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The accelerated approval of the tissue factor–directed antibody and microtubule inhibitor tisotumab vedotin-tftv bolsters the treatment portfolio for patients with recurrent metastatic cervical cancer.
The accelerated approval of the tissue factor–directed antibody and microtubule inhibitor tisotumab vedotin-tftv (Tivdak) bolsters the treatment portfolio for patients with recurrent metastatic cervical cancer. The FDA granted the approval to tisotumab vedotin on September 20, 2021, specifically for patients in this population who have disease progression on or after chemotherapy.1
The approval was based on results from the phase 2 innovaTV 204 trial (NCT03438396), which showed that tisotumab vedotin elicited an overall response rate (ORR) of 24% (95% CI, 15.9%-33.3%), including a 7% complete response rate, among 101 treated patients. The median duration of response was 8.3 months (95% CI, 4.2-not reached).2
In an interview with OncologyLive® Robert L. Coleman, MD, chief scientific officer of The US Oncology Network in The Woodlands, Texas, discussed the need to add new agents to the treatment portfolio of recurrent or metastatic cervical cancer and how the approval of tisotumab vedotin may help to fill this void.
Coleman: This new agent adds to our armamentarium for patients with recurrent metastatic cervical cancer. That’s the bottom line. We have very few effective options. I include immunotherapy in that statement because the vast majority of patients with cervical cancer don’t benefit from immunotherapy. There is certainly a cohort of patients who do remarkably well. We have seen that [immunotherapy is] better than standard chemotherapy in a recent randomized phase 3 trial [KEYNOTE-826, NCT03635567], but that does not close the book. The need for effective therapies, ones that act rapidly, is desperately present in our day-to-day care of patients with advanced metastatic cervical cancer.
The clinical rationale was [primarily] based on the need for effective therapy in patients with recurrent disease post chemotherapy, but also [on the need] to explore a new class of agent. This [agent] is an antibody-drug conjugate that takes advantage of the near-universal expression of tissue factor, which is seen across many solid tumors but is especially high in patients with cervical cancer, [and presents an] opportunity to take advantage of a biological expression of a target and incorporate a targeted smart bomb, so to speak, with chemotherapy that is effective on the cells in the microenvironment.
The headline that catches most individuals' attention is that we have a relatively high response rate. The response rate is in the mid-20s, [which is] usually considered an area that would represent a real clinical advance. That’s why this was submitted under the accelerated approval program. We felt that this was substantially better than our experience with second-line chemotherapy agents in this setting.
The ORR of 24% was felt to be remarkable in this 101-patient trial. The other component of this that sometimes gets lost is that when we treat patients in the clinic, we will make decisions of continuing therapy in the presence of nonprogression. For instance, if a patient comes in who has had a stability in their tumor that we’ve been able to document by exam or by CT scan and symptoms have not accelerated, our strategy at that point is not to change [treatment].
If you look at the proportion of patients for which their best response was progression, it was a really low number. This translates into clinical benefit, which captures the stable disease rate along with all responses. That’s what is meaningful in the clinic. Then, for those patients who respond, the duration of response being more than 9 months or so is substantially meaningful, especially since our life expectancy for this patient population can be quite muted. Of course, we must balance [these advantages] against the toxicity that was observed.
The toxicity that we saw with this treatment was not dissimilar to what we see with chemotherapy, although there were a few notable differences. Common adverse effects that we see with chemotherapy in this setting are things such as asthenia and fatigue, bone marrow suppression, alopecia—various adverse effects that we can see with any kind of cytotoxic agent.
The unique toxicities that we saw with [tisotumab vedotin] were ophthalmologic toxicities. Conjunctivitis and neurotoxicity observed with this class of agent are not dissimilar from other antibody-drug conjugates in the literature.
We were also very concerned early on about bleeding during the phase 1 and phase 2 expansion trial because tissue factor is an element that’s present in the clotting cascade. Our concern was that if we were interrupting this process, we were potentially increasing bleeding events. We were happy to see that that wasn’t the case, and we did monitor it very carefully. So, it would be considered a special interest adverse effect.
Fortunately, most of the bleeding events that we saw were epistaxis and others that we’ve seen with [agents such as] bevacizumab [Avastin]. Most of the bleeding that we saw was grade 1 and most of it was resolvable in a short period of time. Overall, we were reassured, but it doesn’t [change] the fact that the optimal logical component of this needs to be addressed. It’s a unique toxicity that, if investigators have not had experience with it, it certainly would be one that they need to pay attention to when they administer the drug.
The agent was brought into the clinical domain under accelerated approval, which means there needs to be a confirmatory trial. That trial has already launched [innovaTV 301, NCT04697628]. [Tisotumab vedotin has] been matched with several different compounds, not only chemotherapy, but also other antiangiogenic agents and immunotherapies that are being investigated to see what might fit best and where in the clinical domain.
[Additionally, we would like to] see it in an earlier line of therapy where we would have an opportunity to provide benefit to more patients in a broader spectrum. It would be logical to assume that an effective second-line agent or third-line agent could be moved up into earlier lines of therapy, where more patients would have access.