Abstract CT045: A randomized phase II trial of TG4001 plus avelumab versus avelumab alone in recurrent/metastatic (R/M) human papilloma virus (HPV)-16 positive anogenital cancers
Authors: Tourneau Christophe Le , Rolland Frédéric , Daste Amaury , Cassier Philippe , Salas Sébastien , Sánchez Luis Manso , Colon-Otero Gerardo , Eberst Lauriane , Lantz Olivier , Lalanne Ana , Tavernaro Annette , Makhloufi Hakim , Bendjama Kaïdre , Brandely Maud , Delord Jean-Pierre 
Published: April 2023

Abstract
Background: Immune checkpoint inhibitors targeting the PD1/PD-L1 axis have made a breakthrough in advanced solid tumors, leading to improved overall survival (OS) in several cancer types. However, only a minority of patients experience durable responses, requiring further development of anti-tumoral immunotherapies to overcome tumor immune escape. We hypothesized that priming the immune system with TG4001, a vaccine using the highly attenuated Modified Vaccinia virus Ankara as vector expressing the HPV16 E6 and E7 proteins (rendered non-oncogenic) and interleukin-2, would increase the clinical benefit associated with PD-L1 blockade in HPV16+ cancer patients. In the single-arm part of the trial evaluating the combination of TG4001 and avelumab in terms of response rate, the overall response rate (ORR) was 22%. Presence of liver metastases had a profound impact on outcome in terms of ORR and Progression Free Survival (PFS). In patients (pts) without liver metastases an ORR of 32% was observed versus 0% in pts with liver metastases, warranting further development of this combination in this patient population (SITC 2020, Abstract ID 793).
Methods: We have designed a randomized open-label two-arms trial evaluating the efficacy of the combination of TG4001 and avelumab versus avelumab alone (NCT03260023). Eligible pts have R/M HPV-16 positive anogenital cancer including cervical, vulvar, vaginal, penile, and anal cancers with no more than one prior line of chemotherapy for R/M disease and no previous exposure to cancer immunotherapy. HPV-16 positivity is determined in a central laboratory. Patients are randomly assigned 1:1 to receive either TG4001 plus avelumab or avelumab alone. Randomization is stratified by primary tumor type (cervical, anal, genital). TG4001 is administered subcutaneously (SC) at 5 × 107 plaque forming units (pfu) Q1w for 5 weeks, Q2w until month 6 and Q12w until progressive disease and avelumab intravenously (IV) at 800 mg Q2w until progressive disease. A total of up to 140 pts are currently being recruited into two cohorts (A and B) in France, Spain, and USA. For Cohort A, consisting of pts without liver metastases at Baseline (BL), a 2-stage sample size adjustment design is used with PFS by RECIST 1.1 as primary endpoint. Plans are to accrue 120 patients following Interim Analysis and Independent Data Monitoring Committee (IDMC) review. Cohort B recruits pts with liver metastases at BL. To be eligible, hepatic disease is restricted in terms of extent and number of lesions. A total of 20 pts will be recruited and analyzed for the percentage of early progressors. Secondary endpoints include overall survival, objective response rate according to RECIST1.1, duration of response, disease control rate. Exploratory endpoints comprise analyses of blood-based parameters and tumor-based proteins and RNA expression and their impact on clinical outcomes.
Citation Format: Christophe Le Tourneau, Frédéric Rolland, Amaury Daste, Philippe Cassier, Sébastien Salas, Luis Manso Sánchez, Gerardo Colon-Otero, Lauriane Eberst, Olivier Lantz, Ana Lalanne, Annette Tavernaro, Hakim Makhloufi, Kaïdre Bendjama, Maud Brandely, Jean-Pierre Delord. A randomized phase II trial of TG4001 plus avelumab versus avelumab alone in recurrent/metastatic (R/M) human papilloma virus (HPV)-16 positive anogenital cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT045.