Tisotumab Vedotin: A Second-Line ADC Approval in Metastatic Cervical Cancer


Shared insight on the approval of tisotumab vedotin, an antibody-drug conjugate, in the second-line setting of metastatic cervical cancer.


Bradley Monk, MD, FACOG, FACS: Let’s transition to the elephant in the room, which is that checkpoints are being used earlier. That’s good for patients. That clears out the space for second line and for innovation. On September 20, the US Food and Drug Administration approved tisotumab vedotin. This is the first antibody-drug conjugate [ADC] to get approved in a gynecologic malignancy. Bhavana, what’s an antibody-drug conjugate?

Bhavana Pothuri, MD: It’s a molecule that has a linker that can target cancer cells and deliver drugs directly to the cells.

Bradley Monk, MD, FACOG, FACS: It has a target, an antibody, a linker, and a cytotoxin. The idea is to get the cytotoxic payload—preferably in the tumor—to avoid systemic toxicity but enhance the local effect on a bystander. Maybe it’s because of immunogenic cell death, or because there’s an antibody, or maybe antibody-directed cytotoxicity. Warner, tell us about the GOG-0240 study, innovaTV 204—TV stands for tisotumab vedotin—published in Lancet Oncology this year.

Warner K. Huh, MD, FACOG, FACS: It’s a recurrent metastatic cervical cancer trial. It was presented at ESMO [European Society for Medical Oncology Congress] and published in The Lancet. They saw that 7% of the patients had a complete response, and about 17% had a partial response to the drug. It was quite remarkable. The announcement was released by the FDA on September 20, so this is hot off the press. This is the first ADC approved for gynecologic cancer. If you take a step back, it’s cool, much in the same way we were speaking about bevacizumab many years ago. It’s game changing. It’s gratifying to see all these rapid changes occur in a short period of time. They got accelerated approval from the FDA for use in patients with recurrent disease who’ve progressed on chemotherapy. I have several patients who are excited to go on this drug.

Bradley Monk, MD, FACOG, FACS: Krish, tell us about the target, tissue factor.

Krishnansu S. Tewari, MD: I’m thrilled that the drug got approved and that it works. I’ve had patients on study who had phenomenal objective responses. I’m perplexed why it works because tissue factor isn’t a strong biomarker. It’s almost ubiquitously expressed in cervical cancer, so you can’t use it to select this therapy. The payload is a chemotherapy agent that’s phagocytosed into the cell. It’s ingenious. Why doesn’t our chemotherapy work like this to begin with? When I try to think about this on another level, clinically I love it, and I’m going to use it, but I’m surprised it works so well.

Bradley Monk, MD, FACOG, FACS: Tissue factor thromboplastin is overexpressed on cervical cancer— more than 90% to 95% of the time compared with normal tissue. As Bhavana said, there’s more tissue factor in the tumor. The antibody binds preferentially in the tumor, enriches the dose-response curves and the concentration in the tumor and makes this antitubulin, MMAE, effective. This is the fourth antibody-drug conjugate for that particular sponsor, and the first in gynecologic cancer. The GOG-0240 trial had a survival of 17 months. Now you have KEYNOTE-826, which is 24 months. The survival of GOG-0204, is 12 months, and you’re up to 36 months. You have to use chemotherapy and bevacizumab when appropriate, and pembrolizumab and tisotumab vedotin when needed. In a patient population with an average age of 50, they’re living 3 years. When we did the GOG-0204 trial, they were living 12 months. You’re going to get better because you’re smarter. Bhavana and Premal, does that resonate with you? Is it hyperbole, or do you think this is game changing?

Premal H. Thaker, MD, MS: These are incremental benefits that we’re getting to our patients. I like your theory that we need to cure these patients up front and get smarter in choosing our populations. As a fellow years ago, I told patients they had about a year to live when they recurred. We didn’t havesufficient medications or drugs. It’s hard to sit and have those conversations, and now we have options. That’s the exciting thing about cervical cancer.

Bradley Monk, MD, FACOG, FACS: What do you think about taking tisotumab vedotin and inserting it into the KEYNOTE-826 regimen? Presented at ESMO, the response rate of carboplatin-tisotumab vedotin was 55%.

Bhavana Pothuri, MD: That was 33 patients. The [Ignace] Vergote data were provocative in terms of wanting to assess, in a larger trial, whether there’s benefit with this combination. But 55% is significant.

Transcript edited for clarity.

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