FDA Grants Fast Track Designation to BI 764532 for ES-SCLC and Extrapulmonary NEC

The FDA has granted a fast track designation to BI 764532 for the treatment of patients with extensive-stage small cell lung cancer (ES-SCLC) that has progressed following at least 2 prior lines of treatment including platinum-based chemotherapy, and for patients with advanced or metastatic extrapulmonary neuroendocrine carcinoma (epNEC) that has progressed following at least 1 prior line of treatment including platinum-based chemotherapy.¹

BI 764532 is an investigational DLL3/CD3 IgG-like T-cell engager designed to redirect T cells toward DLL3 protein expressed by cancer cells.

“We are delighted about the accelerated clinical development of BI 764532, for which the DLL3 antigen was discovered using our OGAP^® technology platform,” Christian Rohlff, chief executive officer of Oxford Biotherapeutics (OBT), stated in a news release. “This is tremendously exciting for OBT, as it shows the real impact this partnership has for patients in need. Receiving an ES-SCLC or epNEC diagnosis can be life changing and there is an urgent, unmet need for additional targeted immunotherapeutics to ensure that individuals impacted by these aggressive cancers get the care they need.”

The agent is currently under investigation in a first-in-human phase 1 trial (NCT04429087). Data presented at the 2023 ASCO Annual Meeting showed that BI 764532 displayed an acceptable toxicity profile and elicited responses in patients with DLL3-positive SCLC and NEC.²

The overall population treated with BI 764532 at doses of 90 µg/kg or higher (n = 71) achieved an overall response rate (ORR) of 25% and a disease control rate (DCR) of 52%. Patients with SCLC (n = 39) experienced an ORR of 26%, and those with epNEC attained an ORR of 19%. Notably, those with large cell NEC (LCNEC; n = 5) had an ORR of 60%. The DCR was 51%, 44%, and 100% for patients with SCLC, epNEC, and LCNEC, respectively.

The median duration of response for the total population was not reached, and tumor shrinkage was observed across all tumor types.

Safety data showed that 5 dose-limiting toxicities (DLTs) occurred, including grade 3 or 4 cytokine release syndrome (CRS; n = 2), grade 3 confusional state (n = 1), grade 2 infusion-related reaction (n = 1), and grade 3 nervous system disorder (n = 1). All DLTs were reversible, and all patients recovered. The maximum tolerated dose was not yet reached.

The ongoing, nonrandomized, open-label, multicenter trial is enrolling patients at least 18 years of age with SCLC, LCNEC, NEC, or small cell carcinoma of any other origin that is locally advanced or metastatic and not amenable to curative treatment.³ Patients are required to have DLL3-positive tumors per central pathology, and those with tumors with mixed histologies are eligible only if the neuroendocrine carcinoma/small cell component is predominant and represents at least 50% of the overall tumor tissue.

Other key inclusion criteria included an ECOG performance status of 0 or 1, at least 1 evaluable lesion outside the central nervous system per RECIST v1.1 criteria, and adequate liver, bone marrow, and renal function. Those with brain metastases are eligible if radiotherapy or surgery for brain metastases was complete at least 2 weeks prior to enrollment, and patients are off steroids for at least 7 days before enrollment.

Patients are excluded if they receive prior treatment with DLL3-targeted T-cell engagers or cell therapies; are given any other anticancer drug within 3 weeks or within 5 half-life prior to first treatment with BI 764532; or undergo extensive field radiotherapy, including whole brain irradiation, within 2 weeks of study treatment. Major surgery within 28 days of the first dose of study treatment is not allowed.

BI 764532 was initially dosed once every 3 weeks before pharmacokinetic data prompted weekly dosing.² The trial is also examining a step-up dosing over the first 3 administrations of the agent to mitigate CRS and infusion-related reactions.

The primary end points are to identify the MTD and DLTs. Secondary end points consist of ORR per RECIST v1.1 criteria and pharmacokinetics.

Additional safety data showed that 86% of patients (n = 107) experienced at least 1 any-grade treatment-related adverse effect (TRAE). Specifically, 59% of the TRAEs were grade 1 or 2, and 27% were grade 3 to 5.

The most common TRAEs that occurred in more than 10% of patients included CRS (grade 1-2, 57%; grade 3-5, 2%), decreased lymphocyte count (4%; 16%), dysgeusia (20%; 0%), asthenia (18%; <1%), pyrexia (18%; 0%), increased aspartate aminotransferase (12%; 2%), fatigue (13%; <1%), and nausea (12%; 0%).

References

1. Oxford BioTherapeutics announces partner Boehringer Ingelheim received U.S. FDA fast track designation for BI 764532 for the treatment of extensive stage small cell lung cancer and extrapulmonary neuroendocrine cancers. News release. Oxford BioTherapeutics. October 3, 2023. Accessed October 3, 2023. http://www.oxfordbiotherapeutics.com/uploads/9/5/4/2/9542591/03_10_23_bi_764532_fast_track_pr.pdf
2. Wermke M, Felip E, Kuboki Y, et al. First-in-human dose-escalation trial of BI 764532, a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager in patients (pts) with DLL3-positive (DLL3+) small-cell lung cancer (SCLC) and neuroendocrine carcinoma (NEC). J Clin Oncol. 2023;41(suppl 16):8502. doi:10.1200/JCO.2023.41.16_suppl.8502
3. A study to test different doses of BI 764532 in patients with small cell lung cancer and other neuroendocrine tumours that are positive for Delta-Like Ligand 3 (DLL3). ClinicalTrials.gov. Updated August 22, 2023. Accessed October 3, 2023. https://clinicaltrials.gov/ct2/show/NCT04429087