T-DXd Continues to Show Robust CNS Activity in HER2+ Breast Cancer With Brain Metastases

Javier Cortés, MD, PhD

Robust intracranial (IC) responses were observed with fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) vs physician’s choice of comparator regimen in patients with HER2-positive metastatic breast cancer and brain metastases enrolled in the phase 3 DESTINY-Breast01 (NCT03248492), DESTINY-Breast02 (NCT03523585), and DESTINY-Breast03 (NCT03529110) trials—regardless of whether the metastases were treated and stable or untreated and active. This adds to the body of evidence supporting the agent’s role as a standard of care (SOC) for patients with or without brain metastases, according to Javier Cortés, MD, PhD.

Findings from a pooled analysis of the 3 trials were presented at the 2023 ESMO Congress. T-DXd (n = 104) produced an intracranial overall response rate (IC-ORR) of 45.2% in patients with treated/stable brain metastases, which consisted of 17 complete responses (CRs) and 30 partial responses (PRs). The ORR was 27.6% with treatment of physician’s choice (n = 58). Moreover, the median intracranial duration of response (IC-DOR) was 12.3 months (range, 9.1-17.9) in the T-DXd arm vs 11 months (range, 5.6-16.0) in the comparator arm.

Patients with untreated/active brain metastases similarly experienced an IC-ORR of 45.5% in the T-DXd arm (n = 44), including 7 CRs and 13 PRs. The IC-ORR was 12.0% in the comparator arm (n = 325) and consisted of 3 PRs. In this group, the median IC-DOR was 17.5 months (range, 13.6-31.6) with T-DXd.

“T-DXd should be considered the SOC for patients with HER2-positive metastatic breast cancer, regardless of [the presence of] brain metastases,” said Cortés, who is the head of the International Breast Cancer Center, and a clinical investigator in the Breast Cancer Research Program at Vall d’Hebron Institute of Oncology in Barcelona, Spain.

In an interview with OncLive^®, Cortés expanded on the importance of investigating the central nervous system (CNS) activity of T-DXd in patients with HER2-positive breast cancer and brain metastases; key efficacy data from the pooled analysis of the agent in DESTINY-Breast01, -02 and -03; and how these data support the inclusion of those with unstable brain metastases in future phase 3 clinical trials.

OncLive: What was the rationale for conducting this pooled analysis of outcomes with T-DXd in patients with HER2-positive breast cancer and brain metastases enrolled in the DESTINY-Breast trials?

Cortés: We all know the activity that T-DXd has in patients with HER2-positive metastatic breast cancer. We also know that, unfortunately, many patients develop brain metastases in the course of the disease. Those with brain metastases have worse outcomes compared with patients without brain metastases. It is important to understand whether T-DXd also works in patients with unstable or stable brain metastases. [To this end,] we tried to explore the [efficacy] and role of T-DXd in patients included in the DESTINY-Breast01, -02, and -03 trials who have brain metastases.

How were patients from these studies selected for the pooled analysis?

Not all patients were enrolled based on the same inclusion and exclusion criteria. DESTINY-Breast01 enrolled patients only with T-DXd and these patients were heavily pretreated. The majority were pretreated with ado-trastuzumab emtansine [Kadcyla; T-DM1]. In DESTINY-Breast02 all patients were previously treated with T-DM1 and were randomized to T-DXd vs physician’s choice of therapy. Lastly, patients in DESTINY-Breast03 were included if they had received previous treatment with a taxane and trastuzumab [Herceptin;] they were randomized to receive T-DXd or T-DM1.

We did a pooled analysis considering all these aspects. In DESTINY-Breast02 and -03, there was a small number of patients with unstable brain metastases. However, in DESTINY-Breast01, only patients with stable brain metastases were included. In DESTINY-Breast02 and -03 there was an amendment, and patients with unstable brain metastases were not allowed to be included afterward. Overall, the majority of patients did have stable metastases, but there were a small number of patients with unstable brain metastases.

What key data from this study were presented at the 2023 ESMO Congress?

We treated 44 patients with unstable or active brain metastases with T-DXd; 25 patients were treated with the SOC. On the one hand, 104 [patients with] stable or treated brain metastases [were treated with T-DXd], and 58 [were treated with] physician’s choice of SOC. The overall response rate in patients with untreated or active brain metastases was 45.5%. In patients with treated/stable brain metastases, the ORR was 45.2%. [This shows that T-DXd had] similar activity in both treated and stable or untreated and active [brain metastases]. In the comparator arm, 27.6% of patients who had treated/stable brain metastases had a response vs 12.0% of patients with untreated/active brain metastases. Clearly, the activity with T-DXd was much higher than [that achieved with] SOC.

Regarding the exploratory CNS-PFS [analysis] in this population, patients with untreated/active brain metastases [experienced a] median PFS of 4.0 months with SOC and 18.5 months with T-DXd; [this translated to] a hazard ratio of 0.1919. This is a small number of patients but highlights the great activity T-DXd had in this population.

What should be known about the safety profile of T-DXd in these patients? How does it compare with what has been reported in patients without brain metastases?

In patients with brain metastases, we did not see any different adverse effects [AEs] from what we observed in the total population. In general, the safety profile was acceptable and manageable. I would like to highlight only the drug-related serious treatment-emergent AEs [TEAEs]; these were reported in 13.0% of patients with brain metastases [treated with T-DXd] compared with 12.4% [of those in the comparator arm]. Any drug-related TEAE was reported in 94.5% of the total population. In the non–brain metastases total population, [the rate of any-grade TEAEs] was 98.9%. In conclusion, there were no significant differences regarding toxicity for patients with or without brain metastases.

What next steps are planned to further investigate the activity of this agent in patients with HER2-positive breast cancer and brain metastases?

T-DXd is a great drug for patients with brain metastases. We have some prospective clinical [trials] exploring the role of T-DXd in patients with brain metastases, such as the [phase 3] DESTINY-Breast12 study [NCT04739761]. Recruitment was completed for that study, and we potentially expect data [to read out in] 2024. This will, in my opinion, reinforce the data we have with T-DXD, and we do not expect [to see] any significant difference.

Ultimately, we should not exclude patients with unstable brain metastases for randomized phase 3 clinical trials. We do have to stratify based on this [feature] for patients because their prognosis is worse, but activities are similar. We now have drugs like T-DXd that are very active for patients with and without brain metastases.

What is your take-home message regarding this research?

This drug is very effective in patients with HER2-positive metastatic breast cancer with both treated and stable brain metastases, as well as untreated or active brain metastases. The safety profile was very similar for patients with or without brain metastases.

Reference

Hurvitz SA, Modi S, Li W, et al. 377O A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINY-Breast (DB) -01, -02, and -03. Ann Oncol. 2023;34(suppl 2):S334-S390. doi:10.1016.j.annonc.2023.09.554

Editor's Note: This interview was conducted prior to the 2023 San Antonio Breast Cancer Symposium.