Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial

Summary

Background

In the single-arm, phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan showed robust activity in patients with HER2-positive metastatic breast cancer who were refractory or resistant to trastuzumab emtansine; a population with scarce effective treatments. In DESTINY-Breast02, we aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in this patient population.

Methods

This randomised, open-label, multicentre, phase 3 trial was conducted at 227 sites (hospitals, university hospitals, clinics, community centres, and private oncology centres) in North America, Europe, Asia, Australia, Brazil, Israel, and Türkiye. Eligible patients were aged 18 years or older, had unresectable or HER2-positive metastatic breast cancer, previously received trastuzumab emtansine, disease progression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate renal and hepatic function. Patients were randomly assigned (2:1) to receive trastuzumab deruxtecan (intravenously at 5·4 mg/kg once every 3 weeks) or treatment of physician's choice using block randomisation. Treatment of physician's choice was either capecitabine (1250 mg/m²; orally twice per day on days 1–14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m²) plus lapatinib (1250 mg orally once per day on days 1–21), with a 21-day schedule. The primary endpoint was progression-free survival based on blinded independent central review in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03523585.

Findings

Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). 608 (100%) patients were included in the full analysis set. The median age was 54·2 years (IQR 45·5–63·4) in the trastuzumab deruxtecan group and 54·7 years (48·0–63·0) in the treatment of physician's choice group. 384 (63%) patients were White, 603 (99%) were female, and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2–28·4) in the trastuzumab deruxtecan group and 18·6 months (8·8–26·0) in the treatment of physician's choice group. Median progression-free survival by blinded independent central review was 17·8 months (95% CI 14·3–20·8) in the trastuzumab deruxtecan group versus 6·9 months (5·5–8·4) in the treatment of physician's choice group (HR 0·36 [0·28–0·45]; p<0·0001). The most common treatment-emergent adverse events were nausea (293 [73%] of 404 with trastuzumab deruxtecan vs 73 [37%] of 195 with treatment of physician's choice), vomiting (152 [38%] vs 25 [13%]), alopecia (150 [37%] vs eight [4%]), fatigue (147 [36%] vs 52 [27%]), diarrhoea (109 [27%] vs 105 [54%]), and palmar–plantar erythrodysaesthesia (seven [2%] vs 100 [51%]). Grade 3 or higher treatment-emergent adverse events occurred in 213 (53%) patients receiving trastuzumab deruxtecan versus 86 (44%) receiving treatment of physician's choice; whereas drug-related interstitial lung disease occurred in 42 (10%; including two grade 5 death events) versus one (<1%).

Interpretation

DESTINY-Breast02 shows the favourable benefit–risk profile of trastuzumab deruxtecan in patients with HER2 positive metastatic breast cancer, as previously reported in DESTINY-Breast01, and is the first randomised study to show that one antibody-drug conjugate can overcome resistance to a previous one.

Funding

Daiichi Sankyo and AstraZeneca.

Introduction

Approximately 15–20% of patients with breast cancer are diagnosed with tumours characterised by overexpression of HER2 (also known as ERBB2).¹ Although HER2-targeted therapies have improved survival outcomes in this patient population, most patients have disease progression due to acquired resistance.2, 3 As a result, HER2-positive metastatic breast cancer remains incurable and therefore new and effective treatment options are needed in this setting.⁴ First-line treatment options include pertuzumab and trastuzumab in combination with a taxane.5, 6, 7 The antibody-drug conjugate trastuzumab emtansine has been approved as second-line treatment for patients with HER2-positive metastatic breast cancer on the basis of results from the EMILIA trial.8, 9

