Recurrent ovarian cancer remains largely resistant to immunotherapy, with PD-1 inhibitors such as pembrolizumab showing limited activity as monotherapy (ORR ~8% in prior studies). A key driver of this resistance is a highly immunosuppressive tumor microenvironment, enriched with regulatory T cells (Tregs) that inhibit effective antitumor immune responses.
TNFR2 is preferentially expressed on suppressive intratumoral Tregs and plays a central role in immune evasion and tumor progression. BI-1808 is a first-in-class agent designed to disrupt TNFR2-mediated Treg function. Preclinical data suggest that TNFR2 blockade can synergize with PD-1 inhibition, providing a strong rationale for combination strategies.
The KEYNOTE-D20 trial explores whether targeting Treg-driven immunosuppression with BI-1808 can enhance and extend the efficacy of pembrolizumab, offering a potential chemotherapy-free immunotherapy option for patients with recurrent ovarian cancer.
Ovarian Cancer: Symptoms, Causes, Stages, Diagnosis and Treatment
Key Efficacy Signals
In an interim analysis of the phase 2a dose-expansion cohort of KEYNOTE-D20, 17 evaluable patients with recurrent ovarian cancer achieved:
- Disease control rate (DCR): 65% (4 partial responses, 7 stable disease)
- Overall response rate (ORR): 24%
These outcomes exceed historical benchmarks for pembrolizumab monotherapy in this disease (eg, ~8% ORR in KEYNOTE-100), suggesting true combination-driven activity rather than additive effects.
Mechanistic Rationale
BI-1808 is a first-in-class IgG1 antibody targeting TNFR2, a receptor enriched on regulatory T cells (Tregs) within the tumor microenvironment. By disrupting TNFR2-mediated Treg survival and function, BI-1808 is designed to relieve immunosuppression and re-sensitize tumors to PD-1 blockade. Preclinical data demonstrate synergy with pembrolizumab, aligning with the clinical signal observed here.
Safety
The combination was reported to have a generally favorable and manageable safety profile, supporting feasibility of chemotherapy-free immunotherapy in this heavily pretreated population. No unexpected toxicities were highlighted in the interim readout.
Trial Design Snapshot
- Design: Global, multicenter, open-label phase 1/2a (first-in-human)
- Population: Advanced malignancies progressing after standard therapy; current focus on recurrent ovarian cancer
- Intervention: BI-1808 at the recommended phase 2 dose, alone or combined with pembrolizumab
- Endpoints: ORR, duration of response, PFS (RECIST v1.1 / iRECIST)
- An expansion cohort is planned to enroll ~20 additional patients with high-grade serous and clear-cell ovarian cancer, with further data anticipated in 2H 2026.
IO Takeaway
By directly targeting TNFR2-positive Tregs, BI-1808 represents a next-generation immunomodulatory strategy that may unlock durable responses to PD-1 blockade in ovarian cancer—an area of longstanding unmet need. While early and hypothesis-generating, the signal justifies continued development and careful biomarker-guided expansion.
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