Dual-masked PSMA-targeting T-cell engager shows promise in mCRPC

Data from an ongoing phase 1 trial (NCT05997615) showed encouraging preliminary safety and efficacy of the dual-masked prostate-specific membrane antigen (PSMA)-targeting T-cell engager VIR-5500 in patients with metastatic castration-resistant prostate cancer (mCRPC), Vir Biotechnology reported in a news release.¹

At the time of data report, the maximum tolerated dose had not been reached.

The company also shared positive findings from a phase 1 study of their second dual-masked T-cell engager, VIR-5818. The agent is being assessed as a monotherapy and in combination with pembrolizumab (Keytruda) in patients with certain HER2-expressing tumors.

“Overcoming the toxicity-driven limitations of traditional T-cell engagers could address an important unmet medical need in cancer care,” said Marianne De Backer, MSc, PhD, MBA, CEO of Vir Biotechnology, in the news release.¹ “Preliminary safety and efficacy data for our dual-masked T-cell engagers VIR-5818 and VIR-5500 are compelling, and we will continue dose escalation with an opportunity to expand the therapeutic window. We are encouraged that our candidates may enable efficacious and well-tolerated treatment regimens, potentially improving outcomes for people living with a range of solid tumors.”

Overall, preliminary efficacy data from the phase 1 trial of VIR-5500 showed early signs of prostate-specific antigen (PSA) responses. Following an initial dose of VIR-5500 of 120 µg/kg or higher, all patients achieved a PSA reduction, and 58% (7 of 12) of patients achieved a PSA reduction of at least 50%.

Regarding safety, no dose-limiting toxicities were observed among patients who received doses ranging up to 1000 µg/kg without prophylactic corticosteroids. Additionally, treatment-emergent adverse events were generally low-grade. Grade 1 and 2 cytokine release syndrome (CRS) was reported in 17% and 11% of patients, respectively. No instances of grade 3 or higher CRS was reported at any dose level.

Further, the company noted, “No hearing loss has been reported, suggesting safety benefits of dual masking in preventing on-target, off-tumor toxicities.”

They also added, “Preliminary pharmacokinetics and safety data indicate tumor-specific activation with minimal unmasking outside the tumor.”

In total, the phase 1 trial has enrolled 18 adult patients with mCRPC across 8 clinical trial sites in Europe and Australia.² All participants had received 3 to 6 prior lines of therapy.

To be eligible for enrollment, patients need to have histological, pathological, and/or cytological confirmation of prostate adenocarcinoma or metastatic disease typical of prostate cancer; metastatic disease; an ECOG performance score of 0 to 1; and a life expectancy of more than 6 months. Participants also needed to have been treated with at least 1 prior taxane regimen and deemed unsuitable for standard of care options.

For phase 1 of the study, VIR-5500 monotherapy is administered via intravenous infusion over a 21-day cycle. The company is evaluating VIR-5500 in a Q3W dosing regimen due to its half-life of 8 to 10 days.

At the time of data report, the maximum tolerated dose in the study had not been reached.

The trial remains ongoing, with final completion of both phase 1 and phase 2 expected in September 2027.²

References

1. Vir Biotechnology announces encouraging safety and efficacy data in ongoing dose escalation trials for dual masked T-cell engagers VIR-5818 in solid tumors and VIR-5500 in mCRPC. News release. VIR Biotechnology. Published online and accessed January 8, 2025. https://investors.vir.bio/news/news-details/2025/Vir-Biotechnology-Announces-Encouraging-Safety-and-Efficacy-Data-in-Ongoing-Dose-Escalation-Trials-for-Dual-Masked-T-Cell-Engagers-VIR-5818-in-Solid-Tumors-and-VIR-5500-in-mCRPC/default.aspx

2. Safety, pharmacokinetics, and preliminary efficacy of AMX-500 in metastatic castration resistant prostate cancer (mCRPC). ClinicalTrials.gov. Last updated November 18, 2024. Accessed January 8, 2025. https://clinicaltrials.gov/study/NCT05997615