Antibody-Drug Conjugates Offer Platinum-Resistant Patients New Options in Gynecologic Cancers

Antibody-drug conjugates (ADCs) are one of many different classes of anticancer drugs to enter the treatment paradigm.

As of August 2023, there have been 11 approvals for ADCs to treat solid and hematological malignancies, and there are over 100 still in clinical trials.¹ Specifically, 2 ADCs have been approved in the gynecologic oncology space alone.

First came tisotumab vedotin-tftv (Tivdak), which was approved for patients with recurrent or metastatic cervical cancer in September 2021. Its approval was supported by findings from the phase 2 innovaTV 204 trial (NCT03438396), in which the ADC elicited an objective response rate (ORR) of 24% (95% CI, 15.9%-33.3%) per independent review committee using RECIST v1.1 criteria in patients with recurrent or metastatic cervical cancer who received prior doublet chemotherapy and bevacizumab (Avastin).²

Then mirvetuximab soravtansine (Elahere) arrived on the scene. This agent was approved in November 2022 for patients with folate receptor α (FRα)–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. The accelerated approval was supported by findings from the pivotal phase 3 SORAYA trial (NCT04296890), which demonstrated that patients who received mirvetuximab soravtansine achieved an ORR of 31.7% (95% CI, 22.9%-41.6%), including 5 complete responses. The median duration of response was 6.9 months (95% CI, 5.6-9.7).³

Matthew P. Schlumbrecht, MD, MPH, FACOG

According to MATTHEW P. SCHLUMBRECHT, MD, MPH, FACOG, oncologists are optimistic about the impact that these drugs may have for these patient populations. Schlumbrecht is a professor of clinical obstetrics, gynecology, and reproductive sciences and director of the gynecologic oncology fellowship program at the University of Miami Sylvester Comprehensive Cancer Center in Florida.

“These 2 drugs are just the tip of the iceberg in terms of new ADCs,” he told Oncology Nursing News. “I anticipate that we will be seeing more of these in the future. What really stands out about these drugs is that there is truly a component of precision medicine.

“Clinically, we appreciate that cancer treatments are not one-size-fits-all, and it’s very heartening to see the science not just appreciate that, but actively use it as a driving force in the development of new medications,” he added.

As Schlumbrecht explained, these drugs rivaled chemotherapy in terms of patient responses in clinical trials, but what is particularly encouraging is that with both therapies, there were patients who had complete responses—meaning that no more cancer was seen on imaging.

ADCs consist of 3 parts: the monoclonal antibody, the linker, and the potent cytotoxic agent, which is typically referred to as the payload. With tisotumab vedotin, this payload is monomethyl auristatin E, and with mirvetuximab soravtansine, the cytotoxic agent is maytansinoid or DM4. The linker helps the monoclonal antibody attach to specific antigens on the cancer cell—tissue factor with tisotumab vedotin and FRα with mirvetuximab soravtansine. Once attached, the payload of cytotoxic agent is released inside the cell, causing apoptosis. This action also blocks the signal transduction pathway for cell survival and proliferation.

Paula Anastasia, MN, RN, AOCN

Of note, tissue factor overexpression is very common in patients with cervical cancer, which is why patients do not need testing for it prior to receiving tisotumab vedotin.⁴ However, in the SORAYA trial, only approximately 35% to 39% of patients with ovarian cancer who were screened had a high expression of FRα— defined as 75% or greater tumor cells staining at 2+/3 + intensity—and that is why diagnostic testing is so important in this setting.⁵ According to PAULA ANASTASIA, MN, RN, AOCN, many providers across the country have started testing their patients for this expression up front, since their disease will eventually become platinum resistant, and it is good to know which second-or third-line option will be available for their patients when that happens.

Managing Ocular Toxicities

“Now, the black box warnings for both of these ADCs are, of course, very frightening because we’re not used to seeing ocular toxicities,” Anastasia told Oncology Nursing News. “It is kind of like, ‘Oh my gosh, I’ve never taken care of patients who need eye therapy or have the potential to have complications.’ ”

However, she explained that with proper management and due diligence, these toxicities can be easily managed. “If we are proactive, we can successfully manage it, and the more we use these drugs, the more comfortable we become,” she said.

Further, nurses should take care not to unnecessarily scare patients about these eye abnormalities.

“When I talk to patients, I say ocular or eye ‘abnormalities,’ ” she said. “You don’t want to scare them with ‘toxicities’—the first thing they will think is that they are going to go blind, but actually, no patient has gone blind with these medications.”

Tisotumab vedotin

According to Anastasia, the management strategies with tisotumab vedotin are particularly stringent, as patients are required to take steroid drops, vasoconstriction drops, and lubricating drops.

Patients who are about to undergo treatment should receive topical corticosteroids immediately before their infusion and for 72 hours post infusion. Topical ocular vasoconstrictor drops should also be administered in each eye prior to infusion, and cooling eye pads should be applied during administration.

“We put eye pads over their eyes,” Anastasia said. “They have these cosmetic facial eye packs that you can put in the freezer; they’re very inexpensive, you can get them at the discount centers, and patients bring them frozen. We have a freezer that we could put them in, and we change them out every 10 minutes.”

Patients receiving this therapy will also need to apply lubricating eye drops for the duration of their treatment and for 30 days past their last dose. If patients wear contacts, they must switch back to glasses for the duration of treatment.

“The other important thing is patients need to see an eye specialist prior to every infusion with tisotumab,” Anastasia stressed. “You can give cheat sheets to the patient to give to their eye specialist so they know what they’re checking off, but it’s very important that they see their eye specialist.”

