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PurposeTumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18-associated HNSCC.Patients and methodsIn this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS).ResultsOf 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7-47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. 2-fold increase in tumor-infiltrating CD8+ T cells.ConclusionsMEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.

Background: MEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death ligand-1 (PD-L1) axis blockade. Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for the treatment of various solid tumors. We describe the results of the first-in-human study combining intravenous MEDI5395 with durvalumab in patients with advanced solid tumors., Methods: This phase I, open-label, multicenter, dose-escalation, dose-expansion study recruited adult patients with advanced solid tumors, who had relapsed or were refractory or intolerant to ≥1 prior line of standard treatment. MEDI5395 was administered intravenously as six doses over 15-18 days. The dose-escalation phase assessed four-dose levels (10 8 , 10 9 , 10 10 , 10 11 focus forming units (FFU)) of MEDI5395, with sequential or delayed durvalumab. Durvalumab 1500 mg was administered intravenously every 4 weeks up to 2 years. The dose-expansion phase was not initiated. The primary objectives were to evaluate safety and tolerability, dose-limiting toxicities (DLTs) and the dose and schedule of MEDI5395 plus durvalumab administration. Secondary objectives included the assessment of the efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI5395., Results: 39 patients were treated with MEDI5395; 36 patients also received durvalumab. All 39 patients experienced ≥1 treatment-emergent adverse event (TEAE), most commonly fatigue (61.5%), nausea (53.8%) and chills (51.3%). Grade 3-4 TEAEs occurred in 27 (69.2%) patients; these were deemed MEDI5395-related in 12 (30.8%) patients. Two patients experienced a DLT, and the maximum tolerated dose of MEDI5395 with sequential and delayed durvalumab at study termination was 10 11 and 10 10 FFU, respectively. Four patients (10.3%) achieved a partial response (PR). Patients with PR or stable disease tended to have higher baseline PD-L1 and CD8+ levels in their tumor tissue. A tendency to dose-dependent pharmacokinetics of the viral genome was observed in whole blood and a tendency to dose-dependent viral shedding was observed in saliva and urine. Neutralizing antibodies were observed in all patients but did not appear to impact efficacy negatively., Conclusion: This study demonstrates the feasibility, safety and preliminary efficacy of MEDI5395 with durvalumab in patients with advanced solid tumors., Trial Registration Number: NCT03889275., Competing Interests: Competing interests: DD reports Grants/Research Support (institutional) from Arcus, CellSight Technologies, Immunocore, Merck, Regeneron Pharmaceuticals, Tesaro/GSK; Consultant fees from ACM Bio, Ascendis Pharma, Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Merck, Medical Learning Group (MLG), Xilio Therapeutics. CE Speakers’ Bureau from Castle Biosciences; reports Intellectual Property for US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, December 11, 2020; US Patent 63/208,719, “Compositions and Methods For Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021. BAC reports Institutional Research Support from AstraZeneca, AbbVie, Actuate Therapeutics, Astellas, Agenus, Bayer, Dragonfly Therapeutics, Mink Therapeutics, Pfizer, Pyxis Oncology, Repare Therapeutics, Regeneron; Advisory Boards for Seattle Genetics. GKD reports Consulting Fee from Amgen, AstraZeneca, Bayer, Eli Lilly, Janssen, Meru, Mirati, Novartis, Regeneron. SS reports Employment from University of North Carolina; Honoraria from Naveris, Exelixis, Eisai, Medscape, Association of Community Cancer Centers; Consulting fees from Exelixis. Grants or Funds from Merck, AstraZeneca, Exelixis, Regeneron, Inovio, ASCO. MJB reports Grants, Funds, Trial support to institution (Mayo Clinic). KJH reports Scientific Advisory Board Membership for Oncolys, PsiVac, Replimune (paid to institution); Consulting Fees for PsiVac, Replimune, VacV (paid to institution); Grants or Funds from Replimune (paid to institution). SPP reports Consulting Fees from Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb, Certis, Eli Lilly, Jazz, Genentech, Illumina, Merck, Pfizer, Signatera, Tempus; Grants or Funds (research funding to university) from Amgen, AstraZeneca, A2bio, Bristol-Myers Squibb, Eli Lilly, Fate Therapeutics, Gilead, Iovance, Merck, Pfizer, Roche/Genentech. EG reports Consulting Fee from Kiyatec (personal compensation), Karyopharm Therapeutics (Data Safety Monitoring Board, compensation to employer), Boston Scientific (Data Monitoring Committee, compensation to employer), Servier Pharmaceuticals (Advisory Board, compensation to employer), Boehringer Ingelheim (Advisory Board, compensation to employer); Grants or Funds from Servier Pharmaceuticals (formerly Agios Pharmaceuticals), Denovo Biopharma, Celgene, MedImmune. AS reports Consulting fees from Roche and Chugai; Academic grants from Replimune, Histosonics, Oncolytics Biotech, Transgene (all paid to institution). SA: AstraZeneca employee and stock holder. ZC reports no potential conflict of interest. CF: AstraZeneca employee and stock holder. MG: AstraZeneca employee and stock holder. JBu: AstraZeneca employee and stock holder. ET: AstraZeneca employee and stock holder. ND: AstraZeneca employee and stock holder. KL: AstraZeneca employee and stock holder. FA: AstraZeneca employee and stock holder. DZ reports Institutional Grants from Merck, Genentech, AstraZeneca, Plexxikon, and Synthekine; Personal Fees; AstraZeneca, Xencor, Memgen, Takeda, Synthekine, Immunos, Tessa Therapeutics, Miltenyi, and Calidi Biotherapeutics. DZ is a holder of a patent on use of oncolytic NDV for cancer therapy (unrelated to the agent under study)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)