, additional data continued to demonstrate the utility, safety, and efficacy of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in patients with HER2-positive metastatic breast cancer in the phase 3 DESTINY-Breast03 trial (NCT03529110), as well as those with HER2-low and -ultralow metastatic disease in the phase 3 DESTINY-Breast06 trial (NCT04494425), according to Paolo Tarantino, MD.

 T-DXd was compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab (Herceptin) and taxane-based chemotherapy. T-DXd demonstrated improved both progression-free survival (PFS) and overall survival (OS). With T-DXd (n = 261), the median PFS was 29.0 months (95% CI, 23.7-40.0) compared with 7.2 months (95% CI, 6.8-8.3) with T-DM1 (n = 263; HR, 0.30; 95% CI, 0.24-0.38). The median OS was 52.6 months (95% CI, 48.7­–not evaluable [NE]) with T-DXd and 42.7 months (95% CI, 35.4-NE) with T-DM1 (HR, 0.73; 95% CI, 0.56-0.94).

 T-DXd was compared with investigator’s choice of chemotherapy in patients with hormone receptor–positive, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization–) or HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer who received at least 2 prior lines of endocrine therapy and were naive to chemotherapy. Results from the primary analysis of the study showed that treatment with T-DXd led to a statistically significant and clinically meaningful improvement in PFS vs chemotherapy in patients with HER2-low disease. The median PFS was 13.2 months for T-DXd (n = 359) vs 8.1 months for investigator’s choice of chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; 

 <.0001). The median PFS was the same for both arms in the intention-to-treat population, which included patients with both HER2-low and -ultralow disease (HR, 0.63; 0.53-0.75; 

“I was impressed when I saw the first phase 1 trial of T-DXd when it was still called DS-8201a, and I'm still impressed every time I see a new clinical trial with this drug. It's extremely effective, both for HER2-positive metastatic breast cancer, where that was expected, but also for HER2-low and -ultralow [disease],” Tarantino emphasized in an interview with 

In the interview, Tarantino discussed the implications of findings from DESTINY-Breast03 and DESTINY-Breast06, how T-DXd has shifted care across the metastatic breast cancer treatment paradigm, and the future for antibody-drug conjugates (ADCs) in breast cancer treatment across various HER2 expression levels and treatment lines.

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

: Beginning with DESTINY-Breast03, what were some of the key long-term efficacy findings from this trial presented at the 2024 ASCO Annual Meeting?

: It was very interesting to see this update of DESTINY-Breast03, which was a randomized phase 3 trial that compared T-DXd with T-DM1 in the second-line [setting] for [patients with] HER2-positive metastatic breast cancer. This was the first trial comparing 2 ADCs head-to-head.

We previously knew that T-DXd improved both PFS and OS compared with T-DM1 [in DESTINY-Breast03], but in prior presentations of this study, we never had a [numerical] amount of improvement in OS because it was not reached in the treatment arms. At the 2024 ASCO Annual Meeting, we had the final presentation of OS that was published concurrently in 

 by Javier Cortés, MD, PhD, [of Vall d’Hebron Institute of Oncology] and colleagues.

What [the final OS analysis] showed is that the use of T-DXd in the second line compared with T-DM1 prolonged OS by 9.9 months [with a median OS of 52.6 months (95% CI, 48.7-NE) for T-DXd vs 42.7 months (95% CI, 35.4-NE) for T-DM1)]. This is highly relevant and clinically impactful to see an almost 1-year improvement in OS, the most meaningful end point.

Concurrently, when looking at PFS, the updated [analysis] confirmed that T-DXd is associated with a median PFS of [29.0 months (95% CI, 23.7-40.0)] for this population compared with T-DM1, which is associated with a median PFS of 7.2 months [95% CI, 6.8-8.3].

These data reinforced what we already knew and reinforced the position of T-DXd in patients who have progressed after treatment with chemotherapy and trastuzumab [Herceptin] in earlier lines for HER2-positive metastatic breast cancer. We are waiting for the first-line trial, the [phase 3] DESTINY-Breast09 trial [NCT04784715], which is ongoing, and we may hear within the next year about [data from] this first-line trial.

For your community oncology colleagues, what would you share regarding the safety of these ADCs?

