Behind the FDA Approval: Tisotumab Vedotin for Metastatic Cervical Cancer

David S. Hong, MD

Bringing the first antibody-drug conjugate into the treatment armamentarium for patients with metastatic cervical cancer, tisotumab vedotin (Tivdak) was granted accelerated approval from the FDA in September 2021 for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

The approval was said to be an important development in the field by the lead investigator of the phase 2 innovaTV 204 clinical trial, Robert L. Coleman, MD, chief scientific officer, US Oncology Research. Findings from innovaTV 204 supported the FDA’s decision and excited experts in the field, like the lead investigator of the prior phase 1 study, David S. Hong, MD.

Treatment with tisotumab vedotin achieved an objective response rate of 24% (95% CI, 15.9%-33.3%) with complete responses in 7% of patients, partial response in 17%, stable disease in 49%, and progressive disease in 24%. Further, there was a 79% decrease in target lesion size from baseline observed in the study.

The majority of patients who were treated with tisotumab vedotin responded quickly; for example, the time to response was 1.4 months (range, 1.1-5.1), with responses lasting for a median of 8.3 months (range, 4.2–not reached).

In an interview with Targeted Oncology™, Hong, deputy chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, TX, discussed the mark tisotumab vedotin has made on the metastatic cervical cancer landscape thus far.

TARGETED ONCOLOGY: What impact has tisotumab vedotin had in cervical cancer since its approval?

Hong: The primary impact has been in cervical cancer, it's in refractory patients, and this is really in the metastatic setting. Unfortunately, there's not a whole lot after chemotherapy, and there is second-line pembrolizumab [Keytruda], but it’s for patients who are PD-L1-positive, so, the fact that we have another therapy is always a good thing. Right?

I think the hope is that, eventually, we could be able to combine this with PD-1 in the near future, and see better clinical benefit rates in the frontline setting. So, we'll see if that happens. I think that it's good to see that we got accelerated approval, and it's always good to have options beyond just standard chemotherapy.

What unmet medical need did tisotumab vedotin fill and what other unmet needs exist?

In the second-line setting, there's not a whole lot there. Again, you can give them chemotherapy plus or minus, usually something like bevacizumab [Avastin], and then after that, you can give them another round of chemotherapy or in some cases, you can give them pembrolizumab if they are PD-L1-positive. Unfortunately, even with the PD-L1-positive population, in KEYNOTE-028, the response rate was about 15%, which is not a whole lot, and I think duration of response was around 5 months. So, the fact that we are seeing a 24% response rate and the duration of response is much longer than what pembrolizumab has, is a good sign that this drug will have some benefit in the second-line setting.

But just like any other cancer, metastatic cervical cancer is not curable. So, what we can do is try to help these patients live as long as they can with the second-line therapies. The idea and the hope is that eventually whether it's in combination or in frontline, we may be able to hear just how these drugs develop. So, they get approved in like the second[-line]/refractory setting, then they kind of move up with combinations, and then they get tested in the adjuvant or the neoadjuvant setting. And hopefully, that may happen.

What are your key takeaways on the data that supported the FDA approval of tisotumab vedotin for the treatment of metastatic cervical cancer?

I did the phase 1 data and the phase 1 expansion, which is published. My colleague, Robert Coleman, did the remainder of the investigation. So, there was a 24% response rate. The response rate for the large, randomized phase 2, was almost similar to the phase 1b expansion 24% response rate except for they had some complete responders, which I don't think we saw. Then, the duration of response, which led to the accelerated approvals, was 8.3 months.

Just based upon that, the results were better than pembrolizumab for PD-L1-positive patients.

There were adverse effects albeit manageable adverse effects. Most of these were related to the fact that this drug if you think about these antibody-drug conjugates, are kind of like, targeted chemotherapy. So, there are still going to be some off-target effects, whether it's anemia, lymphocyte decrease, peripheral neuropathy, etc.

What else should community oncologists know about this drug before administering it to their patients?

It’s important to note that it shouldn't be given to patients in the frontline setting. Also, there's a subset of patients that are not going to be PD-L1 positive, this drug probably has benefit in those patients who are not in the second-line setting. It's relatively easily given. Oncologists do need to watch out for some unique toxicities, like ocular toxicity, which can develop, and patients get like this grainy feeling in their eyes, but with cold packs on their eyes and steroid drops, these patients do okay.

Although we didn’t see much severe bleeding, patients do develop epistaxis and can develop nosebleeds. There can be some peripheral neuropathy associated primarily because of the payload, which is kind of like a taxol derivative. There are also a few adverse effects that are kind of unique to tisotumab vedotin that you probably won't see with carboplatin or other therapies.

_References:

_{Seagen and Genmab announce FDA accelerated approval for Tivdak™ (tisotumab vedotin-tftv) in previously treated recurrent or metastatic cervical cancer. News release. Seagen, Inc. September 20, 2021. Accessed January 28, 2022. https://bit.ly/3AE9bgC}