BI-1808 Shows Efficacy as Monotherapy and in Combination With Pembrolizumab in T-Cell Lymphomas

Treatment with BI-1808 yielded robust responses as both monotherapy and in combination with pembrolizumab (Keytruda) in patients with T-cell lymphomas, according to findings from the phase 2 CTCL portion of the phase 1/2 19-BI-1808-01/KEYNOTE-D20 trial (NCT04752826) presented at the 6th World Congress on Cutaneous Lymphomas.¹

Overall, responses with BI-1808 monotherapy were reported across subgroups of heavily pretreated patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Among patients who received BI-1808 monotherapy, the overall response rate (ORR) was 40%, including 1 complete response (CR) and 5 partial responses (PRs). The disease control rate (DCR) was 93%. Notable response cases included a patient with stage IV PTCL who had received 6 prior lines of treatment and responded by week 9, as well as a patient with CTCL (mycosis fungoides) who had received 5 prior lines of treatment and responded by week 21.

Of the patients who received BI-1808 in combination with pembrolizumab, the ORR was 50%, including 4 PRs. Additionally, the DCR was 75%.

BI-1808 was also shown to induce sustained CD4-positive T-cell depletion in patients experiencing disease control. Additionally, correlative studies confirmed that BI-1808 increased levels of cytotoxic CD8-positive cells in tumor tissue and increased the CD8/CD4-positive cell ratio, all of which was consistent with the hypothesized mechanism of action of the agent.

“There was a high rate of stable disease, and we term that DCR,” Stefan K. Barta, MD, MS, MRCPCUK, said in an interview with OncLive^®. “[Although] that might not be as important in other diseases, for a disease such as CTCL, where it is hard to meet these classical criteria for PR or CR, even stabilizing the disease for a long time with an agent that has limited toxicity can be meaningful.”

Barta is director of the T-cell lymphoma program and executive officer of the AIDS Malignancy Consortium at the Penn Medicine Abramson Cancer Center, as well as an associate professor of medicine (hematology-oncology) at the Hospital of the University of Pennsylvania in Philadelphia.

What was the rationale for investigating BI-1808 in T-cell lymphomas?

TNFR2 is a potential T-cell lymphoma oncogene; recurrent gain-of-function alterations, as well as point mutations, drive the abnormal expression of this oncogene on CD4-positive, CD26-negative tumor cells.

BI-1808 is a first-in-class IgG1 monoclonal antibody directed against TNFR2. It inhibits TNF-α interaction, enables the depletion of FcγR-dependent malignant cells, reprograms myeloid cells, and promotes the intratumoral expansion of CD8-positive T cells and other cytotoxic activity within the skin. The mechanism of action of BI-1808 is hypothesized to enhance tumor responsiveness to checkpoint blockade.

As monotherapy, BI-1808 has shown activity in CTCL and PTCL, as well as in solid tumors. TNFR2-targeting agents have also shown enhanced antitumor activity when combined with PD-1 inhibitors in preclinical and early clinical studies.

What was the design of the KEYNOTE-D20 trial?

In part A of the phase 1 dose-escalation portion of the trial, BI-1808 monotherapy was administered at ascending doses.² The agent was shown to induce regulatory T cell depletion, activate CD8-positive T cells in responders compared with baseline levels.

Based on findings from the phase 1 dose-finding portion of the trial, 1000 mg every 3 weeks was chosen as the signal-seeking dose for the phase 2 portion.¹ The phase 2a signal-seeking CTCL cohort of this trial enrolled patients with CTCL, who received the signal-seeking dose of BI-1808 with or without pembrolizumab.

BI-1808 is also being studied in this trial as a single agent and in combination with pembrolizumab in patients with solid tumors, including ovarian cancer, melanoma, and non–small cell lung cancer.²

What patients were enrolled in the CTCL phase 2a portion of KEYNOTE-D20?

In the CTCL signal-seeking cohort, patients had a median age of 64 years (range, 27-77) and were heavily pretreated, having received a median of 4 prior systemic therapies (range, 1-14).¹ In total, 43% of patients had Sézary syndrome, and 39% of patients had received prior treatment with mogamulizumab.

What was the safety profile of BI-1808 in T-cell lymphoma?

Among 23 evaluable patients with CTCL and PTCL in the CTCL monotherapy arm, 9% had grade 3 or higher treatment-related adverse effects (TRAEs), and 4% had TRAEs leading to treatment discontinuation.

Among 10 evaluable patients in the combination CTCL arm, 40% had grade 3 or higher TRAEs, and 10% had TRAEs leading to treatment discontinuation.

“We did see an increase in toxicity [with the addition of pembrolizumab], and at this point in time, it might be favorable to just move forward with single-agent BI-1808 initially, as it is a safe drug, and see then if a combination with other agents, such as other checkpoint blockade agents or other immune-stimulatory agents, may be advantageous down the road,” Barta concluded in the interview. “It would be important to have another agent that is safe, not immunosuppressive, has limited toxicity, and provides prolonged disease stabilization for our patients.”

References

1. Querfeld C, Barta S, Morris S, et al. Targeting TNFR2 with BI-1808: immune activation and promising responses in advanced T-cell lymphomas. Presented at: 6th World Congress on Cutaneous Lymphomas; June 25-27, 2026; Montreal, Quebec, Canada. Abstract 6.02.
2. Rohrberg KS, Papai Z, Eefsen RL, et al. 19-BI-1808-01, a phase 1/2a clinical trial of BI-1808, a tumor necrosis factor receptor 2 (TNFR2) blocker/depleter with or without pembrolizumab. J Clin Oncol. 2024;42(suppl 16). doi:10.1200/JCO.2024.42.16_suppl.2641