Transgene (Paris:TNG) (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, announced that detailed results of the data from the Phase 1b/2 trial combining TG4001, a HPV16 targeted therapeutic vaccine, with avelumab (BAVENCIO®), a human anti-PD-L1 antibody, in HPV16-positive recurrent and/or metastatic malignancies, will be presented in a poster presentation at the upcoming virtual meeting of the Society for Immunotherapy of Cancer (SITC) taking place November 9-14, 2020.
The principal investigator Professor Christophe Le Tourneau will present results from a pooled analysis of the Phase 1b/2 trial, including response rate, median progression-free survival, as well as the impact of patient/disease characteristics on outcome and immunogenicity.
As a reminder, the analysis of the trial data demonstrated clinical activity of the combination regimen and confirmed a manageable safety profile.
The purpose of this exploratory Phase 1b/2 trial was to evaluate the safety and efficacy of the combination of TG4001 and an immune checkpoint inhibitor in a heterogeneous group of patients with aggressive, recurrent and/or metastatic HPV16-positive cancer. Clinical activity was observed in the overall study population (34 evaluable patients with oropharyngeal, anal, cervical, or other HPV16-positive cancers).
In addition, Transgene has identified patient characteristics associated with promising clinical activity in this trial. For more than 50% of these patients, the disease had not progressed at 12 weeks, compared to an expected median progression-free survival (PFS) of 8 weeks for this population with current treatment regimens*. Consistent with data presented at ESMO 2019 , durable responses have been observed in most of the responder patients.
The trial was being conducted in collaboration with Merck KGaA, Darmstadt, Germany, and Pfizer.
About the trial
This multi-center, open-label trial is assessing the safety and efficacy of this immunotherapy combination regimen (TG4001 + avelumab) in patients with HPV16-positive cancers who have disease progression after at least one line of systemic treatment for recurrent/metastatic disease (NCT03260023). Prof. Christophe Le Tourneau, M.D., PhD, Head of the Department of Drug Development and Innovation (D3i) at the Curie Institute, and a world expert in drug development and head and neck cancers, is the Principal Investigator of the study. The trial is being conducted in collaboration with Merck KGaA, Darmstadt, Germany, a leading science and technology company, which in the US and Canada operates its biopharmaceutical business as EMD Serono, and Pfizer Inc. (NYSE: PFE).
Patients received TG4001 at the dose of 5x107 pfu, SC, weekly for 6 weeks, every 2 weeks up to six months, and every 12 weeks thereafter, in combination with avelumab at 10 mg/kg, IV every two weeks, until disease progression.
The primary endpoint of the Phase 2 part is the overall response rate (ORR, using RECIST 1.1). Secondary endpoints include progression-free survival, overall survival, disease control rate and other immunological parameters.
More information on the trial is available on clinicaltrials.gov.
About HPV-Positive Cancers
HPV-positive cancers comprise a variety of malignancies, including head and neck cancers and anogenital cancers . Squamous cell carcinoma of the head and neck (SCCHN) is a heterogeneous group of cancers that can affect sites including the oral cavity, pharynx, and larynx . The incidence of HPV16-related SCCHN has significantly increased in recent years . HPV16 infection is associated with more than 85% of oropharynx squamous cell carcinomas , i.e. approximately 10,000 patients at metastatic stage and receiving a second line of treatment . Other HPV16-positive cancers include cervical , vaginal , vulvar , anal  and penile  cancers, i.e. approximately 15,000 cancers at metastatic stage and eligible for a second line of treatment .
Current treatments include chemoradiotherapy, immune checkpoint inhibitors, or surgical resection with radiotherapy. However, better options are needed for advanced and metastatic HPV+ cancers. It is thought that this immunotherapy combined with other immunotherapeutic agents such as immune checkpoint inhibitors could provide a promising potential treatment option that would address this strong medical need [16,17]. With immune checkpoint inhibitors, median overall survival remains inferior to 11 months [2-6] and median progression-free survival is between 2 and 4 months [2-6]. In this heterogenous group of malignancies, overall response rates are around 10–15% [2-6].
