Managing Toxicities Associated with ADCs in Metastatic TNBC

Toxicity and adverse effect (AE) management for patients receiving antibody drug conjugates (ADCs) who have metastatic triple-negative breast cancer (TNBC), took center stage in the second portion to a Satellite Session at Memorial Sloan Kettering Cancer Center. The focus was on 3 ADCs sacituzumab govitean-hziy (Trodelvy), datopotamab deruxtecan-dlnk (dato-DXd; Datroway), and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), which were analyzed across the phase 3 ASCENT-03 trial (NCT05382299), phase 3 ASCENT-04 trial (NCT05382286), phase 3 TROPION-Breast02 trial (NCT05374512), and phase 3 DESTINY-Breast04 trial (NCT03734029).^1-4

Importantly AEs from each trial were noted, with the panelists having the ability to discuss what they have seen in their clinics, and how they have been able to mitigate the toxicities.

For this portion, Monica Fornier, MD, associate attending physician, led the discussion. She was joined by Tiffany Traina, MD, FASCO, vice chair of Outpatient Operations, Department of Medicine, and section head of the Triple Negative Breast Cancer Clinical Research Program; Mila Gosky, MD, associate attending physician; Gabriella D'Andrea-Carlino, MD, a medical oncologist; Devika Gajria, MD, Medical Site Director of MSK Bergen; Diana E. Lake, MD, attending physician; and Amy Xu, MD, director of Metastatic Research Program in the Department of Radiation Oncology.

The first part of the conversation focusing on the efficacy and data from each of the trials can be found here.

Fornier: Do you think that the toxicity, the access, infusion –– do you think all this may affect which ADC or which chemotherapy you use, we went through this before, like day 1 or day 8 vs every 3 [weeks]. For example, let’s say that a patient has, I don’t know, a history of colitis or they have a history of ILD [interstitial lung disease] for whatever reason, do you think that influences your [choice of treatment] or you try to get what is the best option based on clinical trial at a specific juncture?

Lake: You have to consider all of those, [especially] the toxicity first.

Fornier: [Traina] already did already a fantastic review of all of this. Basically, we have the different ADC with sacituzumab. The target is TROP2, and the payload, the mechanism of action, is SN38, which is a topoisomerase 1 inhibitor, and that may cause diarrhea because it’s similar to irinotecan and so forth that our colleagues in GI [gastrointestinal oncology] use all the time.

Then we have datopotamab, also the target is TROP2, and DXd is the payload, so basically the active part. Then we have trastuzumab deruxtecan, which the target is the HER2 receptor, and DXd, which is a topoisomerase-1 inhibitor, as the active payload, the active agent. The structural differences between these different drugs mean different toxicity profiles.

These are the most common, all grades of toxicity. We’re familiar with this in that we have all used these agents. These are based for sacituzumab on ASCENT-03 and ASCENT-04, either as a single agent or in combination with pembrolizumab.

ASCENT-03 Toxicities:

• Neutropenia: 67%​
• Nausea: 61%​
• Alopecia: 55%​
• Diarrhea: 54%​

ASCENT-04 Toxicities:

• Diarrhea: 70%​
• Nausea: 68%​
• Neutropenia: 63%​
• Fatigue: 58%

Gastrointestinal [GI adverse]effects, including nausea, but especially diarrhea I find that it’s a common [adverse] effect. In the 04 study, went up to 70% in combination with pembrolizumab so I’m sure there was an overlapping toxicity in that setting. Some GI [adverse] effect as well in terms of nausea, fatigue, it's always present, and neutropenia. When we’re looking at Dato-DXd and the clinical trials, including TROPION, we find an incidence of stomatitis. Nausea and dry eye as well are an issue.

Then trastuzumab deruxtecan with the payload of DXd, nausea, fatigue, alopecia, otherwise well tolerated, however, there’s the risk of interstitial lung disease [ILD], pneumonitis, which can be up to 12%. We have now become more comfortable with it, in the very beginning when this drug was under study. We have become more comfortable, but that is still a scary toxicity because there were some fatal cases as well, unfortunately. The recommendation is to do a CT scan of the chest, regardless of when you do a PET scan or CT scan chest, abdomen, pelvis, maybe at longer time interval because to assess the disease. There was a discussion at some point besides physical exam and beside asking a patient if they develop shortness of breath, dyspnea to measure pulse oximeter in clinic.

