Dato-DXd Shows Tolerability Vs Chemo in HER2- Metastatic Breast Cancer

There are now 3 antibody-drug conjugates (ADCs) in use for advanced breast cancer where chemotherapy have been employed in the past. Determining when to use these agents and what effect sequencing them will have remain serious concerns for oncologists. In an in-person Case-Based Roundtable event moderated by Kit Yu Lu, MD, a medical oncologist at UPMC Hillman Cancer Center in Harrisburg, Pennsylvania, Lu evaluated the efficacy and safety of these agents including the newest approved ADC, datopotamab deruxtecan (dato-DXd; Datroway).

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: How was the TROPION-Breast01 trial (NCT05104866) designed to investigate dato-DXd?

Kit Yu Lu, MD: TROPION-Breast01 is the phase 3 trial study looking at dato-DXd for hormone receptor–positive, HER2-negative, metastatic breast cancer. In this patient population, they were defined as HER2 negative, so it could be HER2 0 or HER2-low. They were previously treated with 1 to 2 lines of chemotherapy, similar to TROPiCS-02 [NCT03901339]. They had to have progression on endocrine therapy; we think that these patients have endocrine-refractory disease. The patients were randomly assigned on a 1:1 basis to dato-DXd vs the investigator’s choice of chemotherapy, the same type of chemotherapy that we would choose. There were dual primary end points: progression-free survival [PFS] and overall survival [OS]. Looking at the lines of therapy, a majority of the patients had just 1 line of prior chemotherapy, about 60% and then 40% had 2 lines, so they were a little bit earlier compared with the TROPiCS-02 trial.¹

What were the results of the primary end points?

The study did meet the primary PFS primary end point; the median PFS for dato-DXd is 6.9 months vs 4.9 months in the chemotherapy arm, and the HR is 0.63 [95% CI, 0.52-0.76; P < .0001].² The OS at the time of presentation was not statistically significant. The HR did reach the boundaries [HR, 1.01; 95% CI, 0.83-1.22].¹

Why was the OS not met? I think in the presentation there were a couple of variables. One was that maybe the study was not powered enough to detect the OS difference. The other thing was that there were 2 ADCs approved at the time of this study. We have trastuzumab deruxtecan [T-DXd; Enhertu], and then we also have sacituzumab govitecan [Trodelvy]. Upon progression, there were more patients in the standard-of-care arm, 24% of the patients, who ended up getting a secondary ADC [vs 12% with dato-DXd]. Potentially, that could have altered the OS data because they were imbalanced, or more patients in the standard-of-care arm got ADCs compared with the dato-DXd arm.

What other end points were reported from this trial?

If you look at other surrogates of outcomes, with studies being moved up into earlier and earlier lines, we’re now looking at PFS2 as a surrogate of outcomes. This is the time from the first progression, and then time to the second progression. If you break that down consistently, dato-DXd did better compared with the standard-of-care chemotherapy arm [HR, 0.76; 95% CI, 0.63-0.93]. If you look at the surrogate marker, there is an improvement here despite the OS not showing a difference.

If you look at the confirmed overall response rate with the tumor assessment, there was also an improvement with dato-DXd compared with the standard-of-care chemotherapy arm [36.7% vs 22.1%, respectively]. The median duration of response was also longer [7.2 months vs 6.0 months].

How did the tolerability of dato-DXd compare with chemotherapy

As far as treatment-emergent AEs, at the time of follow-up, there weren’t any additional late onset toxicities. The overall safety profile was consistent. There was less grade 3 toxicity with dato-DXd compared with standard chemotherapy: 22% vs 46%. Nausea and stomatitis were some of the common AEs. Neutropenia, interestingly, is less compared with the standard chemotherapy arm. There was also the dry eye and keratitis reported with dato-DXd.

What toxicities are of most concern with dato-DXd?

I would consider these more unique AEs that are different from the other ADCs. Oral stomatitis and mucositis can appear as well as ocular toxicity. Those toxicities sound worrisome, but when you break down the grading of these AEs, a majority of the patients were asymptomatic. In the grading of oral mucositis and the ocular events, the more common AEs were grade 1. Those are an asymptomatic grading, so patients didn’t have any symptoms, but you just have to pay more attention to it. There were clinically more grade 2 AEs with stomatitis, but in this study, they did not require any prophylactic mouthwash. Perhaps with proper intervention, we can also lower this grading as well. Only 10% of the patients had grade 2 ocular events where you have to delay the treatment. Also, the rate of interstitial lung disease seems to be lower compared with T-DXd.

In terms of the ocular events, the common AEs were dry eyes, keratitis—which is corneal inflammation—blepharitis, increased lacrimation, and meibomian gland dysfunction.³ The median time to onset was 2.1 months, although the range was pretty wide [0.03 to 23.2 months], but despite all of that, the permanent discontinuation rate was very low, less than 1%.

What we typically recommend in terms of AE management is an ophthalmology exam at baseline and then annually thereafter.³ The standard recommendation is that you don’t have to wait to get that baseline exam. You can initiate therapy and then get that baseline eye exam at some point during the beginning of their treatment, and then you follow annually with the eye exam, and as clinically indicated, prescribe preservative-free lubricant eyedrops 4 times a day, and [have the patient] avoid contact lens wear. With the stomatitis, I think we’re all familiar with oral steroid mouthwash. Using it 4 times a day seems to decrease the risk of stomatitis. During [infusion], using ice chips or ice water [can] decrease that risk as well. If you see certain specific ocular AEs, you would either withhold and then see if the symptoms resolve, and you can either rechallenge at the same dose or reduce it.

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DISCLOSURES: Lu previously reported consulting or advisory role with AstraZeneca, Daiichi Sankyo, and Gilead Sciences; and speakers’ bureau with AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merck, Seagen, and Stemline Therapeutics.

REFERENCES:

1. Pistilli B, Jhaveri K, IM S-A, et al. VP1-2025: Datopotamab deruxtecan (Dato-DXd) vs chemotherapy (CT) in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Final overall survival (OS) from the phase III TROPION-Breast01 trial. Ann Oncol. 2025;36(30:P348-350. doi:10.1016/j.annonc.2025.01.009

2. Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer: primary results from TROPION-Breast01. J Clin Oncol. 2025;43(3):285-296. doi:10.1200/JCO.24.00920

3. Datroway. Prescribing information. Daiichi Sankyo; 2025. Accessed September 16, 2025. https://tinyurl.com/3seakzy2