TG4001 is an investigational therapeutic vaccine based on a non-propagative, highly attenuated Vaccinia vector (MVA), which is engineered to express HPV16 antigens (E6 & E7) and an adjuvant (IL-2). TG4001 is designed to have a two-pronged antiviral approach: to alert the immune system specifically to HPV-16-infected cells that have started to undergo precancerous transformation (cells presenting the HPV16 E6 and E7 antigens) and to further stimulate the infection-clearing activity of the immune system through interleukin 2 (IL-2). TG4001 has been administered to more than 300 individuals, demonstrating good safety, significant HPV clearance rate and promising efficacy results [1; 18]. Its mechanism of action and good safety profile make TG4001 an excellent candidate for combinations with other therapies in HPV-mediated solid tumors.
Avelumab Approved Indications
Avelumab (BAVENCIO®) is indicated in the US for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Avelumab in combination with axitinib is approved in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
In the US, the FDA granted accelerated approval for BAVENCIO for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.
Avelumab Important Safety Information from the US FDA-Approved Label
The warnings and precautions for avelumab (BAVENCIO®) include immune-mediated adverse reactions (such as pneumonitis and hepatitis [including fatal cases], colitis, endocrinopathies, nephritis, and other immune-mediated adverse reactions as a single agent or in combination with axitinib [which can be severe and have included fatal cases]), infusion-related reactions, hepatotoxicity in combination with axitinib, major adverse cardiovascular events (MACE) in combination with axitinib [which can be severe and have included fatal cases], and embryo-fetal toxicity.
Common adverse reactions (reported in at least 20% of patients) in patients treated with BAVENCIO® monotherapy include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction peripheral edema, decreased appetite, urinary tract infection and rash. Common adverse reactions (reported in at least 20% of patients) in patients receiving BAVENCIO® in combination with axitinib include diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain and headache. Grade 3-4 hematology laboratory value abnormalities reported in at least 10% of patients with Merkel cell carcinoma treated with BAVENCIO® monotherapy include lymphopenia; in patients receiving BAVENCIO® in combination with axitinib, grade 3-4 clinical chemistry abnormalities include blood triglyceride increased and lipase increased.
 Le Tourneau et al. “Phase Ib/II trial of TG4001 (Tipapkinogene sovacivec), a therapeutic HPV-vaccine, and Avelumab in patients with recurrent/metastatic HPV16 positive cancers” 2019 ESMO Annual Meeting, 30 September 2019, Poster presentation
 Cohen et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019;393:156–67
 Ferris et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375:1856-1867
 Morris et al. Nivolumab for Previously Treated Unresectable Metastatic Anal Cancer (NCI9673): A Multicentre, Single-Arm, Phase 2 Study. Lancet Oncol. 2017;18(4):446-453
 Marabelle et al. Pembrolizumab for previously treated advanced anal squamous cell carcinoma: Pooled results from the KEYNOTE-028 and KEYNOTE-158 studies. J Clin Oncol 38: 2020 (suppl; abstr 4020)
 Chung et al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019;10;37(17):1470-1478
 ICO/IARC – HPV Information Center> Prevention at a glance – accessed July 2020
 Kreimer et al., Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467-75
 HPV-positive oropharynx cancer: Company estimates based on: Globocan/IARC 2018 Cancer Fact Sheets: oropharynx (C09-10) – accessed July 2020; ICO/IARC – HPV Information Center 2018 Statistics – accessed July 2020; Kreimer et al., Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467-75
 HPV-positive cervical cancer: Globocan/IARC 2018 Cancer Fact Sheets: cervix uteri (C53) – accessed July 2020; ICO/IARC – HPV Information Center 2018 Statistics – accessed July 2020
 HPV-positive vaginal cancer: Globocan/IARC 2018 Cancer Fact Sheets: vagina (C52) – accessed July 2020; ICO/IARC – HPV Information Center 2018 Statistics – accessed July 2020; Kreimer et al., Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467-75
 HPV-positive vulvar cancer: Globocan/IARC 2018 Cancer Fact Sheets: vulva (C51) – accessed July 2020; ICO/IARC – HPV Information Center 2018 Statistics – accessed July 2020; CDC United States Cancer Statistics: Data Visualizations – accessed July 2020; SEER Cancer stat facts: vulvar cancer – accessed July 2020
 HPV-positive anal cancer: Globocan/IARC 2018 Cancer Fact Sheets: anus (C21) – accessed July 2020; ICO/IARC – HPV Information Center 2018 Statistics – accessed July 2020; CDC>Cancer Home>HPV and Cancer>Statistics>Rates by Race and Ethnicity>HPV-Associated Anal Cancer Rates by Race and Ethnicity– accessed July 2020; American Cancer Society: Anal Cancer – accessed July 2020
 HPV-positive penile cancer: Globocan/IARC 2018 Cancer Fact Sheets: penis (C60) – accessed July 2020; ICO/IARC – HPV Information Center 2018 Statistics – accessed July 2020; CDC>Cancer Home>HPV and Cancer>Statistics>Rates by Race and Ethnicity>HPV-Associated Cancers Rates by Race and Ethnicity – accessed July 2020; Kreimer et al., Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467-75
 Company estimates based on notes 10, 11, 12, 13, 14
 Melero et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15(8): 457-472.
