BT5528 Shows Tolerability in Urothelial and Ovarian Cancer

Meredith McKean, MD, MPH

Tolerability and dose efficacy findings were determined for BT5528, a first-in class bicyclic peptide conjugated to monomethyl auristatin E (MMAE), in a phase 1/2 trial (NCT04180371) in patients with advanced malignancies associated with erythropoietinproducing hepatocellular A2 (EphA2) expression. The results were presented by Meredith McKean, MD, MPH, associate director of the Melanoma and Skin Cancer Research Program at Sarah Cannon Research Institute in Nashville, Tennessee, during the American Association for Cancer Research-National Cancer Institute- European Organisation for Research and Treatment of Cancer Virtual International Conference on Molecular Targets and Cancer Therapeutics.¹ Investigators reported meaningful pharmacodynamic and pharmacokinetic observations, suggesting tumor penetration in the standard 3+ 3 dose-escalation trial.

Observations of patients dosed at 6.5 mg/m² and above were presented during the conference, said McKean.

During the dose-escalation portion of the trial, transient grade 3/4 neutropenia events were noted and weekly dosing was transitioned to every-2-week dosing to allow for additional recovery. Two dose-limiting toxicities of grade 3 fatigue and pneumonitis were experienced at 10 mg/m² and declared as a maximum tolerated dose. The recommended phase 2 dose has not yet been selected.

“Patients with several different tumor types have been treated [in the study], including pancreatic adenocarcinoma, ovarian cancer, Ewing sarcoma, non– small cell lung cancer, and urothelial cancer,” said McKean. Patients with ovarian and urothelial cancer demonstrated signifi cant signs of clinical activity.

Investigators reported a preliminary unconfirmed response in 3 of 24 patients (12.5%) in all patients and for all doses. In patients with ovarian cancer, investigators reported a response rate of 12.5% (1 of 8 patients); in patients with immunohistochemistry (IHC)-positive ovarian cancer, a 20% response rate was observed (1 of 5 patients), as well as an 80% disease control rate (4 of 5 patients). In patients with urothelial cancer, the response rate was 100% (2 of 2 patients).

When reviewing efficacy over time, investigators reported that for patients with ovarian cancer, 4 of 5 with EphA2 IHC staining showed tumor shrinkage. One patient of 8 with ovarian cancer achieved a partial response (PR). Among patients with urothelial cancer, 2 of 2 patients achieved a PR at the first scan at 2 months. One patient continued to have a PR. “A second patient with a PR has continued to have systemic disease control that has had progression of a preexisting central nervous system lesion at 7 months,” McKean said.

McKean noted a preclinical correlation between EphA2 expression and efficacy.² “Now, these early clinical data suggest a signal here,” McKean said. “This does show that tumors with more EphA2 staining on IHC have demonstrated more tumor shrinkage.” She cautioned, however, “that these are very early data and will be reassessed after additional patients are treated on study.”

Twenty-four patients were dosed at 2.2 mg/m² once weekly escalating to 14.6 mg/m² once every 2 weeks. The median age was 65.5 years (range, 49-76) and the majority of patients were female (71%). Patients had a median of 7 prior therapies (range, 1-16). Primary end points were safety and tolerability and secondary end points included pharmacokinetics, pharmacodynamics, and preliminary signs of effi cacy.

Regarding safety, investigators reported 235 total adverse events and 101 events related to BT5528. Adverse events that were greater than grade 3 included neutropenia (8 of 13 patients; 61.5%) and anemia (15.4%). Pneumonitis, ileus, fatigue, and tumor lysis syndrome were reported in 1 patient each (0.08%). Other toxicities that were less than grade 3 were predominantly hematological and gastrointestinal.

Prior research with MEDI-547, an antibody-drug conjugate that incorporated a monoclonal antibody against EphA2 in patients with ovarian cancer, was halted following serious bleeding events in early-phase trials; however, no bleeding events were seen with BT5528 in previous toxicology studies. In the current study, no evidence of clotting abnormalities was observed.

Formal cohort expansion in multiple tumor types and dose escalation trials are being planned. Other bicyclic peptides are undergoing evaluation in the clinic, including a trial evaluating BT8009 in patients with Nectin-4–expressing solid tumors (NCT04561362).

_REFERENCES:

_{1. McKean M. A first in class phase I/II study of the novel bicyclic peptide and MMAE conjugate, BT5528, in patients with advanced malignancies associated with EphA2 expression. Presented at: AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; October 7-10, 2021; Virtual.}

_{2. Bennett G, Brown A, Mudd G, et al. MMAE delivery using the bicycle toxin conjugate BT5528. Mol Cancer Ther. 2020;19(7):1385-1394. doi:10.1158/1535-7163.MCT-19-1092}