Phase II trial of MEDI0457 and durvalumab for patients with recurrent/metastatic HPV-associated cancers.
Authors: Morris Van K. , Jazaeri Amir A. , Westin Shannon Neville , Pettaway Curtis Alvin , George Solly , Huey Ryan , Onstad Michaela , Tu Shi-Ming , Wang Jennifer , Shafer Aaron , Johnson Benny , Xiao Lianchun , Vining David J , Guo Ming , Yuan Ying , Frumovitz Michael M. 
Published: June 2021

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Background: Infection with human papillomavirus (HPV) types 16 or 18 drives oncogenesis for the majority of patients (pts) with cervical, anal, and some penile cancers via viral oncoproteins E6 and E7. While anti-PD1/PD-L1 antibodies have activity in pts with HPV-associated cancers, the majority do not derive benefit from these agents as monotherapy. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 oncogenes for HPV-16/18 and IL-12 adjuvant, has been shown to be safe and to provoke an immune response against the expressed antigens. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for pts with recurrent or metastatic HPV-associated cancers with the goal of improving anti-tumor activity. Methods: Pts with HPV-16/18 cervical cancer or rare (anal, penile, vaginal, or vulvar) HPV- associated cancers that were recurrent and/or metastatic following standard therapies were eligible. No prior immunotherapy was allowed. Pts received 7 mg of MEDI0457 intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks starting at week 4. The primary endpoint was best overall response according to RECIST 1.1. Adverse events (AE) were assessed using CTCAE v4.03. A Simon two-stage phase 2 trial (Ho: p <.15; Ha: p≥.35) using a one-sided alpha =.05 and beta =.20 was conducted. ≥2 responses were needed in both the “cervical” and non-cervical cohorts during the first stage in order for the trial to proceed. Median progression-free survival (PFS) and overall survival (OS) were estimated via Kaplan-Meier. Results: 41 pts were screened between 11/2018-10/2020. 21 pts (12 cervical, 7 anal, 2 penile) were treated. All 21 were evaluable for toxicity and 19 for response. Median age was 49 years (range, 29-75), and 18 (86%) were female. There were 17 squamous cell carcinomas (SCC) and 4 cervical adenocarcinomas. Grade ≥3 AEs occurred in 3 (14%) pts and included transaminitis, elevated lipase/amylase, hyponatremia, and neutropenia. No AE required study discontinuation. Overall response rate (ORR) was 21% (95% CI, 6-46%) and disease control rate (DCR) was 42% (95% CI, 20-67%). There was one patient with a complete response, 3 with partial response, and 4 with stable disease. All responses were noted among SCCs (1 cervical, 2 anal, 1 penile). Median duration of response among responders is 16 months (range, 11-27). Median PFS was 3.7 months (95% CI, 2.8-9.2), and median OS was 13.5 months (95% CI, 10.1-NA). 6-month PFS rate was 36% (95% CI, 20-65). Conclusions: The combination of MEDI0457 and durvalumab demonstrated acceptable safety/tolerability in pts with advanced HPV-16/18 cancers. Despite a clinically meaningful DCR, the low ORR among pts with cervical cancer led to study discontinuation for futility. Correlative studies are ongoing to characterize pts with prolonged disease control with study treatment. Clinical trial information: NCT03439085.