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

Paolo Tarantino, MD

At the 2024 ASCO Annual Meeting, 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.^1,2

In DESTINY-Breast03, 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).¹

In DESTINY-Breast06, 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; P <.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; P < .0001).²

“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 OncLive^®.

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.

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

Tarantino: 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 Nature Medicine 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.

References

1. 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. J Clin Oncol. 2024;42(suppl 16):1025. doi:10.1200/JCO.2024.42.16_suppl.1025
2. 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