Tan Reviews Updates on T-DXd in HER2-Low and -Ultralow Metastatic Breast Cancer

How has practice recently changed for patients with metastatic hormone receptor–positive, HER2-negative breast cancer?

Antoinette Tan, MD, MHS: The NCCN guidelines…are a revolving door. They keep changing. But as of [January], when you look at systemic therapy for metastatic hormone receptor–positive, HER2-negative disease with visceral crisis or endocrine refractory, there is an evolution [in the second line].¹ In late January, the FDA approved trastuzumab deruxtecan [T-DXd; Enhertu] for HER2-low and HER2-ultralow breast cancer that has progressed on 1 or more endocrine therapies in the metastatic setting. Patients did not have to receive chemotherapy. That is a practice change that I just wanted to highlight.

Antoinette R. Tan, MD, MHS

Chief of Breast Medical Oncology

Codirector, Phase I Program

Atrium Health Levine Cancer Institute

Charlotte, NC

Could you describe the outcomes of the DESTINY-Breast04 trial?

DESTINY-Breast04 [NCT03734029] was the randomized phase 3 trial that involved patients with HER2-low metastatic breast cancer who received 1 to 2 prior lines of chemotherapy in the metastatic setting. In addition, patients with hormone receptor–positive disease were also required to be endocrine refractory, so they had to receive at least 1 line of endocrine therapy. The randomization here was 2:1 to T-DXd, compared with the treatment of physician’s choice [TPC], which [included] capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel, and the primary end point was progression-free survival [PFS]. Other key secondary end points were overall survival [OS] for the hormone receptor–positive group and all patients.

The median PFS in the hormone receptor– positive cohort was 10.1 months in the T-DXd group and 5.4 months in the TPC group, with an HR of 0.51 and a significant P value [95% CI, 0.40-0.64; P < .0001].² OS was a key secondary end point. For that hormone receptor–positive cohort, the median OS improved by more than 6 months from 17.5 months [with TPC] to 23.9 months with T-DXd, with the HR there of 0.64 and a statistically significant P value [95% CI, 0.48-0.86; P = .0028]. That resulted in having this drug available for patients with HER2-low metastatic breast cancer.

The data were updated at the European Society for Medical Oncology Annual Congress [in 2023]. It was a 32-month follow-up, and for patients who were hormone receptor–positive in this updated analysis, the data were upheld.³ The median OS is going on [nearly] 2 years [with T-DXd] vs 17.6 months [with TPC], and the 24-month OS rates were higher in the patients who received T-DXd at 49% vs TPC at about 35%. This dataset continues to support the use of T-DXd after 1 line of chemotherapy in patients with HER2-low metastatic breast cancer.

The PFS also continued upholding the results. The median PFS was 9.6 months in the T-DXd arm vs 4.2 months with TPC. When they did the subgroup analysis for the hormone receptor–positive patients, it showed consistent benefit for those treated with T-DXd in all those categories, including IHC 1+ and 2+ cancers with or without prior CDK4/6 inhibitors, and irrespective of the [number of prior] lines of chemotherapy.

It’s important that we talk about the safety profile of this drug. There weren’t any new safety signals for T-DXd in this HER2-low population. The safety profile was consistent with other studies. But I do want to [point] out that there is a higher rate of neutropenia in 51 [of 371 patients], a 14% incidence of grade 3 or 4 events vs 41% with TPC, so it was lower for T-DXd. But when we look at nausea, it was higher with T-DXd at 73% [of any grade] when compared with [23.8% with] TPC.² The nausea, though, is primarily grade 1 and 2. My clinical experience has been that it can be managed well using prophylactic antiemetics. I was looking at our order set; we have the use of aprepitant, dexamethasone, and ondansetron. Then, when patients go home, we send them with the schedule to take dexamethasone, ondansetron, and some prochlorperazine, sometimes lorazepam, so it’s manageable.

What is important is the lung toxicity that can be associated with T-DXd, which requires awareness, vigilance, and early intervention. Twelve percent of patients had interstitial lung disease or pneumonitis. Usually, the median onset is between 4 and 5 months.^2,3 The majority of cases were grade 1 and 2, but there’s a very low incidence, less than 1%, of grade 5 events, with 3 reported deaths. It’s very important that if patients are reporting a change in respiratory status, we’re clued in, and we work it up appropriately with a CT scan of the chest and then determine if the patient needs pulmonary intervention, immediate use of steroids, and an interruption or stoppage of the drug.

