies, according to researchers.
“The success of PD-L1 and anti-PD-1 therapies has overshadowed that of anti-CTLA-4, where single-agent activity has been modest. Data suggest that higher doses of anti-CTLA-4 improve OS, but also increase serious toxicity,” Ben Tran, MBBS, associate professor in the department of oncology at University of Melbourne and lead medical oncologist in the genitourinary medical oncology and genitourinary clinical trials programs at Peter MacCallum Cancer Center in Australia, said during the presentation.
“The challenge for further developing anti-CTLA-4,” Tran continued, “is to find a way to deliver greater CTLA-4 blockade and the associated improved survival without the increase in toxicity and, in doing so in combination with anti-PD-L1, provide our patients with the greatest benefit.”
Background and methodology
MEDI5752 is a monovalent bispecific antibody targeting PD-1 and CTLA-4 with a bispecific format engineered to preferentially inhibit the two checkpoints on activated T cells in tumors, where co-expression is particularly abundant, Tran said. By doing this, MEDI5752 maximizes tumor-specific response and reduces the peripheral toxicity common when targeting these checkpoints independently, he added.
“The bispecific design of MEDI5752 allows preferential inhibition of CTLA-4 on PD-L1-positive activated T cells in addition to comparable inhibition of PD-1,” Tran said.
The analysis included 86 adults (median age, 60.5 years; 75.6% men) with an ECOG performance status of 0 to 1 who had tumors not amenable to standard therapy. The most common cancers in the cohort included renal cell carcinoma (22.1%), non-small cell lung cancer (16.3%), and head and neck cancer (8.1%).
Tran and colleagues treated patients at 10 dose levels from 2.25 mg to 2,500 mg via IV every 3 weeks until progression or unacceptable toxicity. Safety and identification of maximum tolerated dose served as primary objectives; secondary objectives included preliminary antitumor activity by RECIST version 1.1, pharmacokinetics and immunogenicity.
Key findings
Results at data cutoff Sept. 30, 2021, showed MEDI5752 demonstrated dose-dependent pharmacokinetics and sustained peripheral PD-1 receptor occupancy (> 90%) at doses over 225 mg. Tran and colleagues found dose-dependent increases in peripheral T-cell proliferation and activation plateaued at doses of 500 mg and over and demonstrated CTLA-4-specific blockade in the range of 6 mg/kg to 10 mg/kg tremelimumab (MedImmune/AstraZeneca).
Additionally, they found that at doses of at least 500 mg, MEDI5752 significantly expanded new and existing T-cell clones, likely broadening the tumor antigen-driven T-cell response, Tran said. They observed objective responses across all doses in 19.8% of patients (n = 17, one complete and 16 partial) and reported a median duration of response of 17.5 months. Molecular response, defined as 50% or greater reduction in circulating tumor DNA, occurred in 36.5% of patients.
“At doses of 500 mg and higher, MEDI5752 resulted in T-cell proliferation and clonal T-cell expansion that exceeds what is achievable at standard doses of code-administered anti-PD-L1 and anti-CTLA-4,” Tran said.
In safety analysis, Tran and colleagues found doses of at least 1,500 mg (n = 53) to be poorly tolerated; half of patients (50.9%) experienced grade 3 or grade 4 treatment-related adverse events, 45.3% discontinued treatment due to those adverse events and one patient who received the 2,000 mg dose died. However, they noted improved tolerability at doses of less than 1,500 mg (n = 33), with grade 3 or grade 4 treatment-related adverse events in 18.2% of patients and discontinuation due to those events in 9.1%.
Tran said the treatment is currently being investigated in doses of less than 1,500 mg in multiple expansion cohorts.
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Tran B, et al. Abstract CT016. Presented at: American Association for Cancer Research Annual Meeting (hybrid meeting); April 8-13, 2022; New Orleans.
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