 Van der Burg et al. Vaccines for established cancer: overcoming the challenges posed by immune evasion Nat Rev Cancer. 2016;16(4):219-233
 Harper et al. The Efficacy and Safety of Tipapkinogen Sovacivec Therapeutic HPV Vaccine in Cervical Intraepithelial Neoplasia Grades 2 and 3: Randomized Controlled Phase II Trial With 2.5 Years of Follow-Up. Gynecologic Oncology. 2019; 153(3):521-529
Transgene (Euronext: TNG) is a publicly traded French biotechnology company focused on designing and developing targeted immunotherapies for the treatment of cancer. Transgene’s programs utilize viral vector technology with the goal of indirectly or directly killing cancer cells.
The Company’s clinical-stage programs consist of two therapeutic vaccines (TG4001 for the treatment of HPV-positive cancers, and TG4050, the first individualized therapeutic vaccine based on the myvac® platform) as well as two oncolytic viruses (TG6002 for the treatment of solid tumors, and BT-001, the first oncolytic virus based on the Invir.IO™ platform).
With Transgene’s myvac® platform, therapeutic vaccination enters the field of precision medicine with a novel immunotherapy that is fully tailored to each individual. The myvac® approach allows the generation of a virus-based immunotherapy that encodes patient-specific mutations identified and selected by Artificial Intelligence capabilities provided by its partner NEC.
With its proprietary platform Invir.IO™, Transgene is building on its viral vector engineering expertise to design a new generation of multifunctional oncolytic viruses. Transgene has an ongoing Invir.IO™ collaboration with AstraZeneca.
Additional information about Transgene is available at: www.transgene.fr.
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This press release contains forward-looking statements, which are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those anticipated. The occurrence of any of these risks could have a significant negative outcome for the Company’s activities, perspectives, financial situation, results, regulatory authorities’ agreement with development phases, and development. The Company’s ability to commercialize its products depends on but is not limited to the following factors: positive pre-clinical data may not be predictive of human clinical results, the success of clinical studies, the ability to obtain financing and/or partnerships for product manufacturing, development and commercialization, and marketing approval by government regulatory authorities. For a discussion of risks and uncertainties which could cause the Company’s actual results, financial condition, performance or achievements to differ from those contained in the forward-looking statements, please refer to the Risk Factors (“Facteurs de Risque”) section of the Universal Registration Document, available on the AMF website (http://www.amf-france.org) or on Transgene’s website (www.transgene.fr). Forward-looking statements speak only as of the date on which they are made and Transgene undertakes no obligation to update these forward-looking statements, even if new information becomes available in the future.
* Current treatment regimens, including immune checkpoint inhibitors, for patients with metastatic disease receiving a second (or further) line of treatment for their HPV16 associated indications deliver very limited benefit. With immune checkpoint inhibitors, overall response rates are around 10–15% in this heterogenous group of malignancies, while median overall survival is less than 11 months [2-6] and median progression-free survival is around 2 months [2-6].
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