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Komal Jhaveri, MD, FACP, discusses management strategies for ocular toxicities and other ADC-related adverse effects in breast cancer.
As antibody-drug conjugates (ADCs) become further integrated into the breast cancer treatment paradigm, proactive management of ocular toxicities and other adverse effects (AEs), along with patient education regarding these toxicities, are key to ensuring patients derive full benefit from treatment, according to Komal Jhaveri, MD, FACP.
“ADCs are here to stay. I envision a time that we might replace traditional systemic chemotherapy, perhaps with multiple sequential ADCs. We might also see a new wave of combination strategies with ADCs and newer-generation ADCs as well. We’re going to see newer datasets where we’re going to start utilizing these agents in early-stage settings,” Jhaveri said. “It’s important that we appreciate what we have learned from our current experiences with these ADCs in the metastatic setting and apply those [AE] management strategies and toxicity management measures. We must educate our patient-facing staff and our patients so we can use these drugs to their most intended benefit for our patients.”
Managing AEs With ADCs in Breast Cancer
In an interview with OncLive®, Jhaveri discussed how the integration of ADCs has affected the management of various advanced breast cancer subtypes, detailed management strategies for ADC-related toxicities, and explained how awareness and early intervention are crucial for mitigating these AEs.
Jhaveri is the 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.
OncLive: How has the emergence of ADCs affected the management of advanced breast cancer?
Jhaveri: ADCs have truly affected the breast cancer paradigm. [This effort] initiated approximately 1 decade ago with the first prototype ADC—ado-trastuzumab emtansine [T-DM1; Kadcyla]—that got approved for HER2-positive metastatic disease based on the phase 3 EMILIA trial [NCT00829166]. Ever since, we’ve had newer-generation ADCs that initially got approved in HER2-positive breast cancer and replaced T-DM1 in the metastatic setting, but now they have blurred into this subtype modeling that we have. We think about breast cancer subtypes as hormone receptor [HR]–positive, HER2-positive, and triple-negative, but now we have ADCs approved across these subtypes in entities such as HER2-low and HER2-ultralow that could span across these HR-positive and triple-negative subtypes, as well.
We currently have 4 agents that are already approved, starting with T-DM1 initially, later with fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] for HER2-positive, then HER2-low, and more recently, HER2-ultralow [disease]. We have had 2 TROP-2[–directed] ADCs [approved], initially with the approval of sacituzumab govitecan-hziy [Trodelvy] in triple-negative breast cancer [TNBC] and later in HR-positive disease. More recently, we have had datopotamab deruxtecan-dlnk [Dato-DXd; Datroway] approved in HR-positive breast cancer, and there were exciting data presented at the 2025 ESMO Congress, where we heard additional data for both sacituzumab govitecan1 and Dato-DXd2 in the first-line metastatic TNBC setting. We also heard exciting data for T-DXd in the early stage—both neoadjuvant and adjuvant treatment—of HER2-positive breast cancer. These are exciting times.
As these various ADCs went through clinical trials and eventually entered the clinic, what has been learned about the association between ADCs and ocular toxicities?
ADCs are meant to deliver their payload such that we can minimize the systemic AEs and hopefully achieve a better toxicity profile. Although that is true in a sense because we are delivering toxic payloads, which otherwise we would not be able to offer as a naked payload or the naked antibody without this ADC construct, we still have some more room for improvement in optimizing this platform of ADCs, such as better linker technologies and better technologies in terms of how the payload is delivered to the target [with the goal of] minimizing off-target toxicities.
One of the toxicities that we see has been ocular toxicities, especially with Dato-DXd. This ocular AE that we see is, thankfully, low grade, and it’s not necessarily clinically causing a lot of severe grade 3 AEs, grade 3 keratitis, or blindness. It’s more about dry eyes. We think [dry eyes] are related to both on-target and off-target mechanisms. On-target [toxicities could stem from] expression of TROP-2 in the ocular cells, and then off-target [toxicities could be related] to the payload and how the payload is cleaved, and there is a bystander effect, which can also affect this.
We are seeing [ocular toxicities] with certain molecules. We’re seeing that with another investigational TROP-2–directed ADC, sacituzumab tirumotecan, which is in late-phase development. We saw exciting data for [sacituzumab tirumotecan] as well at ESMO 2025, but that is not yet FDA approved. Overall, there are certain toxicities that we see with certain ADCs due to on-target, off-target mechanisms.
What other AEs have been associated with ADCs?
