Bicycle Therapeutics Updates EphA2 Pipeline Data

Bicycle Therapeutics announced updates from its EphA2 pipeline at the American Association for Cancer Research Annual Meeting 2026. Nuzefatide pevedotin, formerly BT5528, a potentially first-in-class EphA2 targeting Bicycle Drug Conjugate, Phase 1/2 data in combination with nivolumab in metastatic urothelial cancer patients. As of the February 9 data cutoff, results from the Phase 1/2 trial evaluating nuzefatide 6.5mg/m2 once every two weeks plus nivolumab 480mg once every four weeks in 14 patients with mUC who had previously progressed on a checkpoint inhibitor showed: 40% confirmed overall response rate among patients with EphA2+ tumors and 100% confirmed ORR among patients with EphA2+ tumors that were monomethyl auristatin E-naive. Patients who achieved a partial response or at least 16 weeks of stable disease were on treatment for a minimum of 56 weeks and most continued on treatment at the time of the data cut-off. Nuzefatide in combination with nivolumab was generally well tolerated with no Grade greater than or equal to3 treatment-related adverse events of clinical interest and no TRAEs of haemorrhage observed. Only one dose-limiting toxicity of Grade 3 fatigue that lasted for five days was reported and improved to Grade 1 without dose reduction. In contrast to other EphA2-targeted agents, nuzefatide has demonstrated a positive emerging efficacy and safety profile in over 150 patients with hard-to-treat tumors to date. Further work has led Bicycle Therapeutics to determine 8mg/m2 Q2W as the preferred dose for the Phase 2 trial in patients with recurrent pancreatic ductal adenocarcinoma. Additional human imaging data of a Bicycle Imaging Agent targeting EphA2 in patients with PDAC. The German Cancer Consortium, part of a cooperative network with the German Cancer Research Center, presented human imaging data conducted with a Bicycle molecule targeting EphA2 labelled with gallium-68. Seven patients with histologically confirmed PDAC underwent PET/CT imaging up to three hours post injection of the EphA2 BIA. Data demonstrated rapid tumor uptake and excretion primarily via the kidneys in six out of seven patients. EphA2 BIA PET imaging successfully detected multiple liver, bone, lymph node, and peritoneal metastases. These data are representative of the results seen in 15 out of 18 patients with PDAC who have undergone EphA2 BIA imaging to date. Bicycle Therapeutics believes these data validate the potential of EphA2 as a novel target in the treatment of cancer, demonstrate the translatability of preclinical data and highlight the potential of Bicycle molecules for targeted radioligand therapies and radiopharmaceutical imaging. Preclinical assessment of nuzefatide anti-tumor activity in patient-derived xenograft models of PDAC. Expression of EphA2 was found in all 16 PDAC PDX models. Of the 14 PDAC PDX models assessed for anti-tumor activity, 10 models were sensitive to nuzefatide, six of which showed high sensitivity. These data support the potential for nuzefatide to offer a novel option for the treatment of patients with PDAC. In March 2026, Bicycle Therapeutics began enrolling patients in a Phase 2 clinical trial to evaluate efficacy, safety, and pharmacokinetics of nuzefatide in adult patients with recurrent PDAC, and the first patient was successfully dosed in April 2026. Preclinical assessment of nuzefatide anti-tumor activity in cell-line-derived xenograft models of head and neck squamous cell carcinoma. Nuzefatide demonstrated potent preclinical anti-tumor activity in EphA2-expressing CDX models of HNSCC.