In general, both T-DM1 and T-DXd are well-tolerated agents. The average experience of patients is that they tolerate them well and don't have major adverse effects [AEs]. It is important to remember that nausea and vomiting are common and need to be managed proactively. It's important to prescribe adequate prophylaxis with 3-drug regimens since T-DXd has been associated with high immunogenicity. With prophylaxis in place, nausea becomes [less] frequent and very manageable.

Apart from that, it's important to remember that both T-DXd and T-DM1 have anti-HER2 antibodies; therefore, they can cause cardiac toxicity. Usually, this is uncommon, [occurring] in less than 10% of patients; it's reversible and usually low-grade, but it's important to monitor patients with echocardiograms at baseline and during treatment. Importantly, since these drugs carry chemotherapy [payloads], they can cause cytopenias. These are also usually manageable.

Finally, with T-DXd, it is extremely important to remember the risk of interstitial lung disease [ILD]. We know that [in DESTINY-Breast03, 16.7%] of patients receiving T-DXd and [3.4% of patients] receiving T-DM1 had ILD. It's important to perform CT scans of the chest for these patients every 6 to 12 weeks to diagnose ILD early. Whenever there is suspicion of ILD, stopping the drug and giving steroids to patients [is important]. The drug can be only restarted if ILD was asymptomatic or resolved.

We are trying to understand if we can reintroduce the drug in patients who have mild symptoms or where ILD doesn't fully resolve. However, for now, to avoid high-grade ILD, it's important to stop the drug and give steroids. DESTINY-Breast03 reinforced the idea that if you have adequate awareness and management of ILD, you can avoid fatal cases. In DESTINY-Breast03, despite prolonged exposure of patients to T-DXd, there were no grade 5 ILD episodes. This was very important, but ILD can still happen, and this is why it is extremely important to be vigilant for this AE.

Looking at the evaluation of T-DXd vs investigator’s choice of chemotherapy in patients with hormone receptor–positive, HER2-low or -ultralow metastatic breast cancer in the DESTINY-Breast06 trial, what were some of the key efficacy findings?

DESTINY-Breast06 was an interesting and bold trial; it's somewhat similar to the phase 3 DESTINY-Breast04 study [NCT03734029], which is the trial that led to 

the standing ovation at the 2022 ASCO Annual Meeting

 The difference was that DESTINY-Breast06 was restricted to patients with hormone receptor–positive metastatic breast cancer who have received [at least] 2 lines of endocrine treatment but never received chemotherapy. Therefore, this was basically a trial looking at the first line of cytotoxic treatment for hormone receptor–positive metastatic breast cancer. It compared T-DXd vs physician’s choice [of chemotherapy] that could be either capecitabine or a taxane.

The population in which this trial was conducted included patients with HER2-low metastatic breast cancer, or HER2-ultralow [disease]. Ultralow is a new category; it is defined [as IHC 0 with membrane staining], but we don't really have ultralow labeled right now in the pathology report. It is going to be important to look at that [testing].

However, the HER2 low plus ultralow [scores comprise] nearly all patients with HER2-negative metastatic breast cancer—approximately 90% [of this population]. Therefore, let's think of [DESTINY-Breast06] as a trial for patients with hormone receptor–positive, HER2-negative metastatic breast cancer. What we saw is that T-DXd was associated with a significant improvement in PFS compared with physician’s choice of chemotherapy [in the intention-to-treat population comprising patients with HER2-low and -ultralow disease], with a median of 13.2 months with T-DXd compared with 8.1 months with chemotherapy. T-DXd also improved objective response rate [ORR], clinical benefit rate, and every measure of efficacy. Very interestingly, the activity of T-DXd was quite similar in HER2-low and -ultralow metastatic breast cancer; there was a median PFS of 13.2 months of PFS in both [subgroups]. This is why I think it is reasonable, looking at this data, to expand the use of T-DXd among patients with HER2-low and -ultralow breast cancer. Ultralow is a subset of HER2-zero, and it includes any tumor that has up to 10% of cells expressing a weak expression of HER2. It's something we still don't have in the pathology reports, but we will need to add it.

The other aspect of the trial—and the main aim for which the trial was designed—was understanding if it's important to take T-DXd to earlier settings in chemotherapy-naive patients. We still don't have a perfect answer because there is not yet any statistical improvement in OS. These data were immature, but we need to follow these data because it is important to look at OS.