When we think about these ADCs and the most common toxicities, we have to make sure we can mitigate them in clinic. Nausea is a good example. All these ADCs, predominantly, are considered to be highly emetogenic, and having a 3- or 4-drug antiemetic regimen has been a game changer for my patients in clinic. This is a great reminder for us that there are certain things we can control, modify, and optimize for our patients, because then the tolerability becomes better. Nausea is one of those good examples. We recommend using 3- or 4-drug regimens, the fourth drug being olanzapine, for our patients who are initiating therapy, say with T-DXd or Dato-DXd.
Diarrhea is an important AE associated with sacituzumab govitecan, in addition to neutropenia. We need to be vigilant about those: monitoring the [neutrophil] counts, making sure patients can get growth factor support for neutropenia, making sure they have dietary modifications and antidiarrheals. They can reach out to immediately with the first occurrence of diarrhea, which is important to educate our patients about.
Last, but not least, a relatively rarer but important AE is interstitial lung disease [ILD]/pneumonitis. We see a lot more of that with T-DXd. We see that a little bit with Dato-DXd, but thankfully, [the incidence] is lower. We do not necessarily see ILD/pneumonitis with sacituzumab govitecan. [ILD/pneumonitis] is something we want to be vigilant about, and something we want to educate our fellows, our nursing and any other patient-facing staff, and our patients about. We want to capture [ILD/pneumonitis] on radiological scans without patients having symptoms, because we can interrupt quickly, give them steroids, and still resume therapy at the same dose or at a lower dose. If patients become symptomatic, we want to hear about [those symptoms] quickly so we can discontinue the drug permanently but still offer them steroids and help them treat this ILD/pneumonitis, which otherwise could be fatal.
It is important for us as a community to be vigilant about all these AEs. Alopecia is one other AE I would highlight, because that can happen [with ADCs]. We’re still trying to figure out if scalp cooling would help. There are some trials looking into that question. I have said yes to patients who want to try. I have explained that we don’t know if [scalp cooling] will definitely help, but it is something that we need to discuss with our patients when we initiate these therapies. It is important to know about all these [AEs] so we can help our patients.
With ocular toxicities, what are some of the specific monitoring and management strategies?
For ocular toxicities, the guidance that we have for Dato-DXd, initially in clinical trials and now in the package insert, is that one can consider an ophthalmological assessment at baseline before patients initiate therapy, and then as clinically indicated during therapy. More importantly, avoiding contact lenses and trying to use artificial tears are the best guidance we can provide our patients—that was included in the trials and is now in the package insert. This is the way we would have treated for dry eyes with, say, a given chemotherapy drug, as well. We know chemotherapy does that, too. It can act as an irritant. It causes dry eyes, so using artificial tears and avoiding contact lenses that could be irritable would be helpful in some settings.
What are some unmet needs that still need to be addressed in terms of managing some of these ADC-related toxicities?
We want to use effective drugs up-front so we can offer a better benefit with respect to efficacy to our patients, and that is exactly what we are doing with strategies [being evaluated] in the phase 3 ASCENT-03 [NCT05382299], ASCENT-04 [NCT05382286], and TROPION-Breast02 [NCT05374512] trials. All these trials recently read out and are a testament to the fact that we want to offer effective therapies up-front. This is important not just for the patients who receive these therapies, so they can have better outcomes, but we have also recognized that there is a significant attrition rate. Up to 50% of our patients with TNBC do not make it to second-line therapy, so offering them the best therapies up-front is important, and makes it even more important for us to recognize the safety profiles of these agents, which might be utilized for even longer durations when we’re giving them in the first-line setting. How should we mitigate these AEs so patients can stay on this therapy for the intended duration to derive the benefit and not have to come off that treatment for toxicity-related reasons?
We need to be vigilant about the common toxicities. What are the common grade 3 or higher toxicities that cause dose modifications, dose reductions, and treatment discontinuations? How can we mitigate those, whether with growth factor support for neutropenia; antidiarrheals, dietary management, and hydration for diarrhea; or ice chips or ice during infusions to mitigate stomatitis, which is another important AE associated with Dato-DXd?
We also recommend our patients get dexamethasone mouthwash as a way for primary prophylaxis with Dato-DXd to minimize stomatitis; use artificial tears, avoid contact lenses, and undergo ophthalmological assessments for ocular AEs; and be vigilant about detection and management of ILD/pneumonitis. If we want to use these therapies up-front, we are going to use them for a longer period of time so our patients can have a better benefit. We want to manage these toxicities even more vigilantly and with the most optimal supportive strategies available to us, so patients can stay on these therapies with better outcomes and a better, improved quality of life.
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