Advances in ADCs: Opportunities for Treatment, Challenges, and Managing Toxicities

Antibody-drug conjugates (ADCs) are an emerging therapy in oncology. While the field is still emerging, there are been great advances already, and speakers at the ESMO Congress 2024 highlighted the future opportunities and challenges with this drug class.

The first ADC approved by the FDA was gemtuzumab ozogamicin in 2000. It was approved through the accelerated pathway for patients 60 years or older with CD33-positive acute myeloid leukemia after their first relapse who are not considered candidates for cytotoxic chemotherapy.¹ Since then, dozens of other ADCs have gained FDA approval in a variety of cancers.

ADCs have a high payload and can deliver what is called a “bystander effect.” This effect can be beneficial when the surrounding cells express the target antigen, but it can also increase off-target toxicity.

Aditya Bardia, MD, MPH

Image credit: UCLA Health

Aditya Bardia, MD, MPH, program director, breast medical oncology, UCLA; assistant chief of hematology/oncology (translational research), and director of translational research integration, Jonsson Comprehensive Cancer Center, mostly focused on breast cancer for his presentation, highlighting 3 specific ADCs:

• Sacituzumab govitecan, a TROP2 ADC
• Trastuzumab deruxtecan, which targets HER2
• Datopotamab deruxtecan, another TROP2-directed therapy, but the antibody, linker, and payload are all different from sacituzumab govitecan

All 3 ADCs have shown superiority over chemotherapy in the metastatic setting, Bardia explained. Other agents being developed are ladiratuzumab vedotin targeting LIV-1, patritumab deruxtecan targeting HER3, NBE-002 targeting ROR1, and praluzatamab ravtansine targeting CD166.

He said that in the foreseeable future, it’s likely these treatments will slowly replace chemotherapy for patients.

Domenica Lorusso, MD, PhD

Domenica Lorusso, MD, PhD, full professor of obstetrics and gynecology, Humanitas University, and head of gynecologic cancer unit, Humanitas Hospital San Pio X, in Milan, Italy, noted that there are more than 260 ADCs in cancer being tested. In ovarian cancer, she called ADCs a “rising star,” because of the high unmet need for these patients. Patients who are platinum resistant have a 1-year median survival.

In ovarian cancer, FRa is an ideal biomarker because it is highly expressed, she said. FRa is also a target in endometrial cancers, along with HER2 and TROP2, according to Toon Van Gorp, MD, a gynecologist oncologist in the Department of Gynecology and Obstetrics at UZ Leuven, in Leuven, Belgium.

Toon Van Gorp, MD

Image credit: Maastricht UMC+

In cervical cancer, TROP2 is a key target because it is highly expressed. As a result, sacituzumab govitecan and sacituzumab tirumotican are 2 of the therapies being studied, he added. He also ran through the promising data on tisotumab vedotin, which is the only drug with phase 3 data in cervical cancer, and trastuzumab deruxtecan.

“It’s going to be very promising in the future,” Van Gorp said. “It’s going to be difficult to decide which ADC we’re going to use for which patient. But it’s a bright future.”

With all of the research being done, there are a number of challenges and questions. For instance, Lorusso noted that the mechanisms of ADC resistance are still being understood to identify the best patients for treatment. Also, because ADCs work differently, a patient who is predominantly resistant to the antibody could be switched from sacituzumab govitecan to datopotamab deruxtecan, Bardia explained; however, that switch wouldn’t work for a patient who was resistant to the payload.

Multiple speakers noted the potential for combinations in the future. Bardia said that understanding the mechanism of action for ADCs will help direct the combination. He gave the example that adding a PARP inhibitor to sacituzumab govitecan would be “synergistic.”

Toxicities are a challenge with ADCs, though. Due to the bystander effect, these therapies could have off-target toxicities that need to be managed. Bardia explained that multidisciplinary management is likely needed for patients.

Ilaria Colombo, MD, MA

Ilaria Colombo, MD, MA, attending physician, Drug Development Unit and Disease Site Lead for Gynecological Cancers, Oncology Institute of Southern Switzerland, focused on some of the toxicities in her presentation. A review of 169 trials found 600 different adverse events (AEs) for ADCs, with a treatment-related discontinuation rate of 13.2%, and a rate of any grade treatment-related AEs (TRAEs) of 91.2%.² The rate of grade 3 or higher TRAEs was 46.1%.

She highlighted some specific ADCs and their toxicities:

1. Mirvetuximab soravtansine has ocular toxicity because FRa is expressed in the retina. Mitigation strategies include an eye exam at baseline and before cycles, using lubricating eye drops, and avoiding the use of contact lenses.
2. Tisotumab vedotin also has ocular toxicity, as well as bleeding, and she noted that there needs to be careful assessment of baseline bleeding or conditions at high risk for bleeding. The mitigation strategies are mostly the same as mirvetuximab soravtansine, except patients on tisotumab vedotin are also recommended to use vasoconstrictor eye drops and cold packs prior to infusion and for 20 minutes after infusion.
3. Trastuzumab deruxtecan has interstitial lung disease and the recommended management is to treat with steroids.
4. Datopotomab deruxtecan has mucositis. The risk factors for it include smoking, poor oral hygiene, younger age, female sex, and genetic factors. The management includes maintaining oral hygiene and using mouthwash as prophylaxis, diagnosing, and treating with increased mouthwash use, cryotherapy, pain management, and potentially a dose delay or reduction.

Colombo echoed Bardia’s comment on using a multidisciplinary approach to manage the AEs. While it’s common to engage in multidisciplinary discussion to identify the right treatment for a patient, “now we are moving [into a] space where we also need multidisciplinary discussion to define which is the best way to manage the toxicities. We have learned [how to do this] very well with immunotherapy, and we need to do this also with the use of antibody-drug conjugates.”

References

1. Bross PF, Beitz J, Chen XH, Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7(6):1490-1496.

2. Zhu Y, Liu K, Wang K, Zhu H. Treatment-related adverse events of antibody-drug conjugates in clinical trials: A systematic review and meta-analysis. Cancer. 2023;129(2):283-295. doi:10.1002/cncr.34507