PHASE 1B TRIAL OF FIRST-LINE BINTRAFUSP ALFA, A BIFUNCTIONAL FUSION PROTEIN TARGETING TGF-beta AND PD-L1, PLUS CHEMOTHERAPY WITH OR WITHOUT BEVACIZUMAB IN CERVICAL CANCER

Introduction/Background* Platinum-containing chemotherapy ± bevacizumab is standard-of-care for recurrent/metastatic/persistent (R/M/P) cervical cancer (CC). Anti-PD-(L)1 therapy has benefit in some patients who progress after first-line (1L) therapy; 1L efficacy is unknown. HPV infection, implicated in >95% of CCs, is linked to TGF-β upregulation. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking PD-L1. Promising activity was observed in patients with recurrent, platinum-experienced CC (response rate 28.2%). We report data from a phase 1b trial evaluating safety of 1L bintrafusp alfa + chemotherapy ± bevacizumab (INTR@PID 046; NCT04551950). Methodology Patients with R/M/P CC who had not received prior systemic therapy were eligible for cohort 1. They received bintrafusp alfa 2400mg q3w plus cisplatin 50mg/m2 or carboplatin AUC5, paclitaxel 175mg/m2 with (cohort 1A)/without (cohort 1B) bevacizumab 15mg/kg until disease progression, death, unacceptable toxicity, or withdrawal. Primary endpoints: occurrence of predefined dose-limiting toxicities (DLT) ≤4 weeks from treatment start; adverse event occurrence. Target recruitment was 8 patients/cohort, with safety assessments when 3 and 8 patients had completed the DLT period. Result(s)* As of May 4, 2021, 8 and 9 patients in cohorts 1A and 1B had received therapy for a median of 10.6 and 9.0 weeks. All patients had completed the DLT period and remained on therapy. Two non-bintrafusp alfa-related DLTs were observed in cohort 1B (grade 4 amylase elevation, grade 3 menorrhagia); neither led to treatment discontinuation. Any-grade treatment-related adverse events (TRAEs) occurred in 62.5% and 100% of patients in cohorts 1A and 1B. Grade 3 TRAEs occurred in 3 and 2 patients (cohort 1A: anemia [n=2], lipase increase, decreased neutrophil count, maculo-papular rash [n=1 each]; cohort 1B: anemia, rectal hemorrhage, vaginal bleeding [n=1 each]); 1 patient in cohort 1B had grade 4 anemia. No treatment-related deaths occurred. Preliminary efficacy based on short follow-up showed 3 and 2 tumor responses (2 and 1 pending confirmation) in cohorts 1A and 1B. Conclusion* No new safety signals were observed with 1L bintrafusp alfa + chemotherapy ± bevacizumab in patients with R/M/P CC. Further studies are warranted.