Background: TGF-β pathway dysregulation may play a critical role in carcinogenesis and immune evasion in HPV-associated cancers (HACs), including anal, cervical, and p16+ squamous cell carcinoma of the head and neck (SCCHN). Targeting this pathway may also enhance clinical response to PD-(L)1 antibodies. M7824 is an innovative first-in-class bifunctional fusion protein composed of two extracellular domains of TGF-βRII (a TGF-β “trap”) fused with a human IgG1 monoclonal antibody against PD-L1. In the dose-escalation cohort of the ongoing Phase I trial of M7824 (NCT02517398), patients with HACs who developed an HPV-specific immune response on M7824 had improved clinical responses. Here we report efficacy and safety data from patients with HPV-positive malignancies from the dose-escalation cohort pooled with data from HAC expansion cohorts for patients with HPV-positive disease. Methods: Patients received M7824 Q2W at 1-30 mg/kg in the dose-escalation phase or at the recommended phase 2 dose of 1200 mg in the expansion cohorts. Treatment continued until progressive disease (PD), unacceptable toxicity, or trial withdrawal; treatment past PD was allowed if clinically justified. Safety and best overall response by RECIST v1.1 were the primary endpoints of the dose-escalation and expansion phases, respectively. Results: As of August 24, 2018, 36 patients with pretreated HPV-positive HACs (4 anal; 18 cervical; 14 SCCHN) had received M7824 for a median duration of 19.0 weeks (range, 2.0-96.0). 10 patients had a response per investigator (2 complete response [CR]; 8 partial response [PR]; ORR 27.8%). 1 additional patient developed a PR after data cutoff; 3 additional patients had a delayed PR after initial PD (total clinical response rate 38.9%). Both patients with CR and 5 patients with PR have an ongoing response. The median duration of response was not reached (range, 4-22+ months). 9 patients (25%) had grade 3 treatment-related adverse events (TRAE): anemia, cystitis, diabetic ketoacidosis, increased γ-glutamyltransferase, gastroparesis, hyperkeratosis, hypokalemia, keratoacanthoma, macular rash, pleural effusion, pneumonitis, and skin SCC. The patient with gastroparesis had asymptomatic grade 3→4 hypokalemia (1 grade 4 TRAE, 2.7%). No treatment-related deaths occurred. 6 patients (16.7%) permanently discontinued M7824 due to TRAEs (gastroparesis, infusion-related reaction, cystitis, pneumonitis, and acneiform and psoriasiform dermatitis). Conclusions: M7824 has a manageable safety profile and shows encouraging clinical efficacy in patients with HPV-positive HACs (total clinical response rate 38.9%). M7824 is a promising therapeutic agent for these patients and is under further evaluation in phase 1b and 2 trials. Updated survival results will be reported. Citation Format: Julius Strauss, Margaret E. Gatti-Mays, Byoung Cho, Sebastien Salas, Edward McClay, Jason Redman, Houssein Abdul Sater, Renee N. Donahue, Elizabeth Lamping, Andrea Burmeister, Jennifer L. Marte, Lisa Cordes, Laureen S. Ojalvo, Christoph Helwig, Alex Rolfe, Christian S. Hinrichs, Ravi A. Madan, Jeffrey Schlom, James Gulley. Phase I evaluation of M7824, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus (HPV)-associated malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT075.