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Tivdak based on Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer. Accelerated approval by FDA


The U.S. Food and Drug Administration ( FDA ) has granted accelerated approval to Tivdak ( Tisotumab vedotin-tftv; Tisotumab vedotin ), the first approved antibody-drug conjugate ( ADC ) for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.
Tivdak is approved under the FDA’s Accelerated Approval Program based on tumor response and the durability of the response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

In the innovaTV 204 clinical trial, Tivdak was evaluated in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior Platinum-based chemotherapy regimen.
Results from the trial have shown a 24% confirmed objective response rate ( ORR ) ( 95% CI; 15.9-33.3 ), as assessed by an independent review committee ( IRC ) using Response Evaluation Criteria in Solid Tumors ( RECIST ) v1.1 criteria.
The median duration of response ( DOR ) was 8.3 months ( 95% CI; 4.2 to not reached ).

The prescribing information for Tivdak includes a Boxed Warning for ocular toxicity, and Warnings for peripheral neuropathy, hemorrhage, pneumonitis, and embryo-fetal toxicity. The most common ( greater than or equal to 25% ) adverse reactions, including laboratory abnormalities, were hemoglobin decreased ( 52% ), fatigue ( 50% ), lymphocytes decreased ( 42% ), nausea ( 41% ), peripheral neuropathy ( 39% ), alopecia ( 39% ), epistaxis ( 39% ), conjunctival adverse reactions ( 37% ), hemorrhage ( 32% ), leukocytes decreased ( 30% ), creatinine increased ( 29% ), dry eye ( 29% ), prothrombin international normalized ratio increased ( 26% ), activated partial thromboplastin time prolonged ( 26% ), diarrhea ( 25% ), and rash ( 25% ).

Tisotumab vedotin is an ADC composed of human monoclonal antibody directed to tissue factor ( TF ) and an ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E ( MMAE ) to the antibody.
Nonclinical data suggests that the anticancer activity of Tisotumab vedotin 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 also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

The innovaTV 204 is an open-label, multicenter, single-arm phase 2 trial that has evaluated Tisotumab vedotin in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior Platinum-based chemotherapy regimen.
Patients were excluded if they had active ocular surface disease, any prior episode of cicatricial conjunctivitis or Stevens-Johnson syndrome, grade 2 or more peripheral neuropathy or known coagulation defects leading to an increased risk of bleeding.
The main efficacy outcome measures were confirmed ORR per RECIST v1.1 as assessed by an IRC and duration of response.

It is estimated that in 2021, more than 14,480 new cases of invasive cervical cancer will be diagnosed in the U.S., and 4,290 women will die from the disease.
Cervical cancer remains one of the leading causes of cancer death in women globally, with over 311,000 women dying of the disease in 2018. ( Xagena )

Source: Genmab & Seagen, 2021

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