What further data support the use of T-DXd in both HER2-low and -ultralow disease?

Next, I want to review DESTINY-Breast06 [NCT04494425] with the role of T-DXd for HER2-low and -ultralow hormone receptor– positive metastatic breast cancer in patients who have not received any chemotherapy. This is looking at the role of T-DXd in an earlier line, as opposed to in DESTINY-Breast04.

In this large trial, 866 patients with metastatic breast cancer that was HER2-low or HER2-ultralow were randomly assigned to either T-DXd or TPC, and here that included capecitabine, paclitaxel or nab-paclitaxel.⁴ They were treated until disease progression or toxicity; the primary end point was PFS in the HER2-low population. The majority of the patients, 713, had HER2-low disease. HER2-ultralow was in a smaller population, approximately 150 patients. Baseline characteristics were balanced between the 2 groups. In the HER2-low population, the PFS was significantly longer with T-DXd than with chemo-therapy. Median PFS was 13.2 months in the T-DXd group and 8.1 months in the chemotherapy group [HR, 0.62; 95% CI, 0.51-0.74; P < .0001]. In the intent-to-treat population, median PFS was significantly longer in those who received T-DXd than with chemotherapy [HR, 0.63; 95% CI, 0.53-0.75; P < .0001]. At the time of the data cutoff, the difference in OS between the 2 treatment groups in the HER2-low population was not significant, but when you look at the 12-month overall survival rate, it favored T-DXd [87.5% vs 81.7% for TPC]. Results of [the OS rate] were also consistent in the intent-to-treat and the HER2-ultralow populations.

In terms of efficacy in the HER2-ultralow population, it was similar to that of the HER2-low and the intent-to-treat populations. The median PFS was 13.2 months in the T-DXd group and 8.3 months in the chemotherapy group, but the benefit in this HER2-ultralow group did not reach statistical significance, most likely due to the decreased power [HR, 0.78; 95% CI, 0.50-1.21].

When you look at the response rate, whether you look at HER2-low or HER2-ultralow, the objective response rates are higher in the patients who receive T-DXd vs TPC [Figure⁵]. In the HER2-low T-DXd-treated group, there were 9 complete responses. In the HER2-ultralow group, there were 4 complete responses. Response rates are higher, favoring T-DXd.

There were data presented at this past San Antonio Breast Cancer Symposium that looked at the efficacy of T-DXd compared with TPC according to the pace of the disease progression on the patient’s previous endocrine therapy.⁶ PFS2 was evaluated, meaning from the time of randomization to the point the patient had a second disease progression. What these data are showing us is that there is sustained benefit with T-DXd. We can see there’s a median PFS2 approaching 2 years [20.3 months] compared with TPC, which was at [14.7] months [HR, 0.62; 95% CI, 0.52-0.74; P < .0001].

When they looked at different periods to progression—less than 6 months, 6 to 12 months, and greater than 12 months— the benefit is maintained with T-DXd, regardless at what point progression occurred. I think it’s reassuring, especially when you’re treating patients who have rapidly progressive disease. Patients with fewer than 3 metastatic sites had a benefit from T-DXd compared with TPC.

DISCLOSURES: Tan previously reported consulting or advisory roles with Jazz Pharmaceuticals, Stemline Therapeutics, AstraZeneca, Eli Lilly, Arvinas, and Incyclix Bio.

REFERENCES:

1. NCCN. Clinical practice guidelines in oncology. Breast cancer, version 3.2025. Accessed April 9, 2025. https://tinyurl.com/58ppyx87

2. Modi S, Jacot W, Yamashita T; DESTINY-Breast04 Trial Investigators; et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

3. Modi S, Jacot W, Iwata H, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): updated survival results of the randomized, phase III DESTINY-Breast04 study. Ann Oncol. 2023;34(suppl 2):S334-S390. doi:10.1016/S0923-7534(23)01260-7

4. Bardia A, Hu X, Dent R; DESTINY-Breast06 Trial Investigators; et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086

5. 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

6. Bardia A, Hu X, Dent R, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) by pace of disease progression on prior endocrine-based therapy: additional analysis from DESTINY-Breast06. Presented at: San Antonio Breast Cancer Symposium; December 10-14, 2024; San Antonio, TX. Abstract LB1-04.