Traina: ILD is scary, although not as common, thankfully, but it's still worries me more than being able to manage diarrhea or neutropenia.

Fornier: It is scary, also maybe because we [don’t] know a number of things. We know less how to manage it, and it tends to start faster, and instead, we are way more comfortable managing the neutropenia and way more comfortable managing diarrhea, I find.

Gorsky: Also, the fear that some of those patients did not survive pneumonia is paralyzing.

Fornier: How do we manage these adverse events? So sacituzumab has an intermediate risk for febrile neutropenia. Now primary prophylaxis with GCSF is recommended for all patients with risk factors. If a patient does develop neutropenia and febrile neutropenia, antibiotics should be started immediately. If there is persistent neutropenia despite GCSF, you should hold until ANC is above 1500 cells/μL or equaling 1500 cells/μL at day 1 and 1000 cells/μL on day 8, and reduce one 1 level [if] diarrhea [occurs], rule out infection and [provide] fluid and electrolytes. For acute diarrhea you can use atropine [Lomotil], otherwise loperamide [Imodium], hold sacituzumab govitecan until grade 1 or less, and reduce by 1 dose level.

Sacituzumab can cause some nausea and vomiting. Prophylaxis [should be used] whether a 3 or a 4-drug antiemetic regimen. If there’s persistent severe nausea and vomiting, then you reduce by 1 dose level. There’s also some warning about patients with UGT1A1 28, which of course they are poor metabolizers of SN38 and experience higher rates of neutropenia and diarrhea, so, close monitoring [is needed]. When we’re discussing [sacituzumab] there’s also some interference with certain medications that may cause either an increase or diminish metabolism. An increased metabolism is in a number of drugs, but especially what I always remember is some of the antiepileptics. This is important because in [ASCENT-03], patients with brain metastases were also allowed to enroll. If your patient is on carbamazepine [Tegretol] and so forth, you should check for interaction because it might diminish the availability of sacituzumab, and therefore your patient will feel less [adverse] effects, but also the drug will have less efficacy.

The phase 2 PRIMED study [NCT05520723] was a multicenter study done in Spain in several hospitals.⁵ The numbers are small. These were 32 patients with [TNBC] and 18 patients with hormone receptor positive [disease]. They did this prevention regimen so to speak, in which they gave GCSF for the first 2 cycles on days 3 and 4, and then days 10 and 11. They gave loperamide at the regular dosing schedule on days 2, 3, 4, 9, 10, and 11, with primary end points of incidence of grade 3 or higher neutropenia and an incidence of grade 2 or higher diarrhea, and then a secondary incidence of febrile neutropenia and so forth.

As expected, the incidence of neutropenia and diarrhea were less than what reported in the phase 3 ASCENT trial [NCT02574455] and the phase 3 TROPiCS-02 trial [NCT03901339]. Therefore, if that’s the possibility for your patient, if you’re concerned about the risk of this toxicity [you may be able to] prevent this with the use of GCSF, or you can use pegfilgrastim also on day 8. Do any of you use this? Do you do aggressive prevention with GCSF? Do you always start GCSF when you’re starting sacituzumab?

Carlino: In my elderly patients, I am almost always going every other week. But if I don't, I’m using Onpro or Neulasta [wearable pegfilgrastim] day 8.

Fornier: Day 8, so you cover them rather than having them come back.

Carlino: Within the first cycle, you can tell if they don’t make it to day 8, if they’re low, then I’m usually switching them to every other week with Onpro.

Fornier: Are you dose reducing or switching them to every other week?

Carlino: If I see that they’re on day 8 they’re low, rather than giving them GCSF at home, I’m usually switching them to every other week with Onpro.

Fornier: I tend to use it 2 weeks on, 1 week off, and I try to adjust the dose more, but maybe I’m the outlier here.

Traina: I do the same, I start day 1, day 8. I don’t use growth factor in everybody, but if they had a tough time getting through their adjuvant regimen or their first line chemotherapy or they’re older then I add day 8 Onpro.

