Tips for Tomorrow: What 4 Experts Wish They Knew Earlier About ADCs

Although antibody-drug conjugates (ADCs) have been approved in select tumor types for years now, the 2024 tumor-agnostic approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for select patients has provided the first ever ADC option in many cancers.1

With this regulatory decision and given that 13 ADCs held FDA approvals going into 2025––now 14 with the approval of datopotamab deruxtecan-dlnk (Dato-DXd; Datroway)—several clinicians are findings themselves navigating a new drug class that is rapidly growing.2-4 With over 100 ADCs under development, 4 clinicians sat down with OncLive® to answer the question: “What do you wish you knew about ADCs when you were first introduced to them?”

Virginia Kaklamani, MD, DSc

The Ruth McLean Bowman Bowers Chair in Breast Cancer Research and Treatment, A.B. Alexander Distinguished Chair in Oncology, leader of the Breast Cancer Program at Mays Cancer Center, and codirector of the Cancer Genetics Program at UT Health San Antonio MD Anderson Cancer Center as well as a professor of Medicine at the University of Texas Health Science Center San Antonio.

We’ve felt for a long time that ADCs have a favorable toxicity profile, but they may not. As of February 2025, there are 3 ADCs approved in breast cancer—T-DXd, sacituzumab govitecan-hziy [Trodelvy], and datopotamab deruxtecan-dlnk [Dato-DXd; Datroway]—and each of them have different adverse effects [AEs]. With T-DXd, we worry about nausea and vomiting [as] it’s considered a highly emetogenic regimen similar to highly emetogenic chemotherapies, [and] there’s also a degree of interstitial lung disease [ILD] that comes with it. With sacituzumab govitecan, there’s neutropenia as well as diarrhea, and then Dato-DXd [is associated with] stomatitis. It’s extremely important that we become very familiar with the AEs because that’s how we can treat our patients more effectively and are also able to give other medications to alleviate those AEs.

I will talk to patients about AEs with ADCs the same way I talk about AEs with chemotherapy. I focus on the main AEs, when patients should be calling our office, what they should be doing to try to prevent some of these AEs or treat them if they happen, the potential for dose reductions, and the potential for holding the dose. All of these are important so that we can give these drugs to our patients safely and effectively.

Rachna T Shroff, MD, MS, FASCO

Interim clinical affairs director, associate director of Clinical Investigations, and coleader of the Gastrointestinal Clinical Research Team at the University of Arizona Cancer Center as well as cancer center chief of the Division of Hematology/Oncology, medical director for the Oncology Service Line, associate dean for Clinical and Translational Research, and a professor at the University of Arizona College of Medicine in Tucson.

ADCs are absolutely a new wave of the future in terms of therapeutic development and the potential is so high. I wish I’d recognize that immediately, so that we could start to think through smart trials and identify potential targets. But just understanding the biology of these drugs in the sense of payload and target, and what that means and how to integrate the idea of using the target but then therapeutically delivering a payload and understanding the science behind that, took me a little time to recognize the value of that. But most importantly, ADCs are here to stay and are being developed in ways that [will enable us to] provide tumor-agnostic therapeutic approaches.

For instance, T-DXd now has a tumor-agnostic approval in addition to the roles that it’s already playing in breast cancer for example. It also speaks to the importance of comprehensive genomic profiling and making sure we know what targets every patient has so that we can strategically think through therapeutic approaches for each of them. The last thing to recognize is that although there are potential toxicities from ADCs, just like chemotherapy when we first started using it and immunotherapy, these are manageable toxicities as long as we know what we’re looking for. [If we] are proactive and preemptive in terms of managing them, patients can receive these treatments for the duration of their benefit hopefully with minimal toxicities.

Funda Meric-Bernstam, MD

The department chair of the Department of Investigational Cancer Therapeutics, medical director of the Department of Khalifa Institute for Personalized Cancer Therapy, the Nellie B. Connally Chair in Breast Cancer, and a professor in the Department of Breast Surgical Oncology, all at the University of Texas MD Anderson Cancer Center in Houston.

ADCs are different based on different payloads and targets. This is definitely a very active drug category. On the other hand, they have their own safety issues that need to be monitored. In the context of T-DXd, it’s important to be knowledgeable about management of pneumonitis and ILD and the importance of monitoring for it because this is one of those things where [with] grade 1 changes—which is just imaging changes on a scan in the pulmonary fields—we want to be proactively assessing patients and interrupting treatment. [This] is different than what you would expect in the standard treatment algorithm. With experience comes more comfort in managing these types of AEs, but it’s important always be vigilant.

Komal Jhaveri, MD, FACP

Breast medical oncologist, section head of the Endocrine Therapy Research Program, clinical director of Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.

The idea with ADCs was can we further improve efficacy, maybe deliver a higher load of chemotherapy straight to the tumor, spare the off-target toxicities, and therefore improve the therapeutic window? That’s what the ADCs have done when we compare them head-to-head with a systemic chemotherapy agent—they’re better than that. But we are still working towards further refining this technology, this platform of having an antibody which is linked to a cytotoxic payload, and we now are exploring novel payloads, bispecific antibodies, radioligand therapeutics, and immune-stimulating therapeutics.

We’re going into the next generation. But just because we think that ADCs are better than chemotherapy does not mean that they don’t have their own toxicities and that they’re perfect. We have made a step forward in terms of what we’ve been able to achieve with these ADCs compared with what we already had with systemic chemotherapy and that has made a big difference, whether it’s in progression-free survival or overall survival benefits, even in heavily pretreated patients across the 3 subtypes of breast cancer. But we’re still far from perfect in terms of having the ideal agent because all these agents still have their own toxicities.

We’re still trying to figure out what we can do to further enhance our understanding of target expression and how to identify that, how to minimize the toxicity to as little as possible without compromising on efficacy, and how to focus on the mechanisms of resistance such that we can use that information to then sequence multiple ADCs to further improve outcomes for our patients. That knowledge we didn’t have upfront, but it is something that we’re now focusing on more as we have begun to appreciate what we learned from our experience from this generation of ADCs, starting from the very first prototype: ado-trastuzumab emtansine [Kadcyla].

References

1. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed February 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
2. Kesireddy M, Kothapalli SR, Gundepalli SG, Asif S. A review of the current FDA-approved antibody-drug conjugates: landmark clinical trials and indications. Pharmaceut Med. 2024;38(1):39-54. doi:10.1007/s40290-023-00505-8
3. Jian A, Zhao G, Zhou J, Wang S, Li N. How to design next-generation of antibody-drug conjugates for cancer treatment: lessons from unsuccessful clinical trials. Cancer Lett. Published online February 7, 2025. doi:10.1016/j.canlet.2025.217535
4. 4. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. FDA. January 17, 2025. Accessed February 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast#:~:text=On%20January%2017%2C%202025%2C%20the,for%20unresectable%20or%20metastatic%20disease