Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer

Abstract

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.

Interobserver variation in the assessment of HER2 low expression in breast cancer: can we improve by adjusting criteria? An international interobserver study.

“…The precision of HER2 IHC scoring is essential to select BC patients for existing and novel HER2-targeting agents. Since T-DXd showed effectiveness in patients with HER2 low tumors, the necessity to distinguish between no expression versus low HER2 expression are likely to become clinically relevant 11,15 . In this study, there was a decrease in the number of cases scored as HER2 0 from the rst (22.8%) to the second (16.3%) round, which is in line with literature 7,22,25 .…”

“…In ongoing clinical trials, these drugs have demonstrated e cacy and safety against HER2 positive metastatic BC 9,10 . Moreover, due to its favorable drug to antibody ratio and its bystander killing effect, ADCs such as trastuzumab-deruxtecan (T-DXd) have also proved to have a signi cant antitumor action in BCs with a low expression level of HER2 (HER2 low), comprising IHC 1 + and IHC 2 + cases without ampli cation [9][10][11][12][13][14][15] . The Destiny-Breast06 clinical trial is currently evaluating the effect of T-DXd in BC with even lower levels of HER2 expression (IHC > 0, <1+), the so-called HER2 ultralow category.…”

Triple-Negative Breast Cancer: A Review of Current Curative Intent Therapies

“…These include sacituzumab govitecan (an ADC consisting of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2) linked to SN-38, a potent topoisomerase inhibitor) [ 25 ], as well as trastuzumab deruxtecan (an ADC consisting of an antibody targeting the HER-2 receptor linked to another topoisomerase inhibitor, deruxtecan). Recent data showed an impressive efficacy of trastuzumab deruxtecan in previously treated metastatic TNBC with a low expression of HER-2 (defined as 1+ on immunohistochemistry (IHC) or 2+ on IHC with negative in situ hybridization testing) [ 26 ]. A phase III clinical trial of sacituzumab govitecan in patients with high relapse risