Liam Davenport

December 11, 2024

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Despite being a targeted therapy, antibody-drug conjugates (ADCs) can cause significant off-target toxicity to the eyes of patients being treated for advanced multiple myeloma or cervical cancer, yet the risks remain relatively unknown, according to oncologists and ophthalmologists.

Such experts called for greater collaboration between oncologists and ophthalmologists, in interviews with Medscape Medical News.

ADCs combine a monoclonal antibody targeted at an antigen overexpressed on cancer cells with a toxic chemotherapy payload — the aim being to maximize the effectiveness of the drug against the tumor while minimizing the damage to healthy tissues and reducing systemic toxicity.

Yet trastuzumab duocarmazine (T-Duo), a third-generation human epidermal growth factor receptor 2 (HER2)–targeted ADC designed to treat HER2-positive breast cancer, was recently found to have a notable adverse effect in the TULIP trial of 437 patients.

As reported by Medscape Medical News, the drug was associated with a significant increase in progression-free survival over physician’s choice of therapy. However, 78% of patients in the ADC group experienced at least one treatment-emergent ocular toxicity adverse event vs 29.2% of those in the control group.

Moreover, grade 3 or high ocular toxicity events were reported by 21% of patients in the experimental group compared with none of those who received physician’s choice.

Ocular Toxicities Seen on Ocular Surface

Ocular toxicities with these drugs are “not necessarily a new thing,” said Joann J. Kang, MD, director, Cornea and Refractive Surgery, and associate professor of ophthalmology at Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

“But what we’re seeing with certain ADCs is a lot of ocular toxicity, especially on the ocular surface,” with the degree toxicity varying depending on the ADC in question. “It’s definitely a real concern.”

Kang noted that separate from T-Duo, certain ADCs already come with black box warnings for ocular toxicity, including:

• Belantamab mafodotin (Blenrep) — approved for relapsed or refractory multiple myeloma and carries a warning specifically for keratopathy.
• Tisotumab vedotin (Tivdak) — indicated for recurrent or metastatic cervical cancer and can cause changes in the corneal epithelium and conjunctiva.
• Mirvetuximab soravtansine (Elahere) — used to treat folate receptor (FR) alpha–positive ovarian, fallopian tube, and peritoneal cancers and can lead to keratopathy, blurred vision, and dry eyes.

Indeed, the American Academy of Ophthalmology 2024 annual meeting saw research presented indicating that mirvetuximab was associated with moderate or severe corneal toxicity in 47% of patients treated for primary gynecologic malignancies.

As reported by Medscape Medical News, the study, by researchers at Byers Eye Institute of Stanford University in Stanford, California, was a retrospective analysis of 36 eyes of 18 women who received mirvetuximab for FR alpha–positive, platinum-resistant primary ovarian cancer.

What Are the Causes?

But why would a drug that is targeted specifically to a cancer tumor, thanks to the presence of a monoclonal antibody, cause off-target effects such as ocular toxicity?

Kathy D. Miller, MD, professor of oncology and medicine at Indiana University School of Medicine in Indianapolis, pointed out that they are targeted in a relative and not absolute sense, meaning that the antigen target may not be truly limited to the tumor cells.

There can also be “a lot of ways that you could get systemic toxicities,” she said.

For example, if the linker connecting the antibody and the chemotherapy payload breaks prematurely or is not stable, or if the drug leaches out into the tumor microenvironment and then is “picked up into the circulation, that can give you systemic toxicity,” she said.

In addition, the drug may, once it is in the tumor cells, be metabolized to an active metabolite that could, again, result in systemic exposure.

Side Effects Are Underappreciated and Distressing

Ocular toxicity remains underappreciated among oncologists prescribing these drugs. One reason is that it “did not get enough attention” in the initial clinical trial reports, Miller said she suspects.

Another potential reason for this is that “we’re not used to thinking about it because it’s not particularly common among the drugs that oncologists use frequently,” she added. Additionally, it tends to come up later during treatment, “so people have to be on therapy for some time before you start to see it.”

Nevertheless, Miller underlined that ocular toxicity “can be particularly distressing for patients, as it’s uncomfortable [and] can lead to scarring, so some of the vision issues can be permanent.”

“We often see in these situations that there are different types of ocular toxicities that present in different patients,” said Jane L. Meisel, MD, co-director, Breast Medical Oncology, Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta.

“Corneal damage is pretty common, and patients can present with blurry vision, or dry eyes, or light sensitivity. And unlike some side effects, these are things that really impact people at every waking moment of their day.”

“So they’re pretty clinically significant side effects, even if they’re not life-threatening,” Meisel emphasized.

Miller suspects that more heavily pretreated patients may be more likely to experience ocular toxicity, as “there’s a much higher incidence of dry eyes in our patients than we recognize.”

She added: “We don’t usually ask about it, and we certainly don’t routinely do Schirmer’s tests,” which determine whether the eye produces enough tears to keep it moist.

Preventive Measures

For patients receiving tisotumab or mirvetuximab who experience ocular toxicity, Kang said the recommendation is to use steroid eye drops before, during, and after treatment with the ADC.

However, she noted that steroids have not been found to be useful in patients given belantamab, so clinicians have tried vasoconstrictor eye drops immediately prior to the infusion, as well as ocular cooling masks, which “are thought to help by reducing blood supply to the ocular areas.”

Other approaches to minimize ocular toxicity have included longer infusion times, so it’s “not so much of a hefty dose at one time,” Kang added.

She underlined that grade 2 and 3 ocular toxicities can lead to dose delays or dose modifications, and “usually by the time you get a grade 4 event, then you may need to discontinue the medication.”

This can have consequences for the patients because they are often “very sick, and this may be their third agent that they’re trying,” or it may be that their tumor is responding to a new treatment, but it has to be withheld because of an ocular toxicity.

“It can be incredibly frustrating for patients, and also for oncologists, and then for ophthalmologists,” Kang said.

Closer Collaboration Between Specialists Needed

What’s known about ocular side effects in patients taking ADCs underlines that there is a need for closer collaboration between oncologists and ophthalmologists.

“In oncology, especially as immunotherapies came to the forefront, our relationships with our endocrinology colleagues have become stronger because we’ve needed them to help us manage things like thyroid toxicity and pituitary issues related to immunotherapy,” Meisel said.

With toxicities that may be “very impactful for patient quality of life, like ocular toxicity, we will need to learn more about them and develop protocols for management, along with our ophthalmology colleagues, so that we can keep patients as comfortable as possible, while maximizing the efficacy of these drugs.”

Miller agreed, saying oncologists need to have “a conversation with a local ophthalmologist,” although she conceded that, in many areas, such specialists “are in short supply.”

The oncologist “not only needs to be aware” of and looking for ocular toxicity when using these ADCs but also needs to be thinking: “If I run into trouble here, who’s my ophthalmology backup? Are they familiar with this drug? And do we have a plan for the multispecialty management of patients who run into this toxicity?”

Setting Counts When Assessing Toxicities

But do all these considerations mean that ADCs’ potential ocular toxicity should give clinicians pause when considering whether to use these drugs?

“What my patients most want are drugs that work; that are effective in controlling their tumors,” Miller said.

“Every drug we use has potential toxicities, and which toxicities are most physically troublesome [or] are the greatest concern may vary from patient to patient, and it may vary a lot from patients with metastatic disease to those in the curative setting.”

She explained that “toxicities that might not be prohibitive at all in the metastatic setting [may] have to be a much bigger part of our considerations” when moving drugs into the adjuvant or neoadjuvant setting.

This, Miller underlined, is where the ocular toxicity with these ADCs “may be much more prohibitive.”

TULIP was funded by Byondis BV.

Turner declared relationships with Novartis, AstraZeneca, Pfizer, Merck Sharp & Dohme, Lilly, Repare Therapeutics, Roche, GlaxoSmithKline, Gilead Sciences, Inivata, Guardant Health, Exact Sciences, and Relay Therapeutics.

Meisel declared relationships with Novartis, AstraZeneca, Genentech, Seagen, Olema Oncology, GE Healthcare, Pfizer, Stemline, and Sermonix Pharmaceuticals.

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