Sequencing ADCs and Managing Ocular Toxicities in Breast Cancer Populations

In a CancerNetwork®-hosted Around the Practice program about antibody-drug conjugates (ADCs) in breast cancer care, a multidisciplinary panel discussed how emerging data from ADC trials are reshaping treatment sequencing, and how oncology, ophthalmology, and nursing teams are collaborating to manage the adverse effects (AEs) that come with these agents.

The panel was moderated by Neil M. Iyengar, MD, co-director of Breast Medical Oncology and director of Cancer Survivorship Services at the Emory Winship Cancer Institute, as well as co-editor-in-chief of the journal ONCOLOGY®. He was joined by Sara Nunnery, MD, MSCI, director of breast cancer research at Tennessee Oncology; Sarah B. Sunshine, MD, assistant professor of Ophthalmology and Visual Sciences, member of Program in Oncology at the University of Maryland; and Debbi-Ann Davidson, DNP, MSN, RN, PMHNP, CBCN, a nurse manager for breast oncology, surgical oncology, and integrative oncology at Emory Winship Cancer Institute.

New ADC Data in Triple-Negative Breast Cancer

Iyengar: We have seen a lot of activity for ADC development in triple-negative breast cancer. We had the original [phase 3 ASCENT trial (NCT02574455)], which ultimately led to the approval of sacituzumab govitecan-hziy [Trodelvy] in the second line setting and beyond.¹ In more recent days, we’ve seen [the phase 3 ASCENT-03 (NCT05382299) and ASCENT-04 (NCT05382286) trials], which have looked at sacituzumab govitecan in the upfront or first line setting, either with or without checkpoint inhibition.^2,3 Can you walk us [those trials and] the high level results that impact clinical practice?

Nunnery: This is an exciting space. We’ve had just chemotherapy for so long, and seeing this new wave of options has been so encouraging. ASCENT-03 looked at sacituzumab govitecan compared with standard of care chemotherapy in the frontline setting for patients who were not a candidate for immunotherapy, typically PD-L1–negative is how we quantify that, but if someone was not a candidate based on other comorbidity factors, they would have been eligible for this trial. What we found is that there was a very significant benefit in progression-free survival [PFS] with sacituzumab govitecan used upfront compared with standard of care chemotherapy. Similarly, ASCENT-04 looked at using sacituzumab govitecan combined with immunotherapy, pembrolizumab [Keytruda], vs standard of care chemotherapy with pembrolizumab. This was for patients who were PD-L1 positive, so they did qualify for immunotherapy. We saw there was a significant benefit in PFS when patients were treated with sacituzumab govitecan and immunotherapy compared with standard of care chemotherapy. Our patients with triple-negative disease have worse outcomes long term, and any time we can improve that survival upfront, improve time on first line therapy upfront, is a big win.

Iyengar: Now, can you tell us a little bit about [the phase 3 TROPION-Breast02 trial (NCT05374512)] and datopotamab deruxtecan-dlnk [Dato-DXd; Datroway]?⁴

Nunnery: Dato-DXd is our newest kid on the block in terms of ADCs. This was a frontline study for patients who were ineligible for immunotherapy; they were [randomly assigned] to [receive] treatment with Dato-DXd or standard of care chemotherapy in this trial. One of the interesting differences that we saw between TROPION-Breast02 and ASCENT-03 is the time from previous neoadjuvant treatment for early-stage disease. We see some of these patients with triple negative disease relapse somewhat quickly after their curative intent chemotherapy, and oftentimes those patients get excluded from clinical trials due to the concern that they just have a more aggressive pace of disease. TROPION-Breast02 allowed patients who had early recurrences on study to be included, so [there was] potentially a little bit more aggressive disease included in this trial. We found a significant improvement in [PFS] and overall survival with frontline Dato-DXd.

Iyengar: What are your thoughts about the exploratory analysis for the use of [fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu)] in our patients with HER2-low, triple negative breast cancer?

Nunnery: It’s an area that is always worth exploring because we need more options for our patients with triple negative breast cancer. It’s not a frontline option, but after progression on other ADCs, it’s an option to consider. It’s also appealing to go after a different target than our other TROP2-targeted ADCs. A lot of us like the ability to change targets, and hopefully get more response from patients, but we have our TROP2 [targeters] as front line therapy, and then we would think about T-DXd subsequently for our patients who are HER2-low.

