Ocular Toxicity With New Drugs for Gynecologic Cancers

Antibody–drug conjugates (ADCs) are relatively new in the gynecologic cancer space, and while they show promise, the novel ocular adverse events associated with this drug class mean that clinicians need to learn how to monitor and manage these patients.

This was the message from Colleen Bohnenkamp, PharmD, an oncology clinical pharmacist at the University of Kansas Health System, speaking at a special session during the recent Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer.

Patients with advanced/recurrent gynecologic cancers have few treatment options, and ADCs are of interest as targeted, biomarker-driven therapies for this population.

ADCs are designed to deliver cytotoxic agents directly to the tumor by using antibodies to target specific proteins in the tumor, Bohnenkamp explained.

“The ‘cytotoxic payload’ is not just any chemotherapy,” she emphasized. “This is a highly toxic agent that if administered by itself would be lethal.”

Bohnenkamp commented that she likes to think of ADCs as “dipping a dart into a highly lethal chemotherapy and, assuming you have the precision, you can hit the bullseye or target of choice.”

Within the past 18 months, the US Food and Drug Administration has approved the first two ADC agents for gynecologic cancers, Bohnenkamp noted.

The first ADC, approved in September 2021, was tisotumab vedotin-tftv (Tivdak, Genmab), a tissue factor-directed antibody indicated for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

A year later, mirvetuximab soravtansine (Elahere, Immunogen) was approved in November 2022. This ADC has an antibody that targets folate receptor alpha and is indicated for the treatment of tumors that show high expression of this protein as well as being platinum-resistant epithelial and are located in the ovary, fallopian tube, or peritoneum, in patients who have received one to three prior systemic treatment regimens.

Bohnenkamp cautioned that both drugs received accelerated approval based on single-arm studies. “This means that approval is contingent on phase 3 studies, which are ongoing,” she said.

Tisotumab Vedotin-tftv

Tisotumab vedotin-tftv was approved based on the innovaTV 204 clinical trial, a multicentered, open-label, single-arm, phase 2 trial that included 101 patients with metastatic or recurrent cervical cancer. Patients received tisotumab vedotin at a dose of 2 mg/kg (maximum 200 mg/dose) intravenously every 3 weeks until disease progression or unacceptable toxicities.

At a median follow-up of 10 months at the time of data cutoff, 24 patients had an objective response and seven were complete responses. “I think that’s very impressive for this late in the game,” commented Bohnenkamp.

The 6-month survival rate was 79% with a median overall survival rate of 12.1 months and a median time to response of 1.4 months.

“For safety, 65% of patients had a low-grade toxicity and 27% a high-grade toxicity,” she pointed out. “Unlike chemotherapy, we don’t see a lot of high-grade cytopenias.”

Common side effects included alopecia, bleeding events, fatigue, nausea, peripheral neuropathy, and ocular toxicities. Reported in 53% of patients in the trial, ocular toxicities included conjunctivitis, dry eye, keratitis, and vision changes, with rare cases of corneal ulceration and severe vision loss.

“The National Comprehensive Cancer Network (NCCN) guidelines recommend tisotumab vedotin as a preferred regimen in second or subsequent therapies,” she noted.

Mirvetuximab Soravtansine

Mirvetuximab soravtansine agent received approval based on the single-arm, phase 2 SORAYA trial, which looked at safety and efficacy in platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The objective response rate was 32.4%, with five complete responses and 29 partial responses, and 20 patients had disease progression. The median duration of response in this population was 6.9 months and progression free survival was 4.3 months.

“For safety, 89% of patients had any grade toxicity and 29% had grade 3 or 4,” she pointed out. “The most common toxicities were ocular, and we don’t usually see alopecia or high rates of hematologic toxicities with this medication.”

Of note, mirvetuximab soravtansine is indicated specifically for patients with tumors that have high expression of folate receptor alpha, so patients will need to be tested, Bohnenkamp noted. “This isn’t a routine test and it needs to be sent out,” she said. “There are currently four labs that will run this test.”

NCCN guidelines have included mirvetuximab as a preferred regimen for targeted therapy with a single agent. And as with tisotumab, confirmatory trials are ongoing.

Ocular Toxicities

Ocular adverse events are common with both tisotumab vedotin and mirvetuximab soravtansine, and product labels for both include boxed warnings regarding ocular toxicity.

These can present as reduced visual acuity, blurred vision, light sensitivity, redness, dryness, and irritation, which may result in conjunctival or corneal inflammation.

Symptoms are often detectable before they become severe, and this allows for early referral for management, commented Meghan Berkenstock, MD, associate professor of ophthalmology, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland.

“Close communication between oncologists and eye care providers is needed,” she said. “Patients should be referred to us if they are having any issues.”

“But most important is coordination of care,” Berkenstock emphasized. “The oncology care team needs to monitor patients for ocular signs and symptoms.”

Ocular toxicity can be prevented and mitigated by utilizing recommended eye care strategies, Berkenstock commented.

While there are some differences in mitigation strategies between the two drugs, the basic protocols are similar. “All patients should have baseline eye exams prior to each infusion and repeated prior to infusion,” she said. Also, patients should be instructed not to wear contact lenses during treatment in order to avoid infectious keratitis or increased surface dryness, she said. Prophylactic steroid eye drops should be given prior to starting the infusion and continued use for 72 hours after infusion for tisotumab and through day 10 for mirvetuximab. “Patients who are using steroid drops for symptom management require follow-up to monitor for cataract progression and to check intraocular pressure,” she commented.

Lubricating eye drops are also used prophylactically throughout treatment as they add moisture to the eye, she explained. “They can be used for self-use as needed through the day from the infusion until 30 days after the last dose.”

Tisotumab also requires vasoconstrictor eye drops that are given prior to each infusion, and cold packs are applied during and after the infusion to decrease blood flow.

Berkenstock finished her talk by adding a “disclaimer.” These are new drugs and these are new ocular toxicities, so many ophthalmologists may not be familiar with these drugs and the associated side effects. They may need background information on the drugs to get up to speed.

But overall, oncologists and eye care providers need to work together, she emphasized. “Make friends with us, get our cell numbers,” she joked. “We are happy to help.”

Bohnenkamp has reported relationships with AstraZeneca, GlaxoSmithKline, MSD, and Novocure. Berkenstock has reported a relationship with Eyepoint Pharmaceuticals.

Presented at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer. Presented March 25, 2023.

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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