Westin Discusses Logistical and Tolerability Challenges in Metastatic Cervical Cancer

Shannon N. Westin, MD, MPH (Moderator)

Clinical Medical Director

Department of Gynecologic Oncology and Reproductive Medicine

Division of Surgery

The University of Texas MD Anderson Cancer Center

Houston, TX

EVENT REGION Colorado, Nevada, North Dakota, South Dakota, Wyoming

PARTICIPANT LIST Elie Fahed, MD | Rita Mukherjee, MD | Holavanahalli S. Keshava-Prasad, MD | Santhosh Ambika, MD | Vijay Rao, MD

DISCUSSION QUESTION

What has been your experience with progression of disease in a patient with cervical cancer?

Westin: What do we do when people don’t respond to therapy, and what are some other challenges in this population?

Fahed: [One challenge is that] the patients who get cervical cancer are usually nonadherent. They don’t get their pap smears, and they don’t follow medical care regularly.

Westin: Yes, it can be tough. It’s a population that needs a lot of support. Sometimes, it’s not even true nonadherence; it’s just that they’re doing everything for their family. They don’t have transportation or they’re working. This is an age group that has a lot of responsibilities, and sometimes they may not have access to care. It can be a tough situation. I would love to hear about your populations, but looking at the stage of diagnosis, are we capturing [disease in] these patients with [Papanicolaou tests]? Are we capturing [their disease] because they’re having symptoms? Are we figuring out they have disease far later than ideal?

Fahed: It’s usually later in my population compared with other cancers. Since I’m a community oncologist, I see different cancers. These patients tend to be less adherent, independent of what’s causing it. Without judging, I have a hard time getting them to continue with follow-up or finish treatment when they sometimes stop in the middle of radiation and chemotherapy and don’t finish the course.

Westin: That’s a huge issue. We know that the best outcomes for chemoradiation happen if we can keep it in a tight duration. The longer a duration that treatment takes, the worse the outcomes, and you’re exactly right. If you’ve got somebody who can’t make it every day for that 15-minute treatment and their weekly chemotherapy, you get even worse outcomes. It can be a tough situation.

The NCCN guidelines [list] preferred regimens for those who are PD-L1 positive.¹ Pembrolizumab is listed with and without bevacizumab, with either cisplatin or carboplatin. How do you choose that? Do you always use carboplatin? Do you use cisplatin for certain cases?

Mukherjee: Platinum depends upon the renal function. Especially if they’ve gone through chemoradiation with cisplatin and the renal functions have deteriorated, then I would consider carboplatin after that.

Westin: That’s a good point on the renal function. [With] carboplatin, it’s so much easier to protect the kidney function. There are some data out of Japan that indicated—it was a subset analysis, so we always have to be a little careful about that—but it did indicate that potentially, in a patient population that has not had cisplatin, they may get a bit more benefit with the utilization of cisplatin with taxane.² Conversely, the patient population that’s already had cisplatin with their chemoradiation therapy may get more benefit from carboplatin. It’s something to think about, but both are very appropriate in this setting. You see the platinum with bevacizumab as well for those patients for whom you don’t want to do, or aren’t able to do, immunotherapy.

CASE UPDATE

• Eight months later
  • On reevaluation, patient complains of dyspnea on mild exertion; persistent, nonproductive cough; and fatigue.
  • Focused physical examination: tachypnea; diminished breath sounds; monophasic wheezing; and scattered crackles
• Imaging studies and diagnostic testing
  • Contrast-enhanced CT of chest, abdomen, and pelvis: revealed heterogeneously enhancing mass 7.5 cm × 4 cm × 6 cm arising from the left upper lobe bronchus; bilateral hilar lymphadenopathy, with a short axis of 3 cm in diameter
  • Patient underwent CT-guided endobronchial biopsy of the lung
  • Histopathology: consistent with poorly differentiated, metastatic adenocarcinoma of the cervix
  • Whole-body fluorodeoxyglucose (FDG)-PET/CT: avid FDG uptake in left upper lobe of lung and hilum; no evidence of osseous or hepatic metastases
• Metastatic disease recurrence confirmed

DISCUSSION QUESTIONS

• What is the mechanism of action of tisotumab vedotin (Tivdak)?
• What adverse events (AEs) are of most concern with tisotumab vedotin?

