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Study design for DESTINY-Breast Respond HER2-low Europe: T-DXd in patients with HER2-low advanced breast cancer.

ABSTRACT: Trastuzumab deruxtecan (T-DXd) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC). Results on T-DXd treatment in HER2-low mBC have so far been limited to clinical trials. DESTINY-Breast Respond HER2-low Europe (NCT05945732) is a multi-center, multi-country, observational, prospective, non-interventional study planning to enroll 1350 patients from 216 sites receiving T-DXd or conventional chemotherapy as their routine clinical care for advanced stage breast cancer in 12 European countries. This non-interventional study will provide real-world insight into T-DXd treatment for HER2-low mBC with data on effectiveness, safety and tolerability, patient-reported outcomes, treatment patterns, geriatric health status and HER2 testing. This will be beneficial for improving guidance to maximize patient treatment benefit.

SUBMITTER: Guarneri V

PROVIDER: S-EPMC11318675 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Study design for DESTINY-Breast Respond HER2-low Europe: T-DXd in patients with HER2-low advanced breast cancer.

Guarneri Valentina V Passos Coelho José Luís JL Duhoux Francois P FP Egle Daniel D García-Sáenz José Ángel JÁ Penault-Llorca Frédérique F Selander Katri K Wildiers Hans H Zaman Khalil K Laeis Petra P Lucerna Markus M Pierga Jean-Yves JY

Future oncology (London, England) 20240409 18

Trastuzumab deruxtecan (T-DXd) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC). Results on T-DXd treatment in HER2-low mBC have so far been limited to clinical trials. DESTINY-Breast Respond HER2-low Europe (NCT05945732) is a multi-center, multi-country, observational, prospective, non-interventional study planning to enroll 1350 patients from 216 sites receiving T-DXd or conventional chemotherapy as their routine clinical care ...[more]

PMID: 38592002

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Project description:BackgroundAmong breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers.MethodsWe conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients.ResultsOf 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events.ConclusionsIn this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).

Project description:BackgroundDisitamab vedotin (DV; RC48-ADC) is an antibody-drug conjugate comprising a human epidermal growth factor receptor 2 (HER2)-directed antibody, linker and monomethyl auristatin E. Preclinical studies have shown that DV demonstrated potent antitumor activity in preclinical models of breast, gastric, and ovarian cancers with different levels of HER2 expression. In this pooled analysis, we report the safety and efficacy of DV in patients with HER2-overexpression and HER2-low advanced breast cancer (ABC).MethodsIn the phase I dose-escalation study (C001 CANCER), HER2-overexpression ABC patients received DV at doses of 0.5-2.5 mg/kg once every two weeks (Q2W) until unacceptable toxicity or progressive disease. The dose range, safety, and pharmacokinetics (PK) were determined. The phase Ib dose-range and expansion study (C003 CANCER) enrolled two cohorts: HER2-overexpression ABC patients receiving DV at doses of 1.5-2.5 mg/kg Q2W, with the recommended phase 2 dose (RP2D) determined, and HER2-low ABC patients receiving DV at doses of 2.0 mg/kg Q2W to explore the efficacy and safety of DV in HER2-low ABC.ResultsTwenty-four patients with HER2-overexpression ABC in C001 CANCER, 46 patients with HER2-overexpression ABC and 66 patients with HER2-low ABC in C003 CANCER were enrolled. At 2.0 mg/kg RP2D Q2W, the confirmed objective response rates were 42.9% (9/21; 95% confidence interval [CI]: 21.8%-66.0%) and 33.3% (22/66; 95% CI: 22.2%-46.0%), with median progression-free survival (PFS) of 5.7 months (95% CI: 5.3-8.4 months) and 5.1 months (95% CI: 4.1-6.6 months) for HER2-overexpression and HER2-low ABC, respectively. Common (≥5%) grade 3 or higher treatment-emergent adverse events included neutrophil count decreased (17.6%), gamma-glutamyl transferase increased (13.2%), asthenia (11.0%), white blood cell count decreased (9.6%), peripheral neuropathy such as hypoesthesia (5.9%) and neurotoxicity (0.7%), and pain (5.9%).ConclusionDV demonstrated promising efficacy in HER2-overexpression and HER2-low ABC, with a favorable safety profile at 2.0 mg/kg Q2W.

