Platinum-Resistant Ovarian
Cancer | Image credit: © Sebastian Kaulitzki
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TILT-123 given in combination with pembrolizumab (Keytruda) was safe and produced early signals of efficacy in patients with platinum-resistant or -refractory ovarian cancer, according to findings from the phase 1a PROTA study (NCT05271318) published in Nature Communications.
Patients who received the combination (n = 15) did not experience any dose-limiting toxicities (DLTs) and there were also no treatment-related adverse effects (TRAEs) related to complete blood count. The most common any-grade adverse effects (AEs) consisted of fever (40%), fatigue (40%), and nausea (40%).
Moreover, efficacy-evaluable patients (n = 14) achieved a median overall survival (OS) of 190 days and a median progression-free survival (PFS) of 98 days. The median time to progression was 98 days. The overall response rate (ORR) was 7.1% and the disease control rate per RECIST 1.1 criteria was 64%.
“TILT-123 is an oncolytic adenovirus encoding TNFα and IL-2, designed to complement T-cell therapies including immune checkpoint inhibition [ICI],” investigators wrote in the study. “The 2 cytokines were selected based on their ability to improve T-cell recruitment and activation in preclinical models of T-cell therapy. Later studies demonstrated outstanding effects—even 100% cure rates—in vivo, when combined with anti–PD-1 or anti–PD-L1, in mouse and hamster models of ICI naive or refractory melanoma, renal cell carcinoma, head and neck, ovarian, pancreatic, and lung cancer.”
Examining the PROTA Study Design and Baseline Characteristics
PROTA enrolled patients with histologically confirmed ovarian cancer that was resistant or refractory to platinum-based chemotherapy, including those with fallopian tube and primary peritoneal cancer. Patients were also required to have a life expectancy of over 3 months, a WHO/ECOG performance status of 0 or 1, and adequate hepatic as well as renal function. They also needed to have at least 1 tumor greater than 14 mm in diameter. Those with autoimmune disease within 2 years preceding enrollment that necessitated the use of immunosuppressive agents were excluded as were those who had received any anti-cancer therapy within 30 days of enrollment, had prior treatment with an anti–PD-1, –PD-L1, or –PD-L2 agent, or other agent directed towards a T-cell immune checkpoint receptor that resulted in discontinuation due to an immune-related adverse effect (AE), or had contraindications to pembrolizumab.
The study employed a 3+3 dose escalation design. In the initial treatment period, patients received 6 injections of TILT-123 and 3 infusions of pembrolizumab at a dose of 200 mg on days 36, 57, and 78. On day 1, patients received intravenous (IV) TILT-123 ranging from3 × 1011 to 4 × 1012 VPs. Subsequent TILT-123 doses ranged from 1 × 1011 to 5 × 1011 VP and were administered locally on days 8, 22, 36, 57, and 78. Patients in cohort 1 (n = 3) received 3 × 1011 VPs via IV infusion and 1 × 1011VPs for intratympanic and intraperitoneal injections; cohort 2 (n = 3) received 1 × 1012 VPs and 3 × 1011VPs, respectively; cohort 3 (n = 3) received 2 × 1012VPs and 3 × 1011VPs, respectively; and cohort 4 (n = 6) received 4 × 1012VPs and 5 × 1011VPs, respectively. An extension treatment period occurred for up to 2 years.
The primary end point of the study was safety measured by the instance and severity of AEs. Secondary end points included determining the maximum tolerated dose, response by standard imaging, changes in CA125 levels, PFS, OS, immune response to the virus and tumor, virus persistence, and virus shedding.
At baseline, the median age was 66 years (range, 36-78) and patients underwent a median of 7 prior lines of systemic therapy. Patients had a WHO/ECOG performance status of 1 (57%) or 0 (43%) and platinum-refractory (27%) or -resistant (73%) disease. The primary cancer types were epithelial ovarian (60%), fallopian tube (20%), and primary peritoneal cancer (20%); the most common histological subtype was high-grade serous ovarian cancer (73%).
Evaluating Additional Efficacy and Safety Findings
Additional findings from PROTA demonstrated that patients treated at the highest dose level of TILT-123 (n = 5) achieved an ORR of 20%. The median OS in cohorts 1, 2, 3, and 4 was 85, 122, 280, and 202.5 days, respectively. Three patients achieved an OS lasting for approximately 12 months after treatment initiation.
In terms of safety, the only grade 3 or higher TRAEs were delirium and hemoperitoneum, occurring in 1 patient each, both of whom were treated in cohort 4. There were no treatment-related deaths. No signs of liver toxicity were reported and there were no notable changes in creatinine, potassium, sodium, or thyroid stimulating hormone levels.
“Phase 1b [of PROTA] investigating TILT-123, pembrolizumab and PEGylated liposomal doxorubicin in a similar patient population is underway,” the study authors wrote.
Reference
Block MS, Clubb JHA, Mäenpää J, et al. The oncolytic adenovirus TILT-123 with pembrolizumab in platinum resistant or refractory ovarian cancer: the phase 1a PROTA trial. Nat Commun. 2025;16(1):1381. doi:10.1038/s41467-025-56482-w