Westin: We’re all comfortable with antibody-drug conjugates [ADCs]. ADCs have the receptor, have a linker, and then have a large payload. The receptor for this particular ADC is tissue factor, and it’s covalently linked to MMAE [monomethyl auristatin E], which is a microtubule disrupting agent, so it has taxanelike properties and AEs. The reason tissue factor was chosen is that it’s highly expressed in cervical cancer, almost 98%, so you don’t even have to test and select for tissue factor. You can just give this drug broadly, which is very successful. As with most ADCs, there’s a multimodal action, so you get the direct cytotoxicity as well as bystander killing and activation of antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, which help to increase the action of this therapy.

The innovaTV 301 study [NCT04697628] was the confirmatory phase 3 study, a randomized study in which the patients were randomly assigned 1:1 to tisotumab vs the investigator’s choice of chemotherapy. You can always tell there’s not a great investigator’s choice if there are 5 choices, [which were]: topotecan, vinorelbine, gemcitabine, irinotecan, and pemetrexed. This was a recurrent metastatic [population that] had less than or equal to 2 prior lines and measurable disease. They had to have a prior chemotherapy doublet with or without bevacizumab and an anti–PD-1 agent. This was perfectly designed for the setting of where we treat patients with KEYNOTE-826 [NCT03635567] or the BEATcc [NCT03556839] regimen. The primary end point was overall survival; they did look at progression-free survival and response.

There are some AEs with tisotumab that are a bit different than with our standard treatments that we use. In addition to bone marrow toxicity, anemia, nausea, and constipation, we saw a high proportion of patients with neuropathy [Table³]. This is an MMAE payload, so we are seeing that taxane activity. Also, something of interest is alopecia. We want patients to know [since many] of our second- and third-line agents don’t cause alopecia. Making sure that we’re educating patients and that they’re aware of it is really important. Epistaxis is not an AE that we can’t handle, but it’s something you want to make a patient aware of, because when it happens, they don’t want to be surprised.

Those are probably the most common [AEs], and then the most unique and important AEs, I would argue, are some of the ocular toxicities. We saw conjunctivitis, keratitis, and dry eye [Figure⁴]. There’s a clear regimen of eye drops and such that we use. We ask patients not to wear contact lenses. In our center, they wear a cold pack while they’re getting their infusion to help reduce the chance of [getting] those eye toxicities.

[Concerning] mitigation strategies for ocular toxicity, when utilizing the eye drops, it’s important, especially in a population that doesn’t have a lot of support, to remind [patients that] they need to bring their eye drops with them and be ready to use them at the time of their infusion, and also continue to use them afterward: 1 [corticosteroid] drop in each eye prior to infusion, and then continue [3 times a day] for 72 hours. For the vasoconstrictor, they’re going to do it just prior [to infusion] and then [continue] lubricating for the whole month [and for 30 days after the last dose].⁵

For eye exams, you want to do it prior to initiation of tisotumab and then every cycle for the first 9 cycles. You need to make friends with your [local] eye professional. It does not need to be an ophthalmologist, although [it] certainly can be, but optometrists can do this just as well. Get somebody who will connect with you and give you reports to make sure that you know that your patient is safe to get the infusion.

DISCUSSION QUESTIONS

• How do you approach treatment of patients with recurrent or metastatic cervical cancer?
• What are your impressions of the safety and efficacy data for tisotumab vedotin?

Keshava-Prasad: We don’t have much choice [of alternate therapies].

Westin: This is definitely an unmet need. This is a space where we need more [options].

Ambika: In the community, it can be a hassle arranging the ophthalmology exam. We had the myeloma drug belantamab mafodotin [Blenrep] and the same thing happened, and it’s a pain sometimes. I’m worried about the neuropathy, and a lot of these patients received a taxane for quite some time. Do you dose reduce if they have preexisting neuropathy?

Westin: We’ve started doing that in our practice. There are no strict guidelines, so you don’t have to, but you can start and see where the patient is at. In patients who have grade 1 or 2 [neuropathy], I’ve been dose reducing, and that seems to help, [as does] trying to be proactive with things like acupuncture and supplements where you can. It’s not 100%, it’s about 28%, but it’s still enough that if you’ve got a patient with preexisting neuropathy, it can be troublesome.3 But, obviously, we’re balancing it with survival.