Project description:ObjectiveThe clinical efficacy and safety profile of trastuzumab deruxtecan (T-DXd) have been demonstrated in previously treated patients with human epidermal growth factor receptor 2 (HER2)-low advanced breast cancer (BC). It is, however, necessary to evaluate the value of T-DXd considering both its clinical efficacy and its cost, given that it is high. This study aimed to evaluate the cost-effectiveness of T-DXd versus chemotherapy in patients with previously treated HER2-low advanced BC.MethodsWe used a partitioned survival model that included three mutually exclusive health states. The patients in the model were identified based on their clinical characteristics and outcomes from the DESTINY-Breast04. Probabilistic and one-way sensitivity analyses were performed to evaluate the model's robustness. Subgroup analyses were also conducted. The measures included costs, life years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), incremental net health benefits (INHBs), and incremental net monetary benefits (INMBs).ResultsThe ICERs of T-DXd vs. chemotherapy were $83,892/QALY, $82,808/QALY, and $93,358/QALY in all HER2-low advanced BC patients, HER2-positive (HER2+) advanced BC patients and HER2-negative (HER2-) advanced BC patients, respectively. In one-way sensitivity analysis, the cost of T-DXd and hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) were also identified as key drivers. If the price of T-DXd decreased to $17.00/mg, $17.13/mg, and $14.07/mg, it would be cost-effective at a willingness to pay (WTP) threshold of $50,000/QALY in all HER2-low advanced BC patients, HER2+ advanced BC patients and HER2- advanced BC patients, respectively. At a WTP threshold of $100,000/QALY, the probability of T-DXd being cost-effective was 81.10%, 82.27%, and 73.78% compared to chemotherapy for all HER2-low advanced BC patients, HER2+ advanced BC patients and HER2- advanced BC patients, respectively. Most subgroups of patients with HER2+ disease had a cost-effectiveness probability of > 50%.ConclusionFrom a third-party payer's perspective in the United States, the findings of the cost-effectiveness analysis revealed that, at the current price, T-DXd is a cost-effective alternative to chemotherapy for patients with prior HER2-low advanced BC, at WTP threshold of $100,000/QALY.

Project description:ObjectiveLimited real-world efficacy and safety data exist regarding the use of trastuzumab deruxtecan (T-DXd) in the Chinese population with human epidermal growth factor receptor (HER2)-positive and HER2-low advanced breast cancer (BC). This multicenter, observational, real-world study aimed to evaluate the efficacy and safety of T-DXd for the treatment of Chinese patients with HER2-positive and HER2-low advanced BC.MethodsThe medical records of 61 patients were collected from The Second Hospital of Dalian Medical University, Beijing Chaoyang District Sanhuan Cancer Hospital, Beijing Jingxin Hospital, and Cancer Hospital of the Chinese Academy of Medical Sciences. The primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), time to response (TTR), and safety. PFS and OS were analyzed using the Kaplan-Meier method and log-rank test.ResultsThe primary endpoint, PFS was 10.51 months (95% confidence interval (CI), 3.02-NE) in the HER2-low group and 10.18 months (95% CI, 3.88-NE) in the HER2-positive group. Regarding the secondary endpoints in the HER2-low and HER2-positive groups, OS data were immature, ORR rates were 37.93% and 62.50%, DCR rates were 79.31% and 87.50%, and the median TTR rates were 1.28 and 1.31 months, respectively. In the subgroup analysis, front-line treatment with T-DXd was associated with increased beneficial effects. The primary adverse events (AEs) related to T-DXd treatment were gastrointestinal reactions and bone marrow suppression, which were predominantly grades 1-2, with no severe grade 4/5 AEs reported, only one patient developed infectious pneumonia.ConclusionThis study was the first multicenter, real-world study of T-DXd for advanced BC in China. The findings demonstrated that T-DXd may be an effective antitumor treatment with controllable adverse reactions in patients with advanced BC irrespective of HER2 expression levels.

Dataset Information

Study design for DESTINY-Breast Respond HER2-low Europe: T-DXd in patients with HER2-low advanced breast cancer.

Publications

Study design for DESTINY-Breast Respond HER2-low Europe: T-DXd in patients with HER2-low advanced breast cancer.

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