Antibody–drug conjugates have promising clinical activity in the treatment of solid tumours. BL-B01D1 is a first-in-class EGFR–HER3 bispecific antibody–drug conjugate. We aimed to assess the safety and preliminary antitumour activity of BL-B01D1 in patients with locally advanced or metastatic solid tumours.

This first-in-human, open-label, multicentre, dose-escalation and dose-expansion phase 1 trial was conducted in seven hospitals in China, enrolling patients aged 18–75 years (dose escalation; phase 1a) or older than 18 years (dose expansion; phase 1b), with a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0–1, and histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment. In the phase 1a i3+3 design, patients received intravenous BL-B01D1 at three different schedules: 0·27 mg/kg, 1·5 mg/kg, and 3·0 mg/kg weekly; 2·5 mg/kg, 3·0 mg/kg, and 3·5 mg/kg on days 1 and 8 of each cycle every 3 weeks; or 5·0 mg/kg and 6·0 mg/kg on day 1 of each cycle every 3 weeks. The primary objectives of phase 1a were to identify the safety, maximum tolerated dose, and dose-limiting toxicity. In phase 1b, patients were treated in two schedules: 2·5 and 3·0 mg/kg on days 1 and 8 every 3 weeks, or 4·5, 5·0, and 6·0 mg/kg on day 1 every 3 weeks. The primary objectives of phase 1b were to assess the safety and recommended phase 2 dose of BL-B01D1, and objective response rate was a key secondary endpoint. Safety was analysed in all patients with safety records who received at least one dose of BL-B01D1. Antitumour activity was assessed in the activity analysis set which included all patients who received at least one dose of BL-B01D1 every 3 weeks. This trial is registered with China Drug Trials, CTR20212923, and ClinicalTrials.gov, NCT05194982, and recruitment is ongoing.

Between Dec 8, 2021, and March 13, 2023, 195 patients (133 [65%] men and 62 [32%] women; 25 in phase 1a and 170 in phase 1b) were consecutively enrolled, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma. In phase 1a, four dose-limiting toxicities were observed (two at 3·0 mg/kg weekly and two at 3·5 mg/kg on days 1 and 8 every 3 weeks; all were febrile neutropenia), thus the maximum tolerated dose was reached at 3·0 mg/kg on days 1 and 8 every 3 weeks and 6·0 mg/kg on day 1 every 3 weeks. Grade 3 or worse treatment-related adverse events occurred in 139 (71%) of 195 patients; the most common of which were neutropenia (91 [47%]), anaemia (76 [39%]), leukopenia (76 [39%]), and thrombocytopenia (63 [32%]). 52 (27%) patients had a dose reduction and five (3%) patients discontinued treatment due to treatment-related adverse events. One patient was reported as having interstitial lung disease. Treatment-related deaths occurred in three (2%) patients (one due to pneumonia, one due to septic shock, and one due to myelosuppression). In 174 patients evaluated for activity, median follow-up was 6·9 months (IQR 4·5–8·9) and 60 (34%; 95% CI 27–42) patients had an objective response.

Our results suggest that BL-B01D1 has preliminary antitumour activity in extensively and heavily treated advanced solid tumours with an acceptable safety profile. Based on the safety and antitumour activity data from both phase 1a and 1b, 2·5 mg/kg on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose in Chinese patients.

Sichuan Baili Pharmaceutical.

For the Chinese translation of the abstract see Supplementary Materials section.