Managing Ocular Toxicity With Datopotamab Deruxtecan

Iyengar: What do we need to know, as oncology clinicians, about the ocular toxicity associated with Dato-DXd?

Sunshine: This is a whole new area for all of oncology, but this area for breast oncology is a little bit newer. It starts with the education and the baseline eye exam, so it’s getting the patients in with an eye care provider, it can be an ophthalmologist or an optometrist, and that sets the stage for the oncology team to be able to educate the patient on what to look out for and what to do about it. Then, by seeing an eye care provider, you’re also giving us the opportunity to be able to educate them on optimizing their ocular surface health initially, again reinforcing the need to either let their oncology team know or ophthalmology know if they’re having symptoms so they’re not waiting longer. A lot of this is monitoring them. We see them at baseline, where there’s a full eye exam, including a dilated eye exam, even though most of the eye problems come from the surface, then every 3 cycles. At the end of the treatment, you do a full eye exam, including dilation, again.

Iyengar: I want to emphasize this new change: The label has changed for the frequency of eye exams for dato-DXD, as you pointed out, Dr. Sunshine. The ocular exams are now recommended every 3 cycles. What are you doing on these exams?

Sunshine: It’s a little bit different for the baseline eye exam vs the more regular eye exams. The every-3-cycle exams are a basic eye exam. It’s just vision and pressure, and then a slit lamp exam, looking at the surface of the eye from the eyelids all the way to the lens, essentially. That allows you to see whether there’s any ocular surface toxicity.

Iyengar: When you say ocular surface toxicity, why is it important to differentiate it as an ocular surface event vs ADC ocular toxicity, where other ADCs may have more severe ocular toxicities?

Sunshine: Most of the ADCs have ocular surface toxicity, but there are different severities of those toxicities. With dato-DXd, what we’re seeing is more mild ocular surface toxicity. We get dry eye disease, which is dryness, a little bit of blurry vision, and some discomfort or tearing. With other ADCs, you can have more severe toxicity; you can have the pseudo-microcysts, which can lead to refractive change and changes in the eyeglass prescriptions, which causes significant blurring of vision. The other thing to note is that with other ADCs and other therapy for cancer, you can also get uveitis or inflammation inside the eye, which is very different than the ocular surface toxicity, and can cause more long-term problems. What is nice about this ADC, and most of the ADCs, is that they’re not usually long term complications that are irreversible, as long as we find them early enough.

Iyengar: Debbi-Ann, how do you approach educating patients about ocular toxicity and the prophylaxis—the lubricating eye drops? What are you telling patients, and what are you hearing from patients about their fears?

Davidson: With the ocular toxicities, we’re robust with patient education and encourage them to use their lubricant eye drops before the symptoms start, to maintain the health of their eyes, and also, as soon as they’re having symptoms, to report them to us. We have a very responsive team at our clinic, where as soon as patients send their concerns to us, we escalate them based on the severity of those concerns.

Iyengar: [Dr. Nunnery], what is your strategy for involving ophthalmology or optometry? How do you optimize getting your patients in, and then communicating with the [eye-care team]?

Nunnery: When you’re implementing this in practice, it can be difficult to get access to ophthalmology. In our network, we fortunately have great ophthalmology partners who we can refer to if someone’s having a complication, but frequently we are referring to optometry—so optometrists in the community for baseline eye exams. Optometrists are very available and accessible for most of our patients in the community, and they’re equipped to do a lot of the necessary baseline exams and handle mild complications. [We] then rely on them to make referrals to our specialists, our ophthalmologists, should things progress.

Patient Case: HR-Positive, HER2-Negative Disease With a History of Dry Eye

Iyengar: We have a 58-year-old female who has hormone receptor—positive, HER2-negative metastatic breast cancer. She progressed after initial endocrine-based therapy plus CDK4/6 inhibition. She has metastasis to the liver as well as the bone, and this includes both radiographic progression and symptomatic progression. She’s feeling more pain. Her performance status is an ECOG 1. In terms of her overall health, she has a history of controlled hypertension. She does have a history of mild dry eye syndrome as well. She’s active both professionally and in terms of her daily function. She wants to maintain independence, so that’s what she’s voicing to us in clinic. She wants to remain active and keep her lifestyle active, but of course she wants efficacious treatment. Dr. Nunnery, what are you thinking about regarding treatment options and balancing that with the toxicity profile?

