BT8009 Generates Encouraging Preliminary Antitumor Activity in Urothelial Cancer


The phase 1 dose-escalation portion of a phase 1/2 trial evaluating BT8009 in patients with urothelial cancer led to promising overall response and clinical benefit rates, including 1 complete response at the 5 mg/m2 dose.

A 50% overall response rate (ORR) and 75% clinical benefit rate was observed in the monotherapy phase 1 dose-escalation portion of an ongoing phase 1/2 trial (NCT04561362) of BT8009, a novel Bicycle Toxin Conjugate (BTC) targeting Nectin-4 in patients with urothelial cancer.1

Findings also revealed that 1 patient with urothelial cancer achieved a complete response at the 5 mg/m2 dose on an intent-to-treat basis.

Full results from this portion of the trial will be presented at the 2023 American Society for Clinical Oncology Genitourinary Cancers Symposium.

"These data reaffirm the possibility for BT8009 to become a significant new treatment option for patients," said Capucine Baldini, MD, medical oncologist, Gustave Roussy, in the press release. "The antitumor activity observed to date in heavily pre-treated urothelial, lung and breast cancer patients shows that BT8009’s Nectin-4–targeting properties make it a potentially differentiated treatment option compared to other available treatments."

BT8009 is a BTC targeting Nectin-4 that has previously demonstrated antitumor activity in heavily pretreated patients with urothelial, lung and breast cancer. The company has established 2 recommended phase 2 doses at 5 mg/m2 weekly and 7.5 mg/m2 using a 2-weeks-on, 1-week-off regimen over a 21-day cycle.

Currently, investigators are enrolling patients in the expansion cohort of the trial and evaluating the 5 mg/m2 weekly dose.

"BT009 has the potential to become an important player in the treatment landscape for urothelial cancer and other solid tumors," said Daniel Petrylak, MD, professor of medicine and Urology, Yale University, in the press release. "Clinicians need differentiated treatments for patients that can offer lower rates of rash and neuropathy thus leading to longer durations of treatment. Given the preliminary tolerability and response pattern with BT8009 in this phase 1 dose-escalation, it justifies exploring BT8009 both as a monotherapy and in combination in the ongoing expansion cohorts."

Part A of the phase 1/2 trial is the 3+3 dose-escalation portion of the study. Here, BT8009 monotherapy was administered weekly to patients at a dose of 2.5 mg/m2, 5 mg/m2, or 7.5 mg/m2 or every other week at 7.5 mg/m2 or 10 mg/m2 of a 28-day cycle, or on days 1 and 8 of a 21-day cycle at 7.5 mg/m2.

The primary end points of the study were to assess safety of the monotherapy and define maximum tolerated dose and recommended phase 2 dose (RP2D) of BT8009. Secondary end points included antitumor activity per RECIST v1.1 and pharmacokinetic parameters.

As of the data cutoff date of September 20, 2022, 49 patients were enrolled and dosed in the phase 1 escalation portion of the ongoing phase 1/2 study. The median age of patients was 66 years, 59% of patients were male, and the median prior lines of therapy was 3 (range, 1-15). Twenty-four patients with urothelial cancer were dosed and 8 of those patients were dosed at the RP2D of 5 mg/m2 weekly.2

Among the 8 patients, 1 achieved a complete response (13%), and 3 patients had a partial response (38%), resulting in an ORR of 50%. Two patients had stable disease for over 16 weeks, which led to a clinical benefit rate (CBR) of 75%. Additionally, 1 patient had stable disease and 1 patient was non-evaluable.

Seven of the 8 patients dosed at 5 mg/m2 weekly were response evaluable, and all (100%) were observed to have at least some degree of tumor shrinkage. This included 4 with a RECIST v1.1 response and an ORR of 57% on a response-evaluable basis.

The median duration of response (DOR) as of January 2023 is estimated to be about 14 months, and 2 of 4 responders within this cohort are currently still on therapy with ongoing responses.

Of patients receiving BT8009 at a dose of 7.5 mg/m2 2 weeks on, 1-week off and 10 mg/m2 every other week, findings were consistent with what was seen in the cohort of patients receiving the dose of 5 mg/m2 weekly. One of 2 patients in the 7.5 mg/m2 cohort reached a partial response while 2 of the 4 patients in the 10 mg/m2 cohort had a partial response, for an ORR of 50% in each cohort.

The median DOR has not yet been reached. However, as of September 20, 2022, the median DOR was at least 11 months. Plasma BT8009 and MMAE each exhibited linear pharmacokinetics. There was a short half-life for BT8009 (< 1 hour) and a longer half-life for MMAE (37-46 hours).

Looking at safety, the most common treatment-related adverse events (TRAE) of any grade experienced by at least 15% of patients included nausea, fatigue, diarrhea, decreased appetite, alopecia, asthenia, pyrexia, and neutrophil count decreased/neutropenia. A majority of these TRAEs were mild or moderate in severity.

There was 1 dose limiting toxicity (DLT) of grade 3 asthenia reported at the 7.5 mg/m2 weekly dose level. Then, 1 DLT of grade 4 sepsis was observed at the 10 mg/m2 biweekly dose level. Treatment-related serious AEs occurred in 5 patients. There were no treatment discontinuations due to an AE, and no treatment-related deaths occurred during the study.

"We are encouraged by the phase 1 dose-escalation results as they continue to demonstrate the potential for BT8009 to be best-in-class for the treatment of urothelial cancer based on the observed antitumor activity and tolerability profile as well as the potential to treat other tumor types with significant unmet need," said Kevin Lee, PhD, chief executive officer of Bicycle Therapeutics PLC, in the press release. "Previously, we had reported a confirmed partial response in a non­–small cell lung cancer patient and today we are pleased to announce a confirmed partial response in a breast cancer patient. Both of these patients are Nectin-4 positive. We are continuing to move forward with the dose expansion and phase 2 portion of the clinical trial and look forward to providing an update by the end of 2023."

1. Bicycle Therapeutics announces phase I dose escalation results from ongoing phase I/II study of BT8009. News release. Bicycle Therapeutics plc. February 14, 2023. Accessed February 16, 2023.
2. Baldini C, Goldschmidt V, Brana I, et al. BT8009-100: A phase I/II study of novel bicyclic peptide and MMAE conjugate BT8009 in patients (pts) with advanced malignancies associated with nectin-4 expression, including urothelial cancer (UC). J Clin Oncol. 2023;41 (suppl 6): Abstract 498. doi:10.1200/JCO.2023.41.6_suppl.498
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