Perspectives on the breakthrough antibody drug conjugate, tisotumab vedotin, its mechanism of action, and the significant clinical benefits it offers to patients with recurrent or metastatic cervical cancer, leading to FDA approval and promising results in a confirmatory trial.
Ramez N. Eskander, MD: One of the areas that was quite relevant for the management of our [patients with cervical cancer], an area of advancement, was identification of efficacy of an antibody-drug conjugate: tisotumab vedotin. So, I want to start by just first explaining, what is an antibody-drug conjugate? Well, thankfully, the title helps explain that to many of us, but it’s an antibody that’s directed toward a target. In this case, tisotumab vedotin…is targeted against tissue factor and tissue factor is almost ubiquitously expressed in cervical carcinomas. Why is that relevant? That informs why there’s not a companion diagnostic. It’s not a biomarker where you [must] determine [whether a patient with cervical cancer] expresses tissue factor because it’s almost ubiquitously expressed. That’s issue No. 1.
The antibody, which targets tissue factor, has a linker. This is a protease cleavable linker. And then it has a payload. It’s an MMAE [monomethyl auristatin E] payload, which is the microtubule-disrupting payload. So, we have an antibody. The antibody is geared toward the target tissue factor. That antibody has a cleavable linker, and that linker is attached to a payload. So, what happens is theoretically this goes toward the malignant cells. There is endocytosis, there’s cleavage of the linker, there’s release of the payload, and then there’s cell death. And of course, there could be bystander effect because you can have some leak of that payload to neighboring malignant cells, and that subsequently leads to an efficacy signal.
So, it’s exciting to see that we’ve had an evolution and…tisotumab vedotin was the first FDA-approved antibody-drug conjugate in the gynecologic cancer space. And of course, here it’s in the cervical cancer space. And tissue factor [is] involved in angiogenesis and in the metastases of cervical cancer. So, it’s thought to be an exceptional target for a therapeutic treatment modality. And as I mentioned, it’s very highly expressed, which negates the need to have a biomarker selection strategy. So, where did tisotumab vedotin emerge? How did we get the therapeutic treatment signal? It came from a study called the innovaTV 204 or GOG protocol 3023, the ENGOT-cx6 trial. This was a phase 2 trial of single-agent tisotumab vedotin. Importantly, it was conducted in patients who had metastatic or recurrent cervical cancer, prior treatment, but less than or equal to 2 prior systemic therapies. A good performance status of ECOG of 0 to 1. These patients were treated with single-agent tisotumab vedotin, 2 mg/kg IV [intravenously] every 3 weeks until disease progression or unacceptable treatment-related [adverse] effects.
I’d like to start by saying the study was positive and this led to an accelerated approval by the FDA in September of 2021 for use of tisotumab vedotin. And you ask…why, Ramez? What drove the accelerated approval? And what drove it was, there were a total of 101 patients that were enrolled and treated on innovaTV 204. The median age of this population was 50 [years]. This highlights something. Many of these cervical cancer patients are young. The age range was 43 to 58 [years]. So, you had a young patient population battling an aggressive disease. And what we saw in this patient cohort was in this previously treated patient population who received tisotumab vedotin as a single agent, the objective response rate was 24%. And again, I want to highlight when you look at contemporary trials, where you look at physician’s choice chemotherapy, monotherapy drugs such as topotecan, such as gemcitabine, such as pemetrexed, the response rate was 6%.
So here we see with tisotumab vedotin a 24% response rate. And what was quite provocative was you got a 7% complete response [CR] rate. We don’t expect complete responses in [patients with] previously treated progressive cervical cancer, but we saw a 7% CR rate, 17% partial response rate, and the clinical benefit rate in this patient population. This is important, but the clinical benefit or disease control rate was over 70%, which in clinical practice matters. Why? Because if I have a [patient with] recurrent cervical cancer…and I can keep their disease stable for a prolonged period…that is a benefit because they have a reasonable quality of life, can tolerate therapy, and have disease control. We’re helping them.
And of course, based on this objective response rate of 24% and the median duration of response, there was an accelerated approval by the FDA, as I mentioned, that was released in September of 2021. And I’m also excited to say that just recently, there was a press release for the confirmatory trial, which compared tisotumab vedotin to physician’s choice chemotherapy in a recurrent cervical cancer patient population. So, the confirmatory trial press release was positive. We [must] wait for [those] data to be presented at a scientific congress. But again, for us, exciting.
Transcript is AI generated and edited for readability.