Finally, the trial was mostly restricted to patients with visceral disease—there were only 3% of patients had bone-only disease. It makes sense to think of T-DXd based on the improvement in PFS and ORR in patients where you need fast activity, such as those who are symptomatic with high burden of disease. However, for patients with low burden of disease or indolent disease, you may still be able to give something like capecitabine [as the first cytotoxic regimen]. It's oral, cheap, and does not commonly cause alopecia. It is well tolerated and still works pretty well. It's always important to remember patient preferences and patient values. T-DXd could be a new option in chemotherapy-naive patients, and it will be important to offer it whenever this is indicated for our patients.

What were the safety findings from DESTINY-Breast06?

DESTINY-Breast06 mostly confirmed what we knew about the safety of T-DXd. One important thing is that there were still 3 cases of grade 5, fatal ILD in DESTINY-Breast06. It is hard to completely get rid of those [AEs]; it's hard to be sure that we're not going to see any more fatal ILD. Although DESTINY-Breast-3 did not have [any instances of grade 5 ILD], this reminds us that it's important to maintain awareness.

We try to recommend the five S's that I found helpful to understand how to monitor and manage ILD with T-DXd. The first S is screening for the patient who you have in front of you to understand the baseline risk. The second S is remembering to scan the patient with CT scans every 6 to 12 weeks. [Third is] synergy with the radiologist, pulmonologists, and the whole care team to manage ILD. [The fourth S] is suspending T-DXd and introducing steroids, which is the fifth S.

Most of the other AEs with T-DXd were very similar to what we knew. [Left ventricular dysfunction] was slightly higher in incidence at 8.1% [for T-DXd] compared with other trials, but we know that it's reversible, we know that it's low-grade, and therefore, it's not a major concern. I do feel that we are learning how to better use ADCs, but it's always important to discuss the management of AEs and develop trials to mitigate the AEs of ADCs. I hope we'll be able to develop some trials to mitigate ILD and other AEs [associated] with T-DXd.

How do you envision the use of T-DXd expanding? How do these findings set a baseline for the future of ADCs in breast cancer?

I expect that the use of T-DXd will expand across categories of HER2 expression; it will expand and will be used in earlier settings when it's needed and required. I would love to leverage the efficacy of this drug to cure patients. We do hope that some of the patients who experience complete response with T-DXd can be cured. We don't know this yet because we don't have enough follow-up, but there was an interesting analysis at the 2024 ASCO Annual Meeting looking at the performance of T-DXd by different categories of response, and patients with complete response at incredibly prolonged responses; we do hope that we can cure them.

The most important part will be taking T-DXd and other ADCs to the early-stage setting and understanding how to best develop them in that setting to prevent recurrence and hopefully cure patients. That is already ongoing. There are several trials in the early-stage setting. I'm currently working on the [phase 2] TRUDI trial [NCT05795101] that is combining T-DXd and durvalumab [Imfinzi] for a very high-risk population of patients with inflammatory breast cancer. [Investigations of T-DXd in earlier settings] are very exciting, and I'm looking forward to those.

For the moment, what we learned from DESTINY-Breast03 is that T-DXd is extremely effective in the second-line for HER2-positive disease, and it's established there. Whenever patients have progression on first-line [treatment] for HER2-positive metastatic breast cancer, think of T-DXd. DESTINY-Breast06 taught us that we must be open-minded across HER2 categories. We know that we could use T-DXd for HER2-positive, HER2-low, and now HER2-ultralow, and maybe even HER2-zero breast cancer. Whenever T-DXd is indicated, or whenever the patient requires or prefers something more active, T-DXd can be thought of in the first cytotoxic line after [progression on] endocrine therapy for hormone receptor–positive metastatic breast cancer.

Hamilton EP, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated survival results of DESTINY-Breast03. 

. 2024;42(suppl 16):1025. doi:10.1200/JCO.2024.42.16_suppl.1025

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). 

. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000

Articles

DESTINY-Breast03 and DESTINY-Breast06 showed that T-DXd is a beneficial treatment approach in HER2-positive, -low, and -ultralow metastatic breast cancer.

DESTINY-Breast Trial Portfolio Spotlights Efficacy of T-DXd in Metastatic Breast Cancer

Paolo Tarantino, MD, discusses updated data from the phase 3 DESTINY-Breast03 trial of trastuzumab deruxtecan in HER2-positive breast cancer.

