Pending Dato-DXd Approval Solidifies Importance of Sequencing in HR+ Breast Cancer

Paolo Tarantino, MD

With the highly anticipated FDA approval of the antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) in hormone receptor (HR)–positive breast cancer, questions about the optimal sequencing of cytotoxic regimens are even more imperative to address, according to Paolo Tarantino, MD.

Once such trial poised to inform the sequencing of the ADC fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and chemotherapy in the HR-positive, HER2-low and -ultralow setting was the phase 3 DESTINY-Breast06 trial (NCT04494425). Data from the primary analysis of this trial were presented at the 2024 ASCO Annual Meeting, and showed that T-DXd significantly improved progression-free survival (PFS) vs investigator’s choice of chemotherapy for patients who progressed on prior endocrine therapy. In the intention-to-treat population, which included patients with HER2-low or -ultralow disease, the median PFS was 13.2 months for patients treated with T-DXd (n = 436) vs 8.1 months for those given chemotherapy (n = 430; HR, 0.63; 95% CI, 0.53-0.75; P < .0001). However, overall survival (OS) were immature at the first interim analysis of the study, necessitating longer follow-up.¹

Other ongoing studies, including the phase 2 SATEEN trial (NCT06100874) and SERIES (NCT06263543) trials, aim to provide better insight into the best sequencing strategy for sacituzumab govitecan-hziy (Trodelvy) and T-DXd in the HR-positive setting.^2,3

“Things are moving fast, and there are a lot of questions in this field regarding sequencing,” Tarantino said in an interview with OncLive^® regarding a recent State of the Science Summit^™ on breast cancer, which he chaired. “However, in truth, our options are increasing in this field, which is great news for our patients.”

In the interview, Tarantino highlighted the evolution of therapies beyond traditional chemotherapy in HR-positive, endocrine-refractory metastatic breast cancer, the impact of the DESTINY-Breast06 trial data on ADC use in the HER2-low space, and crucial unanswered questions regarding the optimal sequencing of ADCs.

Tarantino is a researcher at the European Institute of Oncology in Milan, Italy, and a medical oncologist as well as clinical research fellow at Dana-Farber Cancer Institute in Boston, Massachusetts.

OncLive: How have treatment approaches for HER2-positive metastatic breast cancer expanded beyond traditional chemotherapy?

Tarantino: There has been a real revolution in the past few years in the treatment of HR-positive metastatic breast cancer beyond traditional chemotherapy, and these are the most common patients we see in the clinic with metastatic disease. For a long time, what we had to offer [patients] after [they] exhausted endocrine treatment lines was sequential lines of chemotherapy including anthracyclines, taxanes, capecitabine, etc. At each [subsequent] line, the efficacy of these treatments decreased. In later lines, [there was] up to a 10% response rate and the [median] PFS was 3 to 4 months, which was very unsatisfactory.

In the past few years, we saw at least 2 [ADCs] approved that deliver chemotherapy in a more effective way: T-DXd and sacituzumab govitecan. [Additionally], there is at least 1 more that is expected to be approved soon, and [that is] Dato-DXd. All these agents have been shown to improve PFS over traditional chemotherapy in this population, and both T-DXd and sacituzumab govitecan [improved] OS. This is why, after patients have received chemotherapy, we’ve been [trying] to use [these ADCs]. At the 2024 ASCO Annual Meeting, we even saw the presentation of [data from] DESTINY-Breast06, showing a meaningful benefit with T-DXd used before chemotherapy in the first line [of treatment following endocrine therapy].

How have data from DESTINY-Breast06 impacted treatment sequencing within HER2-low and -ultralow breast cancer?

The biggest question that DESTINY-Breast06 attempted to answer was whether to use T-DXd as the first cytotoxic treatment [following endocrine therapy] or after first-line cytotoxic treatment with chemotherapy. That is where the phase 3 DESTINY-Breast04 study [NCT03734029] had positioned T-DXd. This trial answered the question at least for some patients. It’s always important to look at the population of patients included in each trial to understand which patients [these results] may apply to in real-world practice.

DESTINY-Breast06 was a trial mostly for patients with visceral metastasis from breast cancer, and it included approximately 3% of patients with bone-only metastasis. This tells us that T-DXd should be considered as the first-line cytotoxic treatment primarily for patients who have aggressive visceral disease. For patients who have more indolent bone-only, lymph node–only, or generally non-visceral disease, these data do not apply as much, although it’s still important to discuss the availability of this option with patients [as it] outperforms chemotherapy in terms of PFS.

The other piece [to keep in mind] is overall survival. [Although] we saw a significant benefit in OS [with T-DXd over chemotherapy] in DESTINY-Breast04, there wasn’t a statistically significant survival benefit [seen with this agent] in DESTINY-Breast06. We saw the curves trending in favor of T-DXd, but we don’t know yet if using T-DXd as first cytotoxic treatment improves OS [over chemotherapy]. We will need to wait for more mature data that will also help us understand if we need to use T-DXd before [a treatment such as] capecitabine or after capecitabine.

Finally, when we talk about the first line [HR-positive breast cancer setting], we are always talking about the first line after endocrine treatment. The first-line systemic regimen for most patients with ER-positive, metastatic breast cancer should remain endocrine treatment with CDK4/6 inhibitors or other treatments. We only talk of first-line cytotoxic treatments after the disease is clearly endocrine refractory. It’s important to remember this because whenever we talk about the first line, there is a little confusion between the first-line endocrine treatment and cytotoxic treatment. T-DXd falls in the realm of chemotherapies, and we think of using it after exhausting endocrine treatment options.

What unanswered questions remain regarding the optimal use of ADCs in HR-positive breast cancer?

The main question right now in this field is the sequencing question. Can we use sacituzumab govitecan after T-DXd or [vice versa], and achieve high activity with the second ADC? When Dato-DXd becomes available, can we also use that and in what order? We still don’t have good answers to these questions. We have several real-world analyses suggesting that we don’t have much activity with the second ADC compared with the first one, but some patients will derive benefit from the second ADC.

Right now, it’s still important to keep on producing real-world data and to run prospective trials. For instance, the randomized, phase 2 TRADE-DXd trial is in preparation [which will evaluate the use of] T-DXd after Dato-DXd or the opposite order [in HER2-low breast cancer]. We also have the phase 2 SATEEN trial, which I had the pleasure to develop at Dana-Farber Cancer Institute, testing sacituzumab govitecan after T-DXd in HER2-positive disease. We have another ongoing [phase 2] trial called SERIES that is looking at sacituzumab govitecan after T-DXd [in HR-positive, HER2-low breast cancer.] Then we have the Translational Breast Cancer Research Consortium running a registry. Overall, we have several efforts ongoing that will require some time, but it’s important to keep focus on this clinical question.

References

1. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_ suppl.LBA1000
2. A single-arm phase II Trial of sacituzumab govitecan and trastuzumab for HER2+ metastatic breast cancer after trastuzumab deruxtecan (SATEEN). ClinicalTrials.gov. Updated May 30, 2024. Accessed July 24, 2024. https://clinicaltrials.gov/study/NCT06100874
3. Sequencing antibody drug conjugates in ER+/​HER2 LOW MBC (SERIES). ClinicalTrials.gov. Updated July 3, 2024. Accessed July 24, 2024.https://clinicaltrials.gov/study/NCT06263543