Nunnery: First and foremost, I am making sure we are maximizing lines of endocrine therapy. I would not let the hepatic metastases dissuade you from considering more endocrine therapy, depending on how many prior lines of treatment this patient has had. This patient has progressed on at least first line CDK4/6 inhibition, so thinking about that time that they were on first line can be a good surrogate to gauge if they’re going to still be endocrine sensitive or not. Does it make sense for this patient to try more endocrine therapy, and [if it does], I would go to that first. If we’ve progressed through endocrine therapy, and we don’t think that that would be a good treatment approach at this point, thinking about HER2 status would be the next thing. Is this patient HER2 low or ultra-low? If so, we could consider going to T-DXd as an option, or chemotherapy, like oral capecitabine, it’s still an option as well, if staying on an oral therapy is still a goal of that patient, and many times it is if they don’t want hair loss. We know that from [the phase 3 DESTINY-Breast06 trial (NCT04494425)] that T-DXd had better PFS than capecitabine or other chemotherapies, but [it’s important to talk through] the efficacy vs quality of life impact and make a decision with the patient.⁵ If someone’s HER2 null, and we don’t have T-DXd as an option, then we’re definitely still looking at chemotherapy as the first treatment after progressing through endocrine therapy, then considering our other TROP2-targeted ADCs after that.

The patient has a history of dry eye, and that’s meant to peak our ears. Would dato-DXd be an option for this patient in that situation? Personally, if someone has very well-controlled mild dry eye, I wouldn’t think that would be an absolute contraindication to Dato-DXd.

Iyengar: In this case where we’re progressing after first line therapy, I agree with you. I would do molecular sequencing and see if we have any targetable lesions, and [there’s] certainly a lot going on in the novel endocrine therapy space. Let’s assume that we’re now ready to move on to cytotoxic therapies, particularly an ADC, for this patient. Should we avoid dato-DXd to can in this setting, or can we still reach for it?

Sunshine: It’s very reasonable to reach for it. It’s an important thing to think about and to educate the patients on. I also think this is where that baseline eye exam is important, giving the optometrist or ophthalmologist the opportunity to optimize the ocular surface health and make sure that they’re taking their preservative-free artificial tears as often as possible, at least 4 times a day. If there’s other factors like meibomian gland disease, or some other way that we could optimize this, even before starting treatment, that would give us a little bit of a boost. Women, especially older women, tend are the most common population of patients who have dry eye, so you’re going to see it. Patients are going to have dry eye disease, and it’s not a contraindication.

Iyengar: Debbi-Ann, this case illustrates the patient’s transition from hormone-based therapies to chemotherapies, ADCs, and so forth. This can be an emotionally charged transition. This can be a symptomatically charged transition. How do you support your patients as they’re starting either ADCs or chemotherapy, and they’ve progressed after endocrine-based therapy?

Davidson: One very important thing is providing psychological support for patients. It does go a long way. This is a time in a patient’s life when it seems like everything is falling apart—they’re progressing, it’s frightening, it’s scary. Being there for them—to be able to support them psychologically and refer them to additional support, like social work, if that’s necessary, is very important.

Iyengar: That highlights the multidisciplinary sense of the care that we provide. This case helped to highlight the multiple factors we need to consider for treatment selection in the hormone receptor-positive setting, and how we do need to rely on our multidisciplinary partners to optimize care.

References

1. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485
2. Cortés J, Punie K, Barrios C, et al. Sacituzumab govitecan in untreated, advanced triple-negative breast cancer. N Engl J Med. 2025;393(19):1912-1925. doi:10.1056/NEJMoa2511734
3. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan plus pembrolizumab for advanced triple-negative breast cancer. N Engl J Med. 2026;394(4):354-366. doi:10.1056/NEJMoa2508959
4. Dent R, Shao Z, Schmid P, et al. Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial. Ann Oncol. Published online April 3, 2026. doi:10.1016/j.annonc.2026.03.008
5. Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086