Dr Tarantino on Updated Survival Data With T-DXd in HER2+ Breast Cancer

Paolo Tarantino, MD, researcher, the European Institute of Oncology, clinical research fellow, Dana-Farber Cancer Institute, discusses updated data from the phase 3 DESTINY-Breast03 trial (NCT03529110) investigating fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in patients with metastatic HER2-positive breast cancer.

This pivotal trial was the first head-to-head comparison of T-DXd with the prior standard of care (SOC), ado-trastuzumab emtansine (Kadcyla; T-DM1), in the second line for this patient population, Tarantino begins. Previously reported data from DESTINY-Breast03 showed significant progression-free survival (PFS) and overall survival (OS) benefits with T-DXd vs T-DM1, establishing T-DXd as the preferred second-line treatment option for patients with metastatic HER2-positive breast cancer, he states. However, the exact magnitude of improvement in OS with T-DXd had not been reported in earlier presentations, Tarantino says.

, updated findings from an exploratory analysis of the study were presented and simultaneously published in 

 Tarantino reports. Results showed that T-DXd (n = 261) produced a median investigator-assessed OS of 52.6 months (95% CI, 48.7-not evaluable [NE]). T-DXd prolonged the median OS by 9.9 months compared with T-DM1 (n = 263), which produced a median OS of 42.7 months (95% CI, 35.4-NE; HR, 0.73 [95% CI, 0.56-0.94]). The 36- and 42-month OS rates with T-DXd were 67.6% (95% CI, 61.3%-73.0%) and 62.5% (95% CI, 56.2%-68.3%), respectively; these respective rates with T-DM1 were 55.7% (95% CI, 49.2%-61.7%) and 50.1% (95% CI, 43.6%-56.2%).

Additionally, the updated data demonstrated that T-DXd was associated with a median PFS of 29.0 months (95% CI, 23.7-40.0) vs 7.2 months (95% CI, 6.8-8.3) with T-DM1 (HR, 0.30; 95% CI, 0.24-0.38). The 36-month PFS rates with T-DXd and T-DM1 were 45.7% (95% CI, 38.9%-52.2%) and 12.4% (95% CI, 8.1%-17.7%), respectively. These findings reinforce the already-established superiority of T-DXd over T-DM1 in terms of both PFS and OS, further solidifying T-DXd’s position as the SOC for patients who have progressed on chemotherapy and trastuzumab (Herceptin) in earlier lines, Tarantino explains. Anticipated results from the ongoing phase 3 DESTINY-Breast09 trial (NCT04784715) will further elucidate a potential role for T-DXd with or without pertuzumab (Perjeta) in the first-line setting, Tarantino concludes

Videos

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 

Findings from DESTINY-Breast06 presented at the 

 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; 

 <.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; 

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.

: What was the rationale behind DESTINY-Breast06?

: 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.

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; 

 <.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; 

<.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.

VK Gadi, MD, PhD, discusses findings from the DESTINY-Breast06 trial and the implications for hormone receptor–positive, HER2-low metastatic breast cancer.

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

VK Gadi, MD, PhD, discusses primary results from the phase 3 DESTINY-Breast06 trial of trastuzumab deruxtecan in HR-positive, HER2-low breast cancer.

Dr Gadi on Results From of the DESTINY-Breast06 Trial in HR+/HER2-Low Breast Cancer

VK Gadi, MD, PhD, deputy director, University of Illinois Cancer Center, professor, Department of Medicine, Division of Hematology/Oncology, director, Medical Oncology, University of Illinois College of Medicine Chicago, discusses primary results from the phase 3 DESTINY-Breast06 trial (NCT04494425) investigating treatment with fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in hormone receptor (HR)–positive, HER2-low and -ultralow breast cancer.

DESTINY-Breast06 explored the use of the antibody-drug conjugate (ADC) T-DXd vs physician’s choice of chemotherapy in the metastatic setting for patients with HER2-low or -ultralow disease who progressed on prior endocrine therapy. HER2-low disease was defined as those with an immunohistochemistry (IHC) score of 1+ or IHC 2+ and negative in situ hybridization (ISH). HER2-ultralow disease was defined as an IHC score of 0 with membrane staining.

