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Exploring DESTINY: the Past, Present, and Future of Trastuzumab Deruxtecan

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Azka Ali
Azka Ali
Azka Ali
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Stephanie L. Graff
Stephanie L. Graff
Stephanie L. Graff
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Purpose of Review HER2-positive breast cancer accounts for 10–15% of all breast cancers and fam-trastuzumab deruxtecan (T-DXd) has played a major role in moving the treatment of HER2-expressing disease forward. Recent Findings T-DXd is a novel antibody–drug conjugate (ADC) composed of a humanized IgG1 monoclonal antibody against HER2 receptor bound to a potent topoisomerase I cytotoxin payload by a cleavable peptide linker. It has been shown to have robust preclinical activity in pretreated cancer cell lines, as well as meaningful clinical activity in advanced HER2-expressing breast cancer. Recent studies have demonstrated T-DXd as an active agent for metastatic HER2-positive patients, and as a viable additional line for heavily pretreated patients with HER2-low disease. The toxicity of T-DXd remains manageable and burden of side effects seems to be lower when offered as an earlier line of therapy over the course of treatment. Summary In this review, we discuss the pharmacology of T-DXd, review pertinent preclinical and clinical data, and address potential challenges and future directions related to the use of T-DXd in clinical practice.
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Vol.:(0123456789)
1 3
Current Oncology Reports (2024) 26:1–9
https://doi.org/10.1007/s11912-023-01478-2
Exploring DESTINY: thePast, Present, andFuture ofTrastuzumab
Deruxtecan
AzkaAli1 · StephanieL.Gra2
Accepted: 29 October 2023 / Published online: 13 December 2023
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023
Abstract
Purpose of Review HER2-positive breast cancer accounts for 10–15% of all breast cancers and fam-trastuzumab deruxtecan
(T-DXd) has played a major role in moving the treatment of HER2-expressing disease forward.
Recent Findings T-DXd is a novel antibody–drug conjugate (ADC) composed of a humanized IgG1 monoclonal antibody
against HER2 receptor bound to a potent topoisomerase I cytotoxin payload by a cleavable peptide linker. It has been shown
to have robust preclinical activity in pretreated cancer cell lines, as well as meaningful clinical activity in advanced HER2-
expressing breast cancer. Recent studies have demonstrated T-DXd as an active agent for metastatic HER2-positive patients,
and as a viable additional line for heavily pretreated patients with HER2-low disease. The toxicity of T-DXd remains man-
ageable and burden of side effects seems to be lower when offered as an earlier line of therapy over the course of treatment.
Summary In this review, we discuss the pharmacology of T-DXd, review pertinent preclinical and clinical data, and address
potential challenges and future directions related to the use of T-DXd in clinical practice.
Keywords Breast cancer· HER2-positive· HER2-low· Metastatic breast cancer· Fam-traztuzumab deruxtecan, Antibody
drug conjugate· DESTINY Breast
Introduction
Human epidermal growth factor receptor-2 (HER2) directed
therapies have greatly improved the prognosis of HER2-
positive breast cancer in the early and metastatic settings
[1]. Several classes of anti-HER2 drugs have shown clini-
cal activity and been approved for the treatment of breast
cancer including anti-HER2 monoclonal antibodies (mAb),
HER2-targeted tyrosine kinase inhibitors, and antibody drug
conjugates (ADC) [1].
Fam-trastuzumab deruxtecan (T-DXd, or DS-8201a) is an
ADC, which is composed of a humanized immunoglobulin
G1 monoclonal antibody targeting HER2 followed by a
cleavable peptide linker bound to a derivative of DX-8951
(DXd), a potent topoisomerase I inhibitor payload [1–3].
Lysosomal enzymes such as cathepsins B and L cleave the
antibody and linker-payload, and anti-HER2 antibody binds
the HER2 receptor expressed on tumor cells, and membrane-
permeable payload is released after internalization of the
HER2-ADC complex [3].
Since the first introduction into phase I trials in 2015,
T-DXd has been studied as treatment of several HER2-
expressing cancers including HER2-positive and HER2-low
breast cancer, HER2-positive gastric cancer, HER2-express-
ing colorectal cancer, and HER2-expressing or mutated non-
small cell lung cancer [2].
In this review, we discuss development and unique phar-
macokinetics of T-DXd, review pertinent preclinical and
clinical data on T-DXd in breast cancer patients, address
pertinent adverse events (AEs) and management, and future
direction of research of T-DXd in relation to breast cancer.
* Azka Ali
alia22@ccf.og
Stephanie L. Graff
SGraff1@Lifespan.org
1 Department ofBreast Medical Oncology, Cleveland Clinic
Foundation, Taussig Cancer Institute, 9500 Euclid Ave /
CA-060, Cleveland, OH44195, USA
2 Division ofHematology & Medical Oncology, Lifespan
Cancer Institute, Legorreta Cancer Center atBrown
University, 593 Eddy St., Providence, RI02903, USA
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study
Article
  • May 2023
  • ANN ONCOL
Background: In the DESTINY-Breast03 clinical trial, trastuzumab deruxtecan (T-DXd) showed superior progression-free survival and overall survival versus trastuzumab emtansine (T-DM1) and manageable safety in patients with HER2-positive (HER2+) metastatic breast cancer (mBC). Here, patient-reported outcomes (PROs) are reported along with hospitalization data. Patients and methods: Patients in DESTINY-Breast03 were assessed for prespecified PRO measures, including European Organization for Research and Treatment of Cancer quality of life (EORTC-QoL) questionnaires (the oncology-specific EORTC QLQ-C30 and breast cancer-specific EORTC QLQ-BR45) and the generic EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) visual analogue scale (VAS). Analyses included change from baseline (CFB), time to definitive deterioration (TDD), and hospitalization-related endpoints. Results: EORTC QLQ-C30 baseline global health status (GHS) scores for T-DXd (n = 253) and T-DM1 (n = 260) were similar, with no clinically meaningful change (<10-point CFB) while on either treatment (median treatment duration: T-DXd, 14.3 months; T-DM1, 6.9 months). TDD analyses of QLQ-C30 GHS (primary PRO variable) and all other prespecified PROs (QLQ-C30 subscales, the QLQ-BR45 arm symptoms scale, and the EQ-5D-5L VAS) suggested T-DXd was numerically favored over T-DM1 based on TDD hazard ratios. Of all randomized patients, 18 (6.9%) receiving T-DXd versus 19 (7.2%) receiving T-DM1 were hospitalized, and the median time to first hospitalization was 219.5 versus 60.0 days, respectively. Conclusions: In DESTINY-Breast03, EORTC GHS/QoL was maintained on both therapies throughout treatment, indicating that despite the longer treatment duration with T-DXd versus T-DM1, HRQoL did not worsen on T-DXd. Furthermore, TDD hazard ratios numerically favored T-DXd over T-DM1 in all prespecified variables of interest including pain, suggesting T-DXd may delay time until HRQoL deterioration compared with T-DM1. Median time to first hospitalization was three times longer with T-DXd versus T-DM1. Together with reported improved efficacy and manageable toxicity, these results support the overall benefit of T-DXd for patients with HER2+ mBC.
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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
Article
  • Apr 2023
  • LANCET
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.
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