Mirvetuximab soravtansine

Mirvetuximab soravtansine is different; it is associated with more corneal toxicities than tisotumab vedotin. Ophthalmic topical steroids are recommended with this treatment.

One drop should be administered in each eye 6 times daily starting the day prior to each infusion, until day 4, and then administered 4 times daily for days 5 to 8 of each cycle. Moreover, lubricating eye drops should be used at least 4 times daily. Patients should wait at least 10 minutes after ophthalmic topical steroid administration before using lubricating eye drops.

Unlike with tisotumab vedotin, patients receiving mirvetuximab soravtansine do not need to see an eye specialist before each infusion. They need a baseline assessment, and it is important they see their specialist every other cycle, but overall, the frequency of ophthalmology appointments is reduced because the eye abnormality risk is not as significant.

Patients May Experience Better Quality of Life

For patients with otherwise limited treatment options, both tisotumab vedotin and mirvetuximab soravtansine are opening a door.

“For patients with recurrent or metastatic cervical cancer or patients with platinum-resistant ovarian cancer, again, their disease is going to be chronic,” Anastasia said. “The good thing is we have new options for them. They’re jazzed about that, but it’s still tough for them.”

She shared, for example, the case of a 33-year-old patient with stage IV cervical cancer. This individual began treatment with carboplatin and paclitaxel, but experienced burdensome peripheral neuropathy up front—so much that the team started giving paclitaxel over 6 hours.

“She was an athlete,” Anastasia recalled. “But she was not able to play soccer. She had constant fatigue and bone aches. She just felt awful. She had a very significant decrease in her quality of life.”

Ultimately, her treatment progressed beyond chemotherapy. However, because of the broadening treatment field, her providers had effective treatment options to offer her.

“Lo and behold, we had tisotumab vedotin to offer her, which she was very excited about,” Anastasia said. “Everybody was excited about it.”

The team was very proactive and diligent with her eye care management, and for a while, tisotumab vedotin offered her back some of what she had been missing.

“By the second cycle, oh my gosh, she was full of energy,” Anastasia said. “By the second cycle, she was walking. By the fourth cycle, she was back to playing soccer. It was miraculous. Again, we were concerned because she had peripheral neuropathy that was pretty significant. It didn’t worsen or lessen with tisotumab vedotin, but it became one of the things that she got used to.”

Unfortunately, after the sixth cycle, this patient’s disease progressed, but according to her nurse, for those 6 months, she had a really good quality of life.

“She still has [a] good quality of life,” Anastasia shared. “She’s still alive she’s on a new therapy, and still doing well, although she is still frustrated that her disease is not curable.”

Anastasia has also seen mirvetuximab soravtansine improve outcomes for her patients. She shared the story of 1 patient with BRCA-positive ovarian cancer who was diagnosed in her 40s.

This individual had an 8-year disease-free interval following her initial treatment. When she transferred to Anastasia’s institution, she was still platinum sensitive, and the team was able to offer her a platinum combination with bevacizumab. After doing somatic testing, they offered her immunotherapy as well.

But then the platinum-based chemotherapy treatments stopped working.

“She also had a lot of thrombocytopenia, [and] she was having a lot of nosebleeds on the bevacizumab,” Anastasia recalled. “She was now platinum resistant, which we never want for our patients but eventually will happen to all of them.”

However, folate testing revealed that her disease had an overexpression of greater than 75%, so they were able to offer her an ADC. This patient has now completed 7 cycles of mirvetuximab soravtansine. According to Anastasia, besides some nausea, the treatment has been much more tolerable than chemotherapy for the patient.

“Her energy improved, and her nosebleed stopped,” she said. Further, the patient did not have to come in every week as she did while on the paclitaxel—something that was cutting into not only her time but also her wallet, as parking at the infusion center was not free.

“Her quality of life improved,” Anastasia summarized. “She even went to Europe in between the 3 weeks with her family just for vacation, because she was feeling so good.”

“She’s on cycle 7, and we’re waiting to do her scan to see if we’ll continue with this treatment,” she concluded.

Implications for the Field

Curative treatments are still needed for patients with cervical and ovarian cancer, but according to Anastasia and Schlumbrecht, ADCs are an impressive step forward.

“These drugs contribute significantly to the arsenal of treatments for patients with recurrent gynecologic cancers,” Schlumbrecht said. “For recurrent cervical cancer, specifically, there have been very few new drugs to market in the last 10 years, and tisotumab vedotin provides patients a novel treatment that is not just effective but tolerable.”

“These aren’t necessarily cures, but they’re definitely wonderful treatment options for these patients that are running out of treatments,” Anastasia added.

“We have something else to offer them that can improve their quality of life and provide clinical benefit,” she concluded.

References

1. Gogia P, Ashraf H, Bhasin S, Xu Y. Antibody-drug conjugates: a review of approved drugs and their clinical level of evidence. Cancers (Basel). 2023;15(15):3886. doi:10.3390/cancers15153886
2. Tivdak. Prescribing information. Seagon, Inc; 2021. Accessed October 31, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761208Orig1s000lbledt.pdf
3. Elahere. Prescribing information. ImmunoGen, Inc; 2022. Accessed October 31, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761310s000lbl.pdf
4. Coleman RL, Lorusso D, Gennigens C, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(5):609-619. doi:10.1016/S1470-2045(21)00056-5
5. Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41(13):2436-2445. doi:10.1200/JCO.22.01900