Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer
Authors
Shanu Modi ; William Jacot ; Toshinari Yamashita ; Joohyuk Sohn ; Maria Vidal ; Eriko Tokunaga ; Junji Tsurutani ; Naoto T Ueno ; Aleix Prat ; Yee Soo Chae ; Keun Seok Lee ; Naoki Niikura ; Yeon Hee Park ; Binghe Xu ; Xiaojia Wang ; Miguel Gil-Gil ; Wei Li ; Jean-Yves Pierga ; Seock-Ah Im ; Halle C F Moore ; Hope S Rugo ; Rinat Yerushalmi ; Flora Zagouri ; Andrea Gombos ; Sung-Bae Kim ; Qiang Liu ; Ting Luo ; Cristina Saura ; Peter Schmid ; Tao Sun ; Dhiraj Gambhire ; Lotus Yung ; Yibin Wang ; Jasmeet Singh ; Patrik Vitazka ; Gerold Meinhardt ; Nadia Harbeck ; David A Cameron ; DESTINY-Breast04 Trial Investigators
Citation
NEW ENGLAND JOURNAL OF MEDICINE, Vol.387(1) : 9-20, 2022-07
Background: Among 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.
Methods: We 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.
Results: Of 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.
Conclusions: In 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.).