Trastuzumab Deruxtecan Maintains PFS Benefit Across Subgroups in HER2+ Metastatic Breast Cancer

Sara Hurvitz, MD

A subgroup analysis of the phase 3 DESTINY-Breast03 trial (NCT03529110) confirmed superiority of fam-trastuzumab deruxtecan-nxki (Enhertu) vs ado-trastuzumab emtansine (Kadcyla; T-DM1) in all subgroups, according to Sara Hurvitz, MD.

As initially reported at ESMO 2021, DESTINY-Breast03 improved progression-free survival (PFS) over T-DM1 in patients with previously treated HER2-positive metastatic breast cancer. In this subgroup analysis, investigators examined outcomes based on hormone receptor status (positive vs negative), prior pertuzumab treatment (yes vs no), visceral disease (yes vs no), prior lines of therapy (0-1 vs ≥2), and patients with brain metastases (yes vs no).¹

“These data indicated the trastuzumab deruxtecan has a consistent PFS benefit compared to T-DM1 after treatment with trastuzumab and taxane. [The drug] yields high ORRs [overall response rates] and shows intriguing intracranial efficacy for patients with stable brain metastases at baseline,” Hurvitz said. “These data do support the use of trastuzumab deruxtecan in the second-line setting and beyond and moving T-DM1 out of that that space.”

In an interview with OncLive®, Hurvitz, director of the Breast Cancer Clinical Research Program, co-director of the Santa Monica UCLA Outpatient Hematology/Oncology Practice, and associate professor of medicine in the Division of Hematology/Oncology at the David Geffen School of Medicine at UCLA, discussed the findings from the subgroup analysis of the DESTINY-Breast03 trial, and future research directions for trastuzumab deruxtecan.

OncLive®: What was the rationale behind DESTINY-Breast03? Could you provide any background information that will set the stage for the subgroup analyses?

Hurvitz: The DESTINY-Breast03 trial is a study evaluating trastuzumab deruxtecan vs T-DM1. Trastuzumab deruxtecan was evaluated in a single-arm, phase 2 clinical trial in [patients with] heavily pretreated HER2-positive metastatic breast cancer, called the DESTINY-Breast01 study [NCT03248492]. That trial demonstrated significant ORR of over 60% and a long PFS of over 19 months, which is unheard of in patients who had been so heavily pretreated.

Given those promising phase 2, single-arm data, the FDA did approve [trastuzumab deruxtecan] in 2019 for those with heavily pretreated HER2-positive metastatic disease. To date, however, there was no randomized clinical trial, until 2021, comparing trastuzumab deruxtecan to a standard-of-care therapy. At ESMO in 2021, the DESTINY-Breast03 clinical trial was first presented as an interim analysis, [in which] trastuzumab deruxtecan was compared with T-DM1, a different antibody-drug conjugate, in patients who had received at least 1 prior line of trastuzumab (Herceptin)- or taxane-based therapy and had experienced disease progression. It was a phase 3 randomized clinical trial, [and enrolled] over 500 patients. This study was aimed to compare the PFS of the 2 drugs, and to look at overall survival [OS] and several secondary endpoints.

What was evaluated in the subgroup analyses? What was the design and which patients were included?

The PFS was first presented at ESMO 2021. It was demonstrated that trastuzumab deruxtecan was associated with a significant improvement, with a hazard ratio of 0.28, which is almost unheard of. In my memory, I can't remember a hazard ratio like that in breast cancer. The median PFS had not been met for trastuzumab deruxtecan and was approximately 6.8 months for T-DM1.

[Several] questions then came up, [including] whether any subgroups within the trial may benefit from the use of trastuzumab deruxtecan compared with T-DM1. [Therefore], at this analysis, we looked at outcomes based on whether patients had hormone receptor-coexpression of their tumor, whether they had previously received pertuzumab [Perjeta] treatment, whether they had visceral disease, and whether they had received 0 or 1 prior lines of therapy or 2 or more prior lines of therapy. Also, we wanted to look at the population of patients who had stable brain metastases at [baseline]. No matter how you looked at it, trastuzumab deruxtecan was associated with an improved PFS as well as improved ORR in all those subgroups compared with T-DM1.

We then did a deep dive into how trastuzumab deruxtecan worked compared with T-DM1 in patients who had baseline brain metastases. Interestingly, in those patients who had baseline brain metastases, the median PFS with trastuzumab deruxtecan was approximately 15 months vs only 3 months with T-DM1. Moreover, when we looked at what was happening inside the brain for those patients who came on study with brain metastases at baseline, the intracranial ORR associated with trastuzumab deruxtecan was 63%, and with T-DM1 it was only 34%. [As such], the intracranial responses [are] quite dramatic with trastuzumab deruxtecan in this clinical trial, which are notable.

Did you observe anything surprising regarding the safety profile of trastuzumab deruxtecan?

The safety profile looked similar compared [with] what was previously reported at ESMO in 2021. We did do another look at interstitial lung disease [ILD], and the rates of ILD in the non-Asian group vs the Asian group because sometimes [patients who are] Asian will have differing rates of toxicity with agents. In fact, the rates of ILD remained about 10.5% in the overall patient population with no grade 4 or 5 events, and no differences in rates of ILD [in] the Asian vs non-Asian subgroups.

Are there any next steps planned to be on the lookout for?

I am excited to see the data from the DESTINY-Breast02 clinical trial [NCT03523585] looking at trastuzumab deruxtecan vs lapatinib (Tykerb) or trastuzumab plus capecitabine, which is a confirmatory trial of DESTINY-Breast01 in more heavily pretreated patients. [I’m] also looking forward to seeing trastuzumab deruxtecan being evaluated in the first-line setting and in patients with active brain metastases.

Reference

1. Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. San Antonio, TX. Abstract GS3-01.