DESTINY-Breast06 Data Reveal Another Potential Avenue for T-DXd in HR+, HER2-Low Metastatic Breast Cancer

VK Gadi, MD, PhD

Efficacy data for fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) derived from the phase 3 DESTINY-Breast06 trial (NCT04494425) could lead to further alteration of the treatment landscape for patients with hormone receptor–positive, HER2-low metastatic breast cancer, according to VK Gadi, MD, PhD, who noted that there are still questions to address regarding testing for HER2 expression and individualized treatment approaches.

“This was a positive trial, and we're all excited about it. Now, how do we put this into play? How are we going to individualize [treatment] decisions? There are a lot of thoughtful things that we must move through as the next phase of things,” Gadi said in an interview with OncLive®.

Findings from DESTINY-Breast06 presented at the 2024 ASCO Annual Meeting showed that treatment with T-DXd led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs investigator’s choice of chemotherapy in pretreated patients with hormone receptor–positive, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]–) metastatic breast cancer. Notably, the PFS benefit was consistent in patients with HER2-ultralow disease (IHC 0 with membrane staining).

In patients with HER2-low disease, T-DXd (n = 359) elicited a median PFS of 13.2 months vs 8.1 months for chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; P <.0001). In the intention-to-treat (ITT) population, which included patients with HER2-low and -ultralow disease, the median PFS was 13.2 months for T-DXd (n = 436) vs 8.1 months for chemotherapy (n = 430; HR, 0.63; 95% CI, 0.53-0.75; P <.0001).

Notably, PFS in the HER2-ultralow population was an exploratory end point for the study, and those given T-DXd (n = 76) experienced a median PFS of 13.2 months vs 8.3 months for those given chemotherapy (n = 76; HR, 0.78; 95% CI, 0.50-1.21).

In the interview, Gadi expanded on the rationale behind DESTINY-Breast06, the key data from the study, and the implications of the findings. Gadi is a professor in the Department of Medicine, Division of Hematology/Oncology, at the University of Illinois College of Medicine and the deputy director of the University of Illinois Cancer Center in Chicago.

OncLive: What was the rationale behind DESTINY-Breast06?

Gadi: DESTINY-Breast06 was a trial that [intended to] extend the footprint of T-DXd. This is a drug that's now been FDA approved for a few years; it was initially [approved for] patients who have HER2-positive disease that is relatively late line, so these are patients whose cancers are actually driven by the HER2 oncogene. However, [with T-DXd] being an antibody-drug conjugate, the question was: could we get the active molecule—the chemotherapy portion of it—into cells that have lower levels of HER2 and see efficacy there?

I’ll skip forward in the story to [the phase 3] DESTINY-Breast04 trial [NCT03734029]. In DESTINY-Breast04, we took patients who did not have HER2-driven disease; rather, they had small amounts of HER2 expression on the cancer. The trial was primarily a trial of patients with hormone receptor–positive disease, and there were a handful of patients with hormone receptor–negative disease. That trial was positive and received a lot of attention, and [findings] led to an extension of the FDA approval for [T-DXd] into [the treatment of] patients with HER2-low disease, where lower levels of HER2 expression are not actually contributing to the cancer cells’ growth.

However, [DESTINY-Breast04] studied [T-DXd] in a setting where patients had seen a few lines of chemotherapy, and [patients with hormone receptor–positive disease] had completed all their endocrine therapy.

[Following DESTINY-Breast04], the question was: if T-DXd is beneficial out this late [in the metastatic setting], should we be thinking about it in earlier [lines of treatment]? That was the fundamental question, but they also extended questions in a different direction. Patients with tumors that are HER2 low by IHC testing are 1+ or 2+. We have known for a long time that there are patients who [have a HER2 expression] of [IHC] 0; however, if you look at it under the microscope, they have little speckles that suggest that there are some HER2-positive cells. Therefore, the enrollment criteria in DESTINY-Breast06 included those patients [with HER2-ultralow disease]. This study also focused on only patients with hormone receptor–positive disease.

How was DESTINY-Breast06 designed?

This was a very conventional clinical trial otherwise. Patients were randomly assigned 1:1 [to T-DXd or investigator’s choice of chemotherapy]. Chemotherapy options included capecitabine, which is the most common drug as a standard of care in this setting, but also taxanes such as nab-paclitaxel [Abraxane] and conventional paclitaxel. And at the end of the day, when they looked at the demographics of the patients, they were well balanced between the 2 [arms] in terms of the types of exposure [to prior treatments] and prior lines of endocrine therapy, so there was not a lot of introduced bias because of the size of the trial. They enrolled patients who had a HER2 [expression of IHC 0+], which is the ultralow category, and more conventionally, [they enrolled patients with HER2-low disease defined as ICH 1+ or 2+] where the disease is not driven by HER2.

What were the key findings from DESTINY-Breast06 presented at the 2024 ASCO Annual Meeting?

It was a positive trial. [In patients with HER2-low disease], the hazard ratio for PFS showed a [38% reduction in the risk of progression or death for patients treated with T-DXd (HR, 0.62; 95% CI, 0.51-0.74; P <.0001)]. When you look at the PFS curves, they separate early, they stay separated, and that translated into a median difference of 5.1 months. At different time points [on the PFS curves], T-DXd is comfortably above standard-of-care chemotherapy.

[Investigators] also looked at PFS in the [ITT population] that included patients with [HER2-low and -ultralow disease]. When they did that, the [PFS benefit with T-DXd] was maintained [HR, 0.63; 95% CI, 0.53-0.75; P<.0001]. And then when they broke it out and looked at the [HER2-low and-ultralow] groups independently, the results held up. No matter how you dice it, the results seem to be holding up.

This is a study that was primarily focused on PFS. However, being a large trial, they could also look at overall survival [OS]. Those data were very immature at data cutoff, but there was a trend toward this curve separating [and favoring T-DXd]. Following the data forward, it'll be interesting because there is a chance that the OS end point might be hard to hit because a lot of the patients who don't get T-DXd during DESTINY-Breast06 could get the [agent] afterward, and that might close the [OS] gap. There are a lot of interesting research questions.

What implications could findings from DESTINY-Breast06 have for clinical practice?

There's a chance that [T-DXd] gets regulatory approval to move up into this line [of therapy]. Then the other question, T-DXd is—in some ways—more toxic than what we use otherwise [in this setting]. Capecitabin is an exceptionally well-tolerated drug for most patients; T-DXd is less so. However, the efficacy margin is big enough that it's tempting to look at this [as a treatment option]. It will be an individualized patient decision.

There is a safety signal that has been seen with T-DXd for years now: interstitial lung disease [ILD]. Some patients will die as a result of that. In the most recent studies, we have not seen patients die [from ILD], but 3 patients [0.7%] in the T-DXd arm did [experience grade 5 ILD during DESTINY-Breast06]. This is a call to action for us to be very vigilant for ILD.

Lastly, the study is interesting because of this HER2-low classification. Right now, a lot of pathologists don't report HER2-low status. I'm in an academic medical center and I know my pathologist, [so I can easily ask what the pathologist is] seeing with HER2. In [DESTINY-Breast06], they used a central laboratory for HER2 testing.

However, [in the real-world setting], the majority of patients are being treated in centers and situations where the pathologist may not necessarily talk fluidly with the medical oncologist. It's going to become more of a challenge finding patients [with HER2-low disease] in the community. It's incumbent on trial [investigators], the company, and others to help us solve this problem of how we're going to find patients in whom it would be appropriate [to use T-DXd]. We don't want to exclude patients [simply] because we just don't know about [their HER2 status]. This is one of the enduring challenges from this trial as we go forward.

Reference

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