A Phase 2 Trial of Bintrafusp Alfa Immunotherapy in Recurrent/Metastatic Olfactory Neuroblastoma

Introduction: Olfactory neuroblastoma (ONB) is a rare malignancy of the sinonasal cavity and anterior skull base. Primary treatment of locoregional disease typically consists of surgical resection and adjuvant radiation with or without systemic chemotherapy, with typically good long-term outcomes. In the recurrent or metastatic (R/M) setting combination chemotherapy is used; however, outcomes are poor. Checkpoint blockade (CB) immunotherapy has improved outcomes for many solid tumors but its role in R/M ONB has not been studied prospectively with a clinical trial. Bintrafusp alfa (BA) is a bifunctional anti-PD-L1/TGF-β “trap” fusion protein. We conducted the first clinical trial of immunotherapy in R/M ONB, evaluating the clinical activity of BA (NCT05012098).

Methods: Investigator-initiated, single-center phase 2 study. Eligible patients were adults with histologically confirmed recurrent or metastatic ONB, not amenable to potentially curative local therapies, disease measurable (by RECIST 1.1), ≥1 prior systemic treatments (including a platinum agent; prior CB therapy was allowed), EGOC performance status 0-2 and adequate organ and bone marrow function. Patients received BA 1200 mg intravenously every two weeks for up to 26 doses or until progression of disease. Response was assessed (imaging) every 8 weeks; PET/CT scan (68Ga-DOTATATE or FDG) was obtained for all patients at baseline and first restaging. Baseline and on-treatment biospecimens collected included peripheral blood and optional research biopsies. Primary objective was objective response rate (complete responses (CR) and partial responses (PR) per RECIST 1.1) in the CB-naive patients; secondary endpoints included safety and overall survival, and exploratory endpoints included immune correlates.

Results: Eleven patients were enrolled from June 2022 to June 2024, nine were CB-naïve, 2 had prior CB ([Table 1]). All patients received at least one dose of BA and were eligible for safety assessment. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 27.3% (3/11), and Grade 1 or 2 in 63.6% (7/11). There was no treatment related death. Eight of 9 CB-naive patients received at least one cycle of treatment and had response assessment: there was no objective response by RECIST 1.1; 50% (4/8) patients had stable disease (SD), confirmed in 3 patients, with prolonged duration. In one patient with confirmed prolonged SD (>20 months, ongoing), an increase in DOTATATE uptake in the first restaging (right maxillary sinus, cervical lymph nodes) was followed by DOTATATE uptake clearance from disease sites; a biopsy of the right maxillary sinus lesion revealed only fibrous tissue with chronic inflammation. Of the 2 CB-experienced patients, one had confirmed SD.

Conclusion: In this first clinical trial of immunotherapy in ONB, BA treatment was well tolerated. There were no CR/PR by RECIST, but there was durable SD in 3/8 evaluable CB-naïve patients (including a metabolic response without viable tissue in biopsy), who remained progression-free for a prolonged time. Correlative studies will be performed to elucidate BA activity in R/M ONB. Results from this study show the feasibility of clinical trials for patients with rare sinonasal malignancies and outline their importance for exploring new treatments as well as for improving the available evidence base for these rare malignancies.

Publication History

Article published online:
07 February 2025