Keshava-Prasad: I think there is a lack of any other good options. Before we had immunotherapy and ADCs, we probably used to recycle single-agent chemotherapy, but now, since we have this choice, I think it’s good. As [Dr Ambika] said, I think it’s a hassle with the eye complications sometimes, but it can be done.

Westin: We tried to do [eye exams] internally and our ophthalmologists were so behind. We were waiting and getting annoyed. I’m in Houston, [Texas,] so it’s a busy area, but we found a couple local optometrists who we could get a good connection with. They were willing to fax us reports pretty quickly. We said, “We’ll give you some patients,” and they said, “OK, great.” I think it helped to reach out and establish that [relationship] pre-patient, and say this is the situation we’re in and we really need your help. But it is definitely painful when you’re first trying to knock out those logistics.

Keshava-Prasad: In a lot of these patients with cervical cancer, they have neuropathy and renal failure. Are there any special precautions with tisotumab?

Westin: With renal failure, most of this is cleared through the liver, if I’m not mistaken, and so the patients do pretty well with kidney disease. So, it does present a nice option, because taxanes don’t seem to cause as much [toxicity], so that’s a good thing.

Ambika: Out of curiosity, this has been approved for some time. Is it unique for cervical cancer, or are there data for other cancer types? I haven’t heard much.

Westin: There have not been much data that I’m aware of in other cancer types. They started their development plan in cervical cancer, which was [great] for us who are treating cervical cancer. But I think they’re starting to branch out and look at other cancer types, because tissue factor is expressed in other cancer types, [albeit] maybe not to the level that it is in cervical.

Rao: Are there any predictors for response, because the responses range from complete response to progressive disease, with a 3% complete response rate.3 Are there any predictors or biological markers that help us?

Westin: Sadly, none to my knowledge. I know there are some studies ongoing around this, trying to tease out that population, but I haven’t seen any either long-term data or drill-down molecular data looking at it. The clinical factors that have been reported thus far, as far as location of disease, prior therapies, and those kinds of things, nothing has seemed to predict the benefit or lack of benefit. For now, we give it, and we hope our patients are on the right side of the numbers.

CASE UPDATE

• Treatment
  • Patient initiates tisotumab vedotin via IV every 3 weeks and experiences a partial response.
• Follow-up plan
  • Monitor for continued therapeutic response and tolerability
  • Return to office every 3 weeks
  • Ophthalmologic examination for first 9 cycles of therapy

DISCLOSURE: Westin previously reported consulting fees from AstraZeneca; Caris Life Sciences; Clovis Oncology/Pharma& Schweiz GmbH; Eisai Co, Ltd; EQRx; Gilead Sciences, Inc; GSK; Immunocore Holdings plc; ImmunoGen; Lilly; Loxo Oncology; Merck; Mereo BioPharma; Mersana Therapeutics; NGM Bio; Roche/Genentech; Seagen Inc; Verastem Oncology; Vincerx Pharma Inc; Zentalis Pharmaceuticals; and ZielBio Inc.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Cervical cancer, version 3.2025. Accessed March 6, 2025. https://tinyurl.com/3xdrn94s

2. Kitagawa R, Katsumata N, Shibata T, et al. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505. J Clin Oncol. 2015;33(19):2129-2135. doi:10.1200/JCO.2014.58.4391

3. Vergote I, González-Martín A, Fujiwara K, et al; innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. Tisotumab vedotin as second- or third-line therapy for recurrent cervical cancer. N Engl J Med. 2024;391(1):44-55. doi:10.1056/NEJMoa2313811

4. Vergote IB, Gonzales Martin A, Fujiwara K, et al. LBA9 innovaTV 301/ENGOT-cx12/GOG-3057: a global, randomized, open-label, phase III study of tisotumab vedotin vs investigator’s choice of chemotherapy in 2L or 3L recurrent or metastatic cervical cancer. Ann Oncol. 2023;34(suppl 2):S1276-S1277. doi:10.1016/j.annonc.2023.10.029

5. Tivdak. Prescribing information. Seagen Inc; 2024. Accessed March 6, 2025. https://tinyurl.com/2k44baet