Research in context

Evidence before this study

We searched PubMed for articles published from Nov 9, 2017, to Nov 9, 2022, using the search terms “HER2-targeted therapy”, “HER2-positive”, “breast cancer”, “prior or previous trastuzumab emtansine”, “second-line”, and “third-line”. This search was limited to English language publications. We wanted to identify articles discussing HER2-targeted therapies for patients with HER2 positive metastatic breast cancer whose disease has progressed after two or more HER2-targeted regimens, including trastuzumab emtansine. Results from the CLEOPATRA trial formed the basis for the current standard first-line recommendation for patients with advanced HER2-positive metastatic breast cancer—namely, a regimen of anti-HER2 monoclonal antibodies (trastuzumab plus pertuzumab) combined with a taxane. The anti-HER2 antibody-drug conjugate trastuzumab emtansine was recommended for second-line treatment based on the EMILIA study. The single-arm, phase 2, DESTINY-Breast01 trial reported robust antitumour activity with the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan in patients who previously received trastuzumab emtansine, serving as the basis for accelerated approval in the third-line setting in 2019. The phase 3, DESTINY-Breast02 trial was designed to validate preliminary data reported in DESTINY-Breast01 and assess superiority of trastuzumab deruxtecan over treatment of physician's choice in patients with HER2-positive metastatic breast cancer who previously received trastuzumab emtansine. DESTINY-Breast02 is complementary to DESTINY-Breast03, which first reported superiority of trastuzumab deruxtecan over trastuzumab emtansine in 2021.

Added value of this study

To our knowledge, this study is the first phase 3 trial investigating a HER2-directed agent after patients have received trastuzumab emtansine. We show that trastuzumab deruxtecan is superior to conventional chemotherapy-based treatment options plus HER2-targeted agents in patients with HER2 positive metastatic breast cancer that is resistant or refractory to trastuzumab emtansine. Patients with HER2-positive metastatic breast cancer living in many countries where trastuzumab deruxtecan is not approved or wherein the indication varies have limited access to trastuzumab deruxtecan as a second-line therapy option. Additionally, based on the KATHERINE trial, most patients with residual breast cancer have previously received post-neoadjuvant trastuzumab emtansine because this drug is widely accepted as standard of care. Although access might still be limited with later lines of therapy, our study addresses the efficacy and safety of trastuzumab deruxtecan in patients with more advanced disease after trastuzumab emtansine treatment. We also showed the manageable safety of trastuzumab deruxtecan after two or more HER2-targeted regimens.

Implications of all the available evidence

The results of this trial support the clinical significance of using trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer and, to our knowledge, report for the first time in a randomised trial that an antibody-drug conjugate can overcome the resistance acquired to another antibody-drug conjugate. Considering that some patients might still receive trastuzumab emtansine in the second-line setting, this finding is clinically relevant. Trastuzumab deruxtecan has a superior benefit–risk ratio over conventional chemotherapy-based combinations with HER2-targeting agents. Further investigation on the real-world implication of using trastuzumab deruxtecan after trastuzumab emtansine, and the optimal treatment sequencing of antibody-drug conjugates are warranted.

In later lines of therapy after trastuzumab emtansine, the standard of care for patients with HER2-positive metastatic breast cancer has not been well defined.⁹ When this trial, DESTINY-Breast02, was initiated, available treatment options after trastuzumab emtansine included lapatinib with capecitabine, trastuzumab with capecitabine, or trastuzumab with other single-agent chemotherapy. Because these regimens have shown low objective response rates (approximately 9–27%) and short progression-free survival (median 3·3–6·1 months), more effective treatment options are needed for this patient population.10, 11, 12, 13

Trastuzumab deruxtecan is an antibody-drug conjugate consisting of a humanised monoclonal anti-HER2 antibody bound to a cytotoxic topoisomerase I inhibitor by a cleavable linker.14, 15, 16 Trastuzumab deruxtecan showed robust activity in the phase 2, single-arm, DESTINY-Breast01 trial¹⁷ conducted in heavily pretreated patients with HER2-positive breast cancer who previously received trastuzumab emtansine, reaching objective response rates of 61% (95% CI 53–68; 112 of 184 patients) by independent central review and a median progression-free survival of 16·4 months (12·7–not estimable [NE]). These results led to accelerated approval of trastuzumab deruxtecan for patients with HER2-positive metastatic breast cancer who received at least two previous anti-HER2 antibody-based regimens.¹⁷ Updated results from DESTINY-Breast01 have continued to show sustained efficacy of trastuzumab deruxtecan after trastuzumab emtansine, with patients reaching a median progression-free survival of 19·4 months (14·1–25·0), median overall survival of 29·1 months (24·6–36·1), and objective response rates of 62% (55–69; 114 of 184 patients).¹⁸

DESTINY-Breast02 was designed as a confirmatory trial for DESTINY-Breast01. We aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in patients with HER2 positive metastatic breast cancer which is resistant or refractory to trastuzumab emtansine.