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

Messaggi chiave

• DESTINY-Breast02 è uno studio multicentrico di fase III, randomizzato, in aperto, che ha precedentemente dimostrato un beneficio significativo in sopravvivenza libera da progressione e sopravvivenza globale con trastuzumab deruxtecan rispetto alla terapia a scelta del medico in pazienti con carcinoma mammario metastatico HER2+ in progressione a T-DM1. In questa sede, si riportano i dati relativi agli esiti riferiti dai pazienti (PRO).
• La durata mediana del trattamento è stata di 11,3 vs 4,5 mesi nel braccio sperimentale rispetto ai controlli. In entrambi i bracci, non sono state osservate variazioni significative nel tempo nella variabile PRO primaria di interesse, lo stato di salute globale (GHS) secondo EORTC QLQ-C30. D’altra parte, trastuzumab deruxtecan rispetto alla terapia di confronto ha ritardato il tempo mediano al deterioramento definitivo sia per GHS (14,1 vs 5,9 mesi; HR 0,5573 [IC 95%, 0,4376-0,7099], p <0,0001) sia per tutte le altre variabili PRO considerate.
• Malgrado tassi di ricovero simili nei due bracci, il tempo mediano al ricovero è risultato di quasi 2 mesi più lungo nei pazienti trattati con trastuzumab deruxtecan (133 vs 83 giorni). Nel complesso, questi dati suggeriscono l’assenza di qualsiasi impatto negativo del trattamento sperimentale sulla qualità della vita correlata alla salute e, considerati insieme agli esiti di efficacia e sicurezza dello studio, supportano il beneficio di trastuzumab deruxtecan nella popolazione dello studio.

Abstract

Background

• In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician’s choice.
• We present the patient-reported outcomes (PROs) and hospitalisation data.

Methods

• In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1.
• Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5.4 mg/kg intravenously once every 21 days) or treatment of physician’s choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment.
• 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, which was progression-free survival based on blinded independent central review, has previously been reported.
• PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints.
• This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment.

Findings

• Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n = 406; two did not receive treatment) or treatment of physician’s choice (n = 202; seven did not receive treatment).
• Overall, 603 patients (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 (IQR 8.8-26.0) in the treatment of physician’s choice group.
• Median treatment duration was 11.3 months (IQR 6.2-20.5) in the trastuzumab deruxtecan group and approximately 4.5 months in the treatment of physician’s choice group (4.4 months [IQR 2.5-8.7] with trastuzumab; 4.6 months [2.1-8.9] with capecitabine; and 4.5 months [2.1-10.6] with lapatinib).
• Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n = 393) and treatment of physician’s choice (n = 187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time.
• Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician’s choice for the primary PRO variable EORTC QLQ-C30 GHS (14.1 months [95% CI 10.4-18.7] vs 5.9 months [4.3-7.9]; HR 0.5573 [0.4376-0.7099], p<0.0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale).
• Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician’s choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56-237) with trastuzumab deruxtecan versus 83 days (30-152) with treatment of physician’s choice.

Interpretation

• Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician’s choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan.
• When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine.