Antibody drug conjugates (ADCs)—​​a therapy that’s been dubbed “oncology’s next revolution”

Furlow M, Corridon C, Coyle B, Bonnot R. Oncology’s next revolution: Antibody-drug conjugates and how to push them into the future. ZS.com. March 12, 2024.

is a hot topic of discussion in the breast cancer (BC) space.

During a particularly exciting session at this year’s Miami Breast Cancer Conference (MBCC), Hope Rugo, MD, Director of Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center, said that current data on ADCs “gives us a good feeling about the landscape we are in right now.”

Expanding applications and earlier use

The target population also includes patients with “low/heterogeneous expression of the target antigen on the tumour with trastuzumab deruxtecan or in the case of sacituzumab govitecan, agnostic to target expression,” according to research published in Developmental Therapeutics.

Mythili Shastry et al. Rise of Antibody-Drug Conjugates: The Present and Future. Am Soc Clin Oncol Educ Book 43, e390094(2023). 

The first ADC for breast cancer, trastuzumab emtansine (T-DM1) worked by allowing chemotherapy to hitch a proverbial ride on an antibody that could bind to HER2 proteins expressed in breast cancer cells. From there, the chemotherapy could directly target the HER2 tumor cells without toxifying the body’s healthy cells. 

ADCs were originally developed with advanced or treatment-resistant BC in mind, so their use was more narrow, according to researchers from the Dana Farber Cancer Institute.

Davis N. Antibody-Drug Conjugates: A Cancer Therapy Revolution. Dana Farber Cancer Institute. February 22, 2024.

The system has recently been improved upon, featuring newly approved ADCs such as do-trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), sacituzumab govetican (SG), Sacituzumab tirumotecan (SAC-tmt) and datopotamab deruxtecan (Dato-DXd). 

Exciting trial data

Heather McArthur, MD, MPH, Professor of Internal Medicine and Clinical Director of the Breast Cancer Program at UT Southwestern Medical Center, discussed the ASCENT trial’s data at MBCC, confirming the “clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with metastatic triple-negative breast cancer (mTNBC) in the second line or later.”

Dr. McArthur also noted datopotamab deruxtecan—approved in January 2025—and findings from the TROPION trial. “There is a high response rate with this antibody-drug conjugate,” she said. “It’s very impactful data with durable responses, which is very encouraging.”

“We need to understand mechanisms of resistance and optimal sequencing, [but] there’s a lot of effort in that space because it’s an area of rapid drug development. We need to understand how best to apply these agents,” Dr. McArthur said. “The earlier we apply effective drugs, the earlier the benefits.” 

ADC specifics

In a MBCC session, “Sequencing and Optimal Timing of ADCs in HER2-Negative Breast Cancer,” Dr. Rugo explained how ADCs work:

First, “ADC localises to the tumour and binds the target receptor antigen on the tumour cell surface,” she said. Then, the receptor antigen and ADC are internalized. Next, the ADC is enzymatically degraded with lysosomes the cytotoxic drug binds to the intracellular target. At this point, “ADC-mediated death of antigen-expressing cancer cells” occurs, leading to the so-called ‘bystander effect,’ whereby the “membrane-permeable drug is released and taken up by neighbouring cells.” 

The bystander effect refers to killing not only the targeted cancer cells but also nearby cells, which can help fight against the complexity of heterogeneity in BC. 

Sara Tolaney, MD, MPH, chief of breast oncology at Dana-Farber, told the Dana Farber Cancer Institute’s newsroom, "We used to be so focused on finding oncogenic driver—the mutated genes that fuel cancer growth—and figuring out how to turn them off. But now, the data are telling us we just need to find a little bit of target that's hanging out on the cell. And because we can deliver so much chemo, it'll work much better than anything else. It's changing the way we develop drugs and the way we think about cancer."

The future of ADCs

ADCs are “simple, but elegant,” according to research published in Developmental Therapeutics, but they do have toxicities, warranting close patient monitoring and consideration. The most common include neutropenia, nausea and vomiting, alopecia, diarrhoea, left ventricular dysfunction, interstitial lung disease or pneumonitis.

D'Arienzo A, Verrazzo A, Pagliuca M, et al. Toxicity profile of antibody-drug conjugates in breast cancer: practical considerations. EClinicalMedicine. 2023 Jul 27;62:102113.

“We have a lot of questions [about ADCs] still,” Dr. Rugo said. “So many ADCs are being tested in clinical trials, so we are trying to understand how to evaluate them. Should we sequence them? It’s the big question. Safety considerations are going to play a big role.”

It may come down to side effects when treating patients with ADCs, Dr. Rugo said: “[There are] a lot of considerations as we think about how we’re treating our patients.” One thing is for certain, however: ADCs are here to stay—and they’ll only get better.