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Favourable Benefit-Risk Profile of Trastuzumab Deruxtecan in Patients with HER2-positive MBC Who were Previously Treated with Trastuzumab Emtansine

Findings from the DESTINY-Breast02 study
10 May 2023
Targeted Therapy;  Cytotoxic Therapy
Breast Cancer

Results from DESTINY-Breast02 show the favourable benefit-risk profile of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer (MBC) resistant or refractory to trastuzumab emtansine and support this drug as the preferred treatment for patients who previously received trastuzumab emtansine. At 18 months from random assignment of the last patient, the study team observed a 10.9-month improvement in median progression-free survival (PFS) by blinded independent central review with trastuzumab deruxtecan compared with treatment of physician's choice.

This is the first randomised study to show that one antibody-drug conjugate can overcome resistance to a previous one. The findings are reported by Dr. Ian Krop of the Yale Cancer Center in New Haven, CT, US, and colleagues on 19 April 2023 in The Lancet.

Although HER2-targeted treatment has improved survival outcomes, most patients have disease progression due to acquired resistance and as a result, HER2-positive MBC remains incurable. Therefore, new, and effective treatment options are needed in this setting. First-line treatment options include pertuzumab and trastuzumab in combination with a taxane. The antibody-drug conjugate trastuzumab emtansine has been approved as second-line treatment for patients with HER2-positive MBC based on the results from the EMILIA study.

In later lines of treatment after trastuzumab emtansine, the standard of care for patients with HER2-positive MBC has not been well defined. When DESTINY-Breast02 was initiated, available treatment options after trastuzumab emtansine included lapatinib with capecitabine, trastuzumab with capecitabine, or trastuzumab with other single-agent chemotherapy. These regimens have shown low objective response rates and short PFS.

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. Trastuzumab deruxtecan showed robust activity in the phase II, single-arm, DESTINY-Breast01 study conducted in heavily pretreated patients with HER2-positive breast cancer who previously received trastuzumab emtansine, reaching objective response rates of 61% by independent central review and a median PFS of 16.4 months. Updated results from DESTINY-Breast01 have continued to show sustained efficacy of trastuzumab deruxtecan after trastuzumab emtansine, with patients reaching a median PFS of 19.4 months, median overall survival of 29.1 months, and objective response rates of 62%.

DESTINY-Breast02 was designed as a confirmatory study for DESTINY-Breast01. The study team aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in patients with HER2-positive MBC which is resistant or refractory to trastuzumab emtansine. This randomised, open-label, multicentre, phase III study was conducted at 227 sites in North America, Europe, Asia, Australia, Brazil, Israel, and Türkiye. Eligible patients were aged 18 years or older, had unresectable or HER2-positive MBC, previously received trastuzumab emtansine, disease progression, an ECOG 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 PFS based on blinded independent central review in the full analysis set.

Between 6 September 2018 and 31 December 2020, 608 patients were randomly assigned to receive trastuzumab deruxtecan (406 patients of whom 2 did not receive treatment) or treatment of physician's choice (202 patients of whom 7 did not receive treatment). A total, 608 patients (100%) were included in the full analysis set. The median age was 54.2 years in the trastuzumab deruxtecan group and 54.7 years in the treatment of physician's choice group. In total, 384 patients (63%) were White, 603 (99%) were female, and 5 (<1%) were male.

The median follow-up was 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the treatment of physician's choice group. Median PFS by blinded independent central review was 17.8 months (95% confidence interval [CI] 14.3–20.8) in the trastuzumab deruxtecan group versus 6.9 months in the treatment of physician's choice group (hazard ratio 0.36 [0.28–0.45]; p < 0.0001).

Overall efficacy results in the treatment of physician's choice group were consistent with or better than those observed in previous studies that used similar chemotherapy regimens, whereas the longer PFS with trastuzumab deruxtecan was a statistically significant and clinically meaningful improvement versus treatment of physician's choice. Consistent PFS benefit with trastuzumab deruxtecan versus treatment of physician's choice was shown across all prespecified subgroups, including by randomisation stratification factors (hormone receptor status, previous treatment with pertuzumab, and history of visceral disease) and presence of baseline brain metastases.

The most common treatment-emergent adverse events were nausea in 293 of 404 patients (73%) with trastuzumab deruxtecan versus 73 of 195 patients (37%) with treatment of physician's choice, vomiting in 152 patients (38%) versus 25 (13%), alopecia in 150 (37%) versus 8 (4%), fatigue in 147 (36%) versus 52 (27%), diarrhoea in 109 (27%) versus 105 (54%), and palmar–plantar erythrodysaesthesia in 7 (2%) versus 100 (51%). Grade 3 or higher treatment-emergent adverse events occurred in 213 patients (53%) 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 1 (<1%).

The authors commented that one limitation of the study was the exclusion of patients with symptomatic or clinically active brain metastases. Another limitation is that the treatment of physician's choice group was restricted to capecitabine plus either trastuzumab or lapatinib, although many combination strategies with other chemotherapy agents and HER2-directed drugs approved within the past few years are now used as later lines of treatment for patients with HER2-positive MBC. Capecitabine was chosen because capecitabine-containing regimens are the most prescribed in this setting; however, the results with trastuzumab deruxtecan cannot be directly compared with regimens containing chemotherapy agents other than capecitabine or with other HER2-directed agents.

Before trastuzumab deruxtecan was approved as a second-line treatment option for patients with HER2-positive MBC, trastuzumab emtansine was the guideline-recommended treatment in this setting. Currently, trastuzumab deruxtecan is the recommended second-line treatment for these patients based on efficacy and safety results from DESTINY-Breast03.

In an accompanied editorial article, Dr. Saranya Chumsri of the Division of Hematology and Medical Oncology, Mayo Clinic in Jacksonville, FL, US wrote that the DESTINY Breast-02 study showed robust activity of trastuzumab deruxtecan in patients with HER2-positive MBC who previously received trastuzumab emtansine. Trastuzumab deruxtecan had more side effects than the previous generation of antibody-drug conjugates, such as trastuzumab emtansine, with 58 patients (14%) discontinuing treatment due to treatment-emergent adverse events.

A substantial number of patients received antiemetics during the study, and the protocol was subsequently amended to include prophylactic antiemetic treatment before trastuzumab deruxtecan. There were numerically more patients with left ventricular dysfunction in the trastuzumab deruxtecan group than in the treatment of physician’s choice group. Nevertheless, the treatment discontinuation rate due to left ventricular dysfunction was less than 1% in both groups.

Another key side effect of trastuzumab deruxtecan is interstitial lung disease and there were 2 grade 5 treatment-related deaths due to interstitial lung disease. Thus, following the established guidelines on managing interstitial lung disease is imperative in patients receiving this drug with early implementation of corticosteroids and permanent discontinuation if interstitial lung disease of grade 2 or higher occurs. Patients should be followed-up for an extended period because the median time to onset of interstitial lung disease was more than 6 months after the initiation of trastuzumab deruxtecan.

Further research is ongoing to expand the benefit of this treatment in patients with low HER2 expression and in earlier disease settings.

The study was funded by Daiichi Sankyo and AstraZeneca 


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