Data from the open-label, randomized study

. These results demonstrated a statistically significant and clinically meaningful progression-free survival (PFS) benefit with T-DXd vs physician’s choice of chemotherapy in patients with HER2-low disease, which were consistent in the HER2-ultralow population, Gadi reports. In the intention-to-treat (ITT) population, comprising both HER2-low and HER2-ultralow populations, the median PFS increased from 8.1 months with chemotherapy to 13.2 months with T-DXd, resulting in a hazard ratio (HR) of 0.63 (95% CI, 0.53-0.75; 

 < .0001). This 5.1-month difference in median PFS was also observed with T-DXd in the HER2-low group alone (HR, 0.62; 95% CI, 0.51-0.74; 

Overall survival (OS) data were immature at the data cutoff, but a trend toward improved OS was observed with T-DXd vs chemotherapy, Gadi continues. At approximately 40% maturity, the 12-month OS rate in the HER2-low population was 87.6% with T-DXd and 81.7% with chemotherapy (HR, 0.83; 95% CI, 0.66-1.05; 

 = .1181). In the ITT population, these rates were 87.0% and 81.1%, respectively (HR, 0.81; 95% CI, 0.65- 1.00).

The safety profile of T-DXd was consistent with prior data. Although T-DXd is not considered to be tolerated as well as other agents, the efficacy margin is large enough to support its consideration for those in this population, Gadi explains. As such, treatment with T-DXd will likely be an individualized patient decision, he notes.

Overall, results from DESTINY-Breast06 indicate that T-DXd should be considered a standard of care for patients with HER2-low and -ultralow breast cancer who progressed on endocrine-based therapy. These data may support future regulatory approval for T-DXd in earlier treatment lines, as well as subsequent guideline updates in HER2-low breast cancer, Gadi speculates.

Dr Pegram on the Implications and Safety of T-DXd in HR+/HER2– Breast Cancer

Mark Pegram, MD, Suzy Yuan-Huey Hung Endowed Professor of Medical Oncology, associate dean, Clinical Research Quality the Stanford University School of Medicine; associate director, Clinical Research, the Stanford Comprehensive Cancer Institute; medical director, the Stanford Clinical Translational Research Unit, discusses the implications of data from 

the primary analysis of the phase 3 DESTINY-Breast06 trial

 (NCT04494425) which evaluated fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in pretreated patients with hormone receptor–positive, HER2-low and -ultralow metastatic breast cancer. Notably, these data were presented at the 

The randomized DESTINY-Breast06 trial marks an initial step beyond endocrine therapy treatment in HR-positive metastatic disease, he begins. The trial yielded positive results and a highly significant p-value. The median progression-free survival (PFS) in the cohort of patients with HER2-low disease (n = 359) was 13.2 months with T-DXd vs 8.1 months with chemotherapy (HR, 0.62; 95% CI, 0.51-0.74; 

 < .0001), indicating a statistically significant and clinically relevant benefit with the antibody-drug conjugate (ADC) compared with the control, he reports. As a result, T-DXd may become a new option for select patients with hormone receptor–positive disease in the future, Pegram details.

It is also important to be aware of the adverse effects (AEs) associated with T-DXd, according to Pegram. The safety data from DESTINY-Breast06 revealed expected AEs, including gastrointestinal toxicity, alopecia, and interstitial lung disease (ILD), with some cases of grade 5 ILD. No new safety signals were detected, but it is crucial to monitor for these known toxicities, he advises.

T-DXd may be most suitable for high-risk patients who had a short duration of benefit from prior endocrine therapy, especially those with visceral disease or rapid progression, he continues. For patients requiring a quick response, the ADC is a sensible option, Pegram notes. Conversely, patients with a slow, indolent disease progression and a long history of response to CDK4/6 inhibitors plus endocrine therapy might consider other non-ADC options, such as capecitabine (Xeloda), Pegram says.

Ultimately, most patients will receive various treatments over time, so the order of administration may not be critically important, Pegram explains. Nonetheless, the robust data from DESTINY-Breast06 appear promising for patients who need a rapid treatment response to regain disease control after becoming resistant to endocrine therapy, Pegram concludes.

Mark Pegram, MD, discusses implications of and safety data from the primary analysis of the DESTINY-Breast06 trial in HR+/HER2– metastatic breast cancer.

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