Fornier: [In PRIMED] if you use prophylactic GCSF and antidiarrheal therapy, there were overall less adverse events leading to dose reduction, less adverse events leading to treatment interruption, and less adverse events leading to permanent discontinuation. If a patient develops neutropenia, then you’re going to cancel day 8, maybe the patient comes back the following week, their counts are borderline, so you might postpone [treatment]. You do treatment interruption, and you dose reduce, going down from 10 to 7.5 and even 5. Overall, if you do this aggressive prevention regimen, you’re able to maintain a higher dose intensity, so to speak.

Looking at Dato-DXd instead, management of adverse events, oral mucositis, [Lake] said that she sees that all the time, stomatitis, and mucositis. We use steroid-containing mouthwash pretty frequently. If it’s grade 2, hold until grade 1, reduce dose. Grade 3, again, hold until grade 1 and reduce by one dose level, and grade 4, stop permanently. There is ocular toxicity as well. This is another odd toxicity where they were perhaps not that much comfortable with, as opposed to neutropenia and diarrhea. Patients should have a baseline eye exam, and then once a year during treatment, and then as needed. They can use lubricants, eye drops, and avoid wearing contact lenses during treatment. I find this is the most difficult part for patients who wear contact lenses daily, that you’re going to tell them for a few months they’re not going to be able to wear contacts that’s a little bit difficult. There’s dose modification for keratitis as per package label. There is some incidence of ILD pneumonitis. It’s rare, but can be severe. Grade 1, hold, wait, if it gets better in less than 28 days, then you can maintain the same dose. Otherwise, if it takes longer to get better, you can go down 1 dose level. If it’s symptomatic and above grade 2, then stop and give steroids and permanently discontinue the drug, and then nausea and vomiting that you had to use prophylaxis toxic with 3 to 4 antiemetic regimens. Have any of you has seen the ocular toxicity?

Traina: I did a trial for one of my patients that escalated more than just the simple lubricating eye drops. For the majority of the patients [who] I’ve treated, it’s just been eye drops. I have some patients who have cheated and want to wear their contacts. When they’re exercising, they wear their contacts, or if they have a special event, they wear their contacts and then take them out. They don’t wear them as much.

The label does allow you to have them. See an optometrist, not just an ophthalmologist, because the baseline exam is like basic. On [the manufacturer’s] webpage for the drug is a printout sheet that the patient can bring to the optometrist with what it is they need to do on the exam. That helps with the access.

Fornier: For T-DXd the most important toxicity is ILD pneumonitis. We have to monitor these patients because it can be severe. It may result in a fatality. If it's a symptomatic grade 1 hold until complete resolution, consider steroids. Then if you can maintain the same dose if it gets better within 28 days, approximately, however it lasts longer, go down by one dose level. If it’s symptomatic, grade 2 or higher stop and give steroids because again, this can evolve.

Carlino: It's very difficult. I find the caliber and the variability of outside pulmonologists just confusing. I have a woman who’s doing phenomenally well with resolution of liver and adenopathy on [T-DXd], she had lung disease, she had pleural effusion, she had pleural thickening, and then developed a cough and had these not quite diffuse, but ground glass opacities. We held her [treatment] and she improved. Then I sent her to a pulmonologist and gave her steroids. She’s even better still, she’s been off [T-DXd] now for maybe 2 cycles, so 6 weeks. Her lymph nodes in her neck are already growing. It’s frustrating because it’s probably the drug that’s doing the toxicity, but also the response.

Fornier: It’s difficult. These are thresholds, right? You don’t know because you don’t even know when it started.

Carlino: She’s always got a cough. She’s always a little short of breath from her disease. This drug is clearly active in many regards.

References

1. Cortés JC, Bardia A, Punie K, et al. Primary results from ASCENT-03: a randomized phase III study of sacituzumab govitecan (SG) vs chemotherapy (chemo) in patients (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are unable to receive PD-(L)1 inhibitors (PD-[L]1i). Abstract presented at: European Society for Medical Oncology Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA20.
2. 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
3. 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
4. Modi S, Jacot W, Iwata H, et al. Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial. Nat Med. 2025;31(12):4205-4213. doi:10.1038/s41591-025-03981-4
5. Pérez-García JM, Gion M, Ruiz-Borrego M, et al. Prevention of sacituzumab govitecan-related neutropenia and diarrhea in patients with HER2-negative advanced breast cancer (PRIMED): an open-label, single-arm, phase 2 trial. EClinicalMedicine. 2025;85:103309. Published June 18, 2025. doi:10.1016/j.eclinm.2025.103309