Results from the phase 2 clinical trial DESTINY-Breast01 showed that the investigational human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate [Fam-] trastuzumab deruxtecan (T-DXd) has just as durable responses in heavily pre-treated HER2-positive breast cancer patients with brain metastases, as in patients without brain metastases. Physician’s Weekly spoke with Guy Jerusalem, MD, PhD, Professor of oncology at Liège University, Belgium, who presented the subgroup analysis from DESTINY-Breast01 in patient with a history of brain metastases at the American Society of Clinical Oncology (ASCO) Annual Meeting, which was held virtually 4-10 June, 2021  [1].

Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate consisting of a HER2-directed monoclonal antibody and a topoisomerase I inhibitor payload, with a peptide-based cleavable linker. In a phase 1 trial, it showed an objective response rate of 59% in patients with advanced HER2-positive breast cancer who were previously treated with T-DM1 [2]. Krop et al. conducted a phase 2 DESTINY-Breast01 (NCT03248492) study in which 253 patients with metastatic HER2-positive breast cancer previously treated with T-DM1 were included [3]. Median age of the patients was 55 years, 34.2% was Asian, 28.8% North American, and 37% European; 52.7% was HER2+ and 45.1% was HER2- (of 2.2% of patients, the HER2 status was unknown). The median prior lines of cancer therapy was 6 (range 2-27). In total, 184 patients received the recommended phase 2 dose of 5.4 mg/kg T-DXd.

However, patients with HER2+ metastatic breast cancer are at high risk of developing brain metastases, which is associated with a poor prognosis. Like the phase 1 predecessor, the phase 2 DESTINY-Breast01 trial demonstrated a similar objective response rate of 60.3%, including a 4.3% complete response rate and a 56% partial response rate in the entire cohort of patients with metastatic HER2-positive breast cancer (n=184). Patients with brain metastases at baseline (n=24) were the focus of this subgroup analysis presented at ASCO 2021, who were followed with brain MRIs every 6 weeks during follow-up. Contrary to expectation, the objective response rate (58.3%  brain metastases patients versus 60.9% overall cohort), median progression-free survival (18.1 versus 16.4 months), and median duration of response  (16.9 versus 14.8 months) in patients with brain metastases were comparable to patients without brain metasases. Baseline metastases diameter data was assessed where available, which showed a central nervous system (CNS) response rate of 50%. Overall, T-DXd showed strong clinical activity in patients with breast cancer and brain metastases.

Physician’s Weekly spoke with Prof. Jerusalem, to place these findings in context.

What is the take-away message?

“This study was not a randomized trial and there was a dose finding part, followed by dose extension part. In the end, patients were included in the trial were either TDM-1 intolerant or resistant, or presented relapse after TDM-1. Keep in mind that the current analysis was restricted to the patient with the recommended dose of 5.4 milligram per kilogram.”

“The main findings were that there is very high antitumor activity, with a very impressive objective response rate in this late line, it was 60.9% for the whole patient population. The duration of the response was very long, 14.8 months. And the median progression-free survival is 16.4 months. Taking into account what you expect with standard therapies in this setting, this was really impressive.” “Concerning the safety profile, it was generally manageable, had a low incident rate, it is mainly neutropenia, the higher grade neutropenia, in a little bit more than 20% of the patients, then anemia and nausea. One important side effect that has to be mentioned is interstitial lung disease, mostly it was low-grade interstitial lung disease, 10.9%, but there were a few have higher grade toxicities. It is important to mention that they have been heavily pretreated, these patients, the median number of 6 prior lines. There were no safety signs concerning cardiac toxicity.”

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“ In the 24 patients who had prior history of brain metastasis, 17 of these 24 patients still had lesions that could be detected. Some had been treated before and were in complete remission. And for 15 of the 17, we had the possibility to have a follow-up with repeated imaging so that we can interpret the results. And so among these 15, 7 had an objective response in the brain, 7 had stable disease and only one patient had progressive disease. I have never seen this result at this stage.

“Now, of course, I have to point out that, in this particular trial, all the patients with brain metastasis had received prior treatment and then when they were included either they had no progression or at least not the progression that needs a specific local therapy. What we have not yet done is look specifically at patients with active symptomatic brain metastasis, but now there are several ongoing trials to look also to this group.”

Did you observe any prophylactic effect?

“Perhaps. I can also say that now, if you look specifically to new events in the brain, among these 184 patients 4 had presented new events, 2 in the CNS subgroup. And there, it was relatively early after 78 and 85 days. And then another 2 in patient population without CNS brain metastases history there, it was after 323 and 498 days. These data are quite remarkable, in  that you have so few new brain metastases in a patient population where you expect many, many brain lesions. This is of course not yet solid.”

Limitations to this study?

“The sample size is the primary limitation here. In the beginning, they look at 17. We have data for 15 and then we have 7 partial responses. It is also a post-hoc analysis, performed after the primary endpoint was met, and we suspected this interesting signal. One additional consideration is that all patients analyzed here had finished radiotherapy more than 60 days earlier, but nevertheless, even after several months, some shrinkage can occur after radiotherapy. Thus, when we talk about 7 partial responses, we should consider that some of these patients that received radiotherapy could be late shrinkage related to radiotherapy. It is not very frequent to observe such late shrinkage due to the patient’s last radiotherapy, but you have to take this into account.’’

  1. Jerusalem G et al. J Clin Oncol 39, 2021 (suppl 15; abstr 526) DOI

10.1200/JCO.2021.39.15_suppl.526

  1. Tamura K, et al. Lancet Oncol. 2019;20(6);816-826.
  2. Krop IA, et al. GS1-03. SABCS 2019.