Trastuzumab Deruxtecan Elicits Statistically Significant PFS in HR-Positive/HER2-Low Breast Cancer


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Fam-trastuzumab deruxtecan-nxki demonstrated a statistically significant benefit in progression-free survival in patients with HER2-low metastatic breast cancer, meeting the primary end point of the phase 3 DESTINY-Breast04 trial and changing the standard of care for this patient population.

Shanu Modi, MD

Shanu Modi, MD

Fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated a statistically significant benefit in progression-free survival (PFS) in patients with HER2-low metastatic breast cancer, meeting the primary end point of the phase 3 DESTINY-Breast04 trial (NCT03734029) and changing the standard of care for this patient population, according to Shanu Modi, MD. Data from the practice-changing study were presented at the 2022 ASCO Annual Meeting and published in the New England Journal of Medicine.1

A total of 557 patients were enrolled on the trial and were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of chemotherapy. In patients with hormone receptor–positive, HER2-low advanced breast cancer, trastuzumab deruxtecan achieved a median PFS of 10.1 months (95% CI, 9.5-11.5) compared with 5.4 months (95% CI, 4.4-7.1) in the chemotherapy arm (hazard ratio [HR], 0.51; 95% CI, 0.40-0.64; P < .001). In this population, the median overall survival (OS) for patients in the trastuzumab deruxtecan arm was 23.9 months (95% CI, 20.8-24.8) vs 17.5 months (95% CI, 15.2-22.4) in the chemotherapy arm (HR, 0.64; 95% CI, 0.40-0.86; P = .003).

Among all patients treated on the trial, regardless of hormone receptor status, trastuzumab deruxtecan demonstrated a median PFS of 9.9 months (95% CI, 9.0-11.3) vs 5.1 months (95% CI, 4.2-6.8) for chemotherapy (HR, 0.50; 95% CI, 0.40-0.63; P < .001). The overall median OS for trastuzumab deruxtecan was 23.4 months (95% CI, 20.0-24.8) compared with 16.8 months (95% CI, 14.5-20.0) for the control arm (HR, 0.64; 95% CI, 0.49-0.84; P = .001).

“The DESTINY-Breast04 data established patients with HER2-low disease as a targetable population, and these data are going to compel us to rethink subgroups within the HER2-negative category of breast cancer,” Modi said. “These findings are specific to the drug trastuzumab deruxtecan. This is our new standard of care for this population of patients. It is exciting that we’ve been able to now translate HER2-targeted therapy to a broader group of patients with HER2-expressing breast cancer.”

In an interview with OncLive®, Modi, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the efficacy findings from the phase 3 DESTINY-Breast04 trial and the implications for patients with HER2-low metastatic breast cancer.

OncLive®: Could you provide background on the DESTINY-Breast04 trial?

Modi: The DESTINY-Breast04 trial is an important study. It is the first randomized trial of trastuzumab deruxtecan for patients with HER2-low metastatic breast cancer. In this study, we specifically enrolled patients with HER2-low metastatic breast cancer, which we defined as cancers with immunohistochemistry scores of 1+ or 2+ without gene amplification.

These were patients who had at least 1 but no more than 2 prior lines of chemotherapy. For those patients whose tumors were hormone receptor–positive, they had to have at least 1 line of endocrine therapy and their disease had to be considered endocrine refractory.

All patients were randomized 2:1 in this trial. The patients on the trastuzumab deruxtecan arm received the approved standard dose of trastuzumab deruxtecan [at 5.4 mg/kg]. On the control arm, patients [received] physician’s choice of chemotherapy, which included several commonly used chemotherapy drugs, such as gemcitabine, capecitabine, paclitaxel, nab-paclitaxel [Abraxane], and eribulin.

The primary end point of the study was to look at PFS. We looked specifically at [patients with hormone receptor–positive breast cancer] using hierarchical testing. If that result was positive, we went on to look at the PFS for the whole study population. Similarly for OS, we started by examining patients with hormone receptor–positive disease, then all patients on study.

What efficacy results have been observed so far in DESTINY-Breast04?

We had some exciting efficacy results from this trial. Starting with the primary end point, which was PFS, we saw positive an HR of 0.5 in patients with hormone receptor–positive breast cancer, which then allowed us to test all patients on study [for PFS]. The PFS for all patients on trial [had an HR] of 0.5, which was statistically significant. The P value was less than 0.001.

This translates to an improvement in median PFS from approximately 5 months [in the control arm] to approximately 10 months [in the trastuzumab deruxtecan arm], which is significant and an important finding for patients with advanced disease.

One of the key secondary end points was OS. We saw similar results for the hormone receptor–positive subgroup and overall patients on the study. The HR was 0.64 and statistically significant, and this this led to an improvement in median OS from approximately 17 months [in the control arm] to almost 24 months with trastuzumab deruxtecan.

This is compelling efficacy data. It is not common to see survival advantage in more advanced breast cancer patients. These are exciting results for our patients.

Are there any notable toxicities associated with trastuzumab deruxtecan?

One of the important toxicities of trastuzumab deruxtecan is lung toxicity, which we are monitoring very closely. In this trial, we saw an overall incidence [of lung toxicity] of 12%, and most of the lung toxicity was low grade and reversible. But there were 3 deaths attributed to lung toxicity on this trial, translating to an incidence of 0.8%. This is a reminder that this is a toxicity clinicians must pay close attention to when treating patients. It is important to be prepared to intervene and act promptly to attempt to minimize potentially serious consequences.

What next steps will be taken with this research?

For the short term, our goal is to present some of the subgroup analyses from DESTINY-Breast04, including the patient-reported outcomes, which are important. We hope to present that later this year. We also have a lot of correlative studies planned for the tissue we collected, including baseline tissue on the patients, which is an important resource. We are hoping to understand more of the science behind how [trastuzumab deruxtecan] works, as well as who may be the best target population.

There are some ongoing studies with trastuzumab deruxtecan in the HER2-low space that are important, including the phase 3 DESTINY-Breast06 study [NCT04494425], which is a follow-up trial [to DESTINY-Breast04]. We are again looking at a hormone receptor–positive, HER2-low population with advanced cancer, but [these patients] are more treatment naïve, including those without prior chemotherapy.

DESTINY-Breast06 also includes a subset of patients who have ultra-low HER2-expressing breast cancer, and we will be trying to define the lower boundary of the HER2-low population. This is an exciting trial that is already enrolling patients.

Ultimately, there’s a lot of interest in moving [trastuzumab deruxtecan] to patients with high-risk, early-stage disease. There’s a lot more exciting information to come from this drug and for this group of patients.

What has the emergence of trastuzumab deruxtecan meant for the breast cancer treatment paradigm?

These data are exciting, but in many ways, these data are about more than just this drug and breast cancer. We are entering an era of exciting progress in cancer treatment, and there’s a lot of optimism for the future.


  1. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. Published online June 5, 2022. doi:10.1056/NEJMoa2203690

Sponsored in part by Daiichi Sankyo. Content independently developed by OncLive®

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