공시 • Oct 27
Transgene Announces Detailed Results from the Phase 1B/2 Trial Combining TG4001
Transgene announced the detailed results 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. 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 cancers. An overall response rate of 23.5% was observed in the 34 evaluable patients. 8 patients achieved confirmed response, including 1 complete response and 7 partial responses (according to RECIST 1.1). Responses were observed in all primary tumor types and across all lines of prior therapy. These results compare favorably to current standards of care and single-agent immune checkpoint inhibitors. In patients without liver metastases (n=23), the response rate is 34.8% and median progression free survival (PFS) reaches 5.6 months versus 0% and a PFS of 1.4 month in patients with liver metastases (n=11). The presence of liver metastases is generally associated with very poor prognosis [9] even when patients are treated with an anti-PD-1/PD-L1. The trial is conducted in collaboration with Merck KGaA, Darmstadt, Germany, and Pfizer. 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 cells presenting the HPV16 E6 and E7 antigens, that can be found in HPV16-related tumors, 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 [8; 24]. Its mechanism of action and good safety profile make TG4001 an excellent candidate for combinations with other therapies in HPV-mediated solid tumors. HPV-positive cancers comprise a variety of malignancies, including head and neck cancers and anogenital cancers [13]. 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 [14]. The incidence of HPV16-related SCCHN has significantly increased in recent years [14]. HPV16 infection is associated with more than 85% of oropharynx squamous cell carcinomas [14], i.e. approximately 10,000 patients at metastatic stage and receiving a second line of treatment [15]. Other HPV16-positive cancers include cervical [16], vaginal [17], vulvar [18], anal [19] and penile [20] 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 [23,24]. With immune checkpoint inhibitors, median overall survival remains inferior to 11 months [1-7] and median progression-free survival is between 2 and 4 months. In this heterogenous group of malignancies, overall response rates are around 10–15%. 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. 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.