Dato-DXd Could Alter First-Line SOC in Immunotherapy-Ineligible TNBC

Consistent efficacy data and a manageable safety profile position datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) to alter the frontline standard of care for patients with advanced triple-negative breast cancer (TNBC) who are ineligible for immunotherapy, particularly among patients with short disease-free intervals (DFIs) between adjuvant therapy and progression to advanced disease, according to Rebecca Dent, MD, MSc.

Findings from the phase 3 TROPION-Breast02 trial (NCT05374512) presented at the 2025 ESMO Congress demonstrated that among patients with locally recurrent inoperable or metastatic TNBC who could not receive immunotherapy and were naive to treatment in the advanced setting, Dato-DXd (n = 323) generated a median progression-free survival (PFS) of 10.8 months (95% CI, 8.6-13.0) per blinded independent central review (BICR) compared with 5.6 months (95% CI, 5.0-7.0) for investigator’s choice of chemotherapy (n = 321; HR, 0.57; 95% CI, 0.47-0.69; P < .0001).1,2

Additionally, patients in the Dato-DXd arm achieved a median overall survival (OS) of 23.7 months (95% CI, 19.8-25.6) compared with 18.7 months (95% CI, 16.0-21.8) for those given chemotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .0291).

"We potentially have a new standard of care in the first line [for patients with immunotherapy-ineligible TNBC]. For anybody who's back in clinic, I think we have prospective data that are very consistent. PFS by BICR, PFS by investigator assessment, OS, overall response rate [ORR], and duration of response [DOR] are all consistent,” Dent said. “We also can see this reassuring safety profile that is consistent with what we've seen previously. It is very reasonable to consider [Dato-DXd] in these [patients with] early relapsing TNBC who, to be honest, are very young when we see them in clinic.”

In an interview with OncLive®, Dent explained the current treatment challenges for patients with immunotherapy-ineligible advanced TNBC, highlighted the unique design aspects of TROPION-Breast02 that allowed for the enrollment of patients with short DFIs, and expanded on what the efficacy and safety data for the antibody-drug conjugate (ADC) could mean for clinical practice.

Dent is deputy chief executive officer at the National Cancer Center Singapore at SingHealth and a senior consultant in the breast medical oncology service, as well as a professor at Duke-NUS Medical School.

OncLive: For patients of advanced TNBC who are ineligible for immunotherapy, what are some of the challenges with current treatment strategies?

Dent: When we're treating patients with advanced or metastatic TNBC, we know that this is a group of patients who—up until recently, especially if they [have] PD-L1–negative [disease]—have [not had any] new therapies for well over a decade. Chemotherapy is the mainstay, and if they've had neoadjuvant therapy, they've already [been exposed to] several types of chemotherapy, so the median PFS is extremely short in those patients [after they reach the advanced setting]. They have aggressive disease, such that many of them don't even have the opportunity to get to second-line [treatment].

Unlike hormone receptor–positive or HER2-positive breast cancers, where we think a lot about [considerations for] first-line or second-line treatment, in TNBC, there is no question. We need to give our best drug first, because approximately 50% of those patients never receive second-line therapy.

What was the rationale behind evaluating Dato-DXd as a single agent in the frontline treatment of patients with advanced TNBC who are ineligible for immunotherapy in TROPION-Breast02?

The technology around ADCs allows us to deliver more potent chemotherapy. The active metabolite for a lot of these ADCs is a topoisomerase I inhibitor, which is the active metabolite of irinotecan, a chemotherapy that we used years ago in breast cancer. It was very active, but it was just too toxic to deliver to patients. The ADC technology allows us to deliver this potent chemotherapy to a level that is easier and better tolerated. In this particular case, [where we’re] giving [Dato-DXd] to patients with TNBC, there's rationale in terms of the type of chemotherapy that's given, but also the delivery mechanism. Giving it in the first line allows us to stabilize that disease.

The second thing is that we know that this ADC technology potentially has immunogenic effects, as well. What you're seeing across numerous ADCs is that you get a fantastic response, and in this trial, we had a more than doubling of the ORR [with Dato-DXd vs chemotherapy], but that response is sustained. Often, when you give chemotherapy in clinic, do that scan, and then a month later, the patient is already progressing. However, [responses in TROPION-Breast02] were sustained—we saw a 5-month improvement in DOR. Therefore, [Dato-DXd] is clearly having an impact on the tumor microenvironment. That's important because that means subsequent therapies are more likely to be effective as well.

How was immunotherapy ineligibility defined for enrollment in TROPION-Breast02? Were there any other key inclusion criteria to note?

This was a first-line trial, and there was no limit on DFI, which is very unusual. What that means is that patients could enroll any time after they had finished their adjuvant therapy, or even [if they had progressed while still] on their adjuvant therapy. Fifteen percent of patients [in the Dato-DXd arm and 16% in the chemotherapy arm] had a DFI was only 0 to 6 months—we capped it at 20%.

Patients were eligible if they had asymptomatic, stable brain metastases—up to 50% of patients with TNBC have brain metastases. The other thing that's unique is that this was a global trial, so we had patients from all around the world who were included. For me, when I'm in clinic, trying to get those [patients with] early relapse on a study is so important, because they really have no other options.

What were the key efficacy data from TROPION-Breast02 presented at the 2025 ESMO Congress?

We had dual primary end points for this study: PFS by BICR and OS. We saw a [5.3-month] improvement in terms of PFS and a HR that was unprecedented, with a P value of less than .0001. We also saw a 5.0-month improvement in OS in the first-line setting for a predominantly PD-L1–negative population. [The median OS] was 18.7 months [with chemotherapy vs 23.7 months] in patients getting Dato-DXd. Again, we just have not seen that [type of outcome] in this population in that first-line setting.

What's quite remarkable is the consistency of the data. When you're in clinic, the first thing you look at is if [a patient] is getting a response. We saw more than a doubling of ORR; in patients getting Dato-DXd, the ORR was 62.5%, with a delta of 33.2%. There was also a higher complete response rate [with Dato-DXd (9.0% vs 2.5%)], and the DOR was quite remarkable [12.3 months vs 7.1 months].

What should be known about the safety profile of Dato-DXd in TNBC?

Dato-DXd is a TROP-2–directed ADC. We know now that TROP-2 is expressed in the oral mucosa, as well as the epithelium of the cornea. Comparing patients' median DOR [in TROPION-Breast02] with some of the other trials with Dato-DXd, people were on [treatment] for almost a year.

We also saw higher rates of mucositis. They were mostly grade 1 and 2, but we did see higher rates of grade 3 [mucositis]. At the time of data cut off, 90% of [instances of mucositis] had resolved, and no patients came off study because of mucositis. However, you do need to use prophylaxis. We need to learn how to manage adverse effects [AEs], and our health care professionals who help us need to encourage patients to use the prophylaxis, because it works.

When it comes to ocular surface AEs, patients did have baseline eye exams and were followed every 3 cycles. Again, prophylaxis is important, using those eyedrops. Dose reductions will probably help, because we know [ocular toxicities] are potentially related to TROP-2 expression.

What's really reassuring is the [data for] interstitial lung disease [ILD] and pneumonitis. In both arms, ILD/pneumonitis was rare. No patients in either arm died [due to treatment-related AEs]. What differentiates Dato-DXd from other ADCs that we've seen is that we don't see myelosuppression. We don't see febrile neutropenia. We don't see sepsis.

The once-every-3-week dosing is extremely convenient. The first infusion is 90 minutes, and then subsequently, it's 30 minutes. That's important. We talk a lot about time toxicity for patients who are coming back and forth from the hospital. This is what's important for patients.

Provided that these data help support approval of Dato-DXd for patients with immunotherapy-ineligible TNBC, how might this ADC benefit patients?

Some would argue that anybody [with TNBC] likely benefits from this particular ADC. [In TROPION-Breast02,] 90% of the patients were PD-L1–low [with a combined positive score (CPS) below 10], and 10% were PD-L1–high [with a CPS of at least 10]. It certainly looks like both of those groups benefited [from Dato-DXd].

What we're anxiously awaiting is [data elucidating] whether we can augment [the efficacy of] Dato-DXd even further. We have ongoing trials looking at combining Dato-DXd with immune checkpoint inhibition, and I have a feeling we'll see even more robust data from this. There's more to come, and I think we'll [achieve] even more responses, but only time will tell.

References

1. Dent RA, Shao Z, Schmid P, et al. First-line datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option: Primary results from the randomised, phase 3 TROPION-Breast02 trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA21.
2. Rosa K. TROPION-Breast02 data support Dato-DXd as new first-line SOC in triple-negative breast cancer. OncLive.com. October 20, 2025. Accessed October 30, 2025. https://www.onclive.com/view/tropion-breast02-data-support-dato-dxd-as-new-first-line-soc-in-triple-negative-breast-cancer