BT8009 Bicyclic Toxin Conjugate Shows ‘Promising Tolerability’ in First-in-Human Trial

Author: By Laura Cowen, medwireNews Reporter 

medwireNews: The novel drug BT8009, which comes from a class of chemically synthesised molecules known as Bicycle® Toxin Conjugates (BTC™), has shown promising tolerability and efficacy in a phase I/II clinical trial among patients with Nectin-4 expressing advanced solid tumours. 

Speaking at the 2022 AACR Annual Meeting in New Orleans, Louisiana, USA, Meredith McKean, from Sarah Cannon Research Institute in Nashville, Tennessee, USA, explained that BT8009 is made up of a bicyclic peptide targeting Nectin-4 tumour antigen linked to the cytotoxin monomethyl auristatin E (MMAE) via a valine–citrulline cleavable linker. 

Its unique properties include a very low molecular weight, of 1.5-2.0 kDa, which is 50 to 100 times smaller than antibodies, and its high selectivity for tumour antigens, explained the presenter. 

The first-in-human trial included 37 patients (median age 66 years, 59.5% men) with advanced solid tumours associated with Nectin-4 expression, who had received a median of three prior lines of therapy but had not been exposed to the Nectin-4 targeting antibody–drug conjugate (ADC) enfortumab vedotin. 

Just under half (49%) of participants had urothelial cancer, 16% had pancreatic cancer, 14% had lung cancer, 11% breast cancer, 5% head or neck cancer and 3% each had oesophageal or ovarian cancer. 

The dose-escalation phase of the study began with seven patients receiving BT8009 2.5 mg/m2 per week until disease progression or intolerable toxicity. Twenty patients received 5.0 mg/m2 per week, four were given 7.5 mg/m2 per week and three received 7.5 mg/m2 every 2 weeks. 

Pharmacokinetic analysis showed that BT8009 has a short terminal half-life with no systemic exposure after 12 hours but delivers sustained MMAE concentrations that Meredith McKean said are “broadly similar to those observed with ADCs”. 

The most common treatment-emergent adverse events (AEs) were fatigue (41%) and nausea (38%) followed by diarrhoea, pyrexia, anaemia and decreased appetite, which occurred in 32% each. Seven (19%) patients had treatment-emergent serious AEs and two patients experienced a dose-limiting toxicity (grade 4 neutropenia and grade 3 asthenia). 

Among the AEs of interest previously associated with Nectin-4 targeting molecules, 14% of patients had grade 3 or worse neutropenia, 5% had grade 3 or worse diarrhoea, and 3% each had grade 3 or worse neuropathy, nausea and vomiting. There were no cases of grade 3 or worse rash or ocular toxicity. 

Treatment-emergent AEs resulting in dose interruptions or reductions were observed in five (14%) patients each. Two patients discontinued treatment for reasons unrelated to the study drug. 

An efficacy analysis including eight patients with urothelial carcinoma who received BT8009 5.0 mg/m2 per week revealed that one patient had a complete response (CR) and three had deep partial responses ranging from 54% to 71% tumour reduction, giving an overall response rate of 50%. Three of the four patients had ongoing responses, with the longest lasting over 5 months. 

Meredith McKean concluded that BT8009 has a “promising preliminary tolerability profile with the absence of significant skin and ocular toxicity.” 

She added that the treatment “exhibits a robust efficacy signal” in people with urothelial carcinoma, where “deep and durable responses” were observed. 

The researchers are now continuing with dose optimisation and planning a phase II expansion study with BT8009 monotherapy and in combination with immune checkpoint inhibition. 

Reference  

McKean M, Baldini C, Verlingue L, et al. BT8009-100 phase I/II study of novel bicyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies associated with nectin-4 expression. AACR Annual Meeting 2022; New Orleans, Louisiana, USA: 8–13 April.