Background: Until the recent FDA approval of pembrolizumab in combination with chemotherapy ± bevacizumab, there have been limited treatment options that address the underlying biology for pts with persistent, recurrent, or metastatic (P/R/M) or locally advanced (LA) cervical cancer. Persistent HPV infection is associated with 99% of cervical cancers and is linked to upregulation of TGF-β. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β“trap”) fused to a human IgG1 mAb blocking PD-L1, has shown promising clinical activity and manageable safety in pts with recurrent or metastatic cervical cancer. We report data from a phase 1 trial evaluating safety of first-line bintrafusp alfa plus chemotherapy ± bevacizumab for pts with P/R/M cervical cancer or bintrafusp alfa plus chemoradiotherapy for pts with LA cervical cancer (INTR@PID 046; NCT04551950). Methods: Pts with P/R/M cervical cancer who had not received prior systemic therapy received bintrafusp alfa 2400 mg Q3W plus cisplatin/carboplatin and paclitaxel with (cohort 1A) or without (cohort 1B) bevacizumab. Pts with LA cervical cancer received bintrafusp alfa 2400 mg Q3W plus concurrent weekly cisplatin and radiotherapy followed by maintenance therapy with bintrafusp alfa (cohort 2). Pts were treated until disease progression, death, unacceptable toxicity, or withdrawal. Primary endpoints were safety and tolerability of bintrafusp alfa in combination with current standard-of-care therapies in pts with P/R/M or LA cervical cancer. Results: As of November 25, 2021, 8 pts in cohort 1A, 9 in cohort 1B, and 8 in cohort 2 had received bintrafusp alfa for a median of 11.6, 10.0, and 5.6 cycles, respectively. At the time of this analysis, 11 of 25 pts remained on bintrafusp alfa therapy. Any-grade bintrafusp alfa–related adverse events (AEs) occurred in 75.0%, 100.0%, and 75.0% of pts in cohorts 1A, 1B, and 2, respectively (Table). The most-common grade ≥3 AEs were anemia and hematuria (25.0% each) in cohort 1A and vaginal hemorrhage (22.2%) in cohort 1B. One pt had grade 4 anemia and vaginal hemorrhage in cohort 1B. No treatment-related deaths occurred. AEs led to permanent discontinuation of bintrafusp alfa in 37.5%, 33.3%, and 12.5% of pts in cohorts 1A, 1B, and 2, respectively; the most common any-grade AE was vaginal hemorrhage (22.2%). Conclusions: No new safety signals were observed with first-line bintrafusp alfa plus chemotherapy ± bevacizumab or chemoradiotherapy in pts with P/R/M or LA cervical cancer. Clinical trial information: NCT04551950.