공시 • Jan 10
Pfizer Inc. and Genmab A/S Announce U.S. Food and Drug Administration Accepts TIVDAK® Supplemental Biologics License Application
Pfizer Inc. and Genmab A/S announced that the U.S. Food and Drug Administration (FDA) has accepted the supplemental Biologics License Application (sBLA) seeking to convert the accelerated approval of TIVDAK® (tisotumab vedotin-tftv) to full approval, for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after first-line therapy. The application has been granted Priority Review with a Prescription Drug User Fee Act (PDUFA) goal date of May 9, 2024. The sBLA is supported by efficacy and safety data from the global, randomized, Phase 3 innovaTV 301 trial (NCT04697628), in which TIVDAK demonstrated superior overall survival (OS), progression-free survival (PFS) and confirmed objective response rate (ORR), as assessed by the investigator, in patients with previously treated recurrent or metastatic cervical cancer compared to chemotherapy. The safety profile of TIVDAK in innovaTV 301 was consistent with its known safety profile as presented in the U.S. prescribing information. In October 2023, results from the innovaTV 301 study were presented during a Presidential Symposium at the European Society of Medical Oncology (ESMO) Congress. The U.S. Prescribing Information for TIVDAK includes a BOXED WARNING for Ocular Toxicity as well as the following Warnings and Precautions: peripheral neuropathy, hemorrhage, pneumonitis, severe cutaneous adverse reactions, and embryo-fetal toxicity. Please see below for additional Important Safety Information. TIVDAK was granted accelerated approval in the U.S. by the FDA in September 2021. The accelerated approval is based on tumor response and durability of response from the innovaTV 204 pivotal Phase 2 single-arm clinical trial evaluating TIVDAK as monotherapy in patients with previously treated recurrent or metastatic cervical cancer. The data from innovaTV 301 will support global regulatory submissions. The innovaTV 301 trial (NCT04697628) is a global, 1:1 randomized, open-label Phase 3 trial evaluating (tisotumab vedotin-tftv) versus investigator’s choice of chemotherapy alone (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in 502 randomized patients with recurrent or metastatic cervical cancer who received one or two prior systemic regimens in the recurrent or metastatic setting. Patients with recurrent or metastatic cervical cancer with squamous cell, adenocarcinoma, or adenosquamous histology, and disease progression during or after treatment with chemotherapy doublet +/- bevacizumab and an anti-PD-(L)1 agent (if eligible) are included. The primary endpoint is overall survival. The main secondary outcomes are progression-free survival, confirmed objective response rate, time to response, and duration of response, as assessed by the investigator, as well as safety and quality of life outcomes. The study was conducted by Seagen, recently acquired by Pfizer, in collaboration with Genmab, European Network of Gynaecological Oncological Trial Groups (ENGOT, study number ENGOT cx-12) and the Gynecologic Oncology Group (GOG) Foundation (study number GOG 3057), as well as other global gynecological oncology cooperative groups. TIVDAK® (tisotumab vedotin-tftv) is an antibody-drug conjugate (ADC) composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Pfizer’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. Determination of TF expression is not required. Nonclinical data suggest that the anticancer activity of tisotumab vedotin-tftv is due to the binding of the ADC to TF-expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin-tftv also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity. TIVDAK is indicated in the U.S. for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care before, during, and after infusion. Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity. Warnings and Precautions: Ocular adverse reactions occurred in 60% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8% of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose. In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200. Refer patients to an eye care provider for an ophthalmic exam, including visual acuity and slit lamp exam, at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold dose, reduce the dose, or permanently discontinue TIVDAK based on the severity of the adverse reaction. Adverse Reactions: Serious adverse reactions occurred in 43% of patients; the most common (=3%) were ileus (6%), hemorrhage (5%), pneumonia (4%), PN, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received TIVDAK, including septic shock, pneumonitis, sudden death, and multisystem organ failure (each 1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (=3%) were PN (5%) and corneal adverse reactions (4%). Adverse reactions leading to dose interruption occurred in 47% of patients; the most common (=3%) were PN (8%), conjunctival adverse reactions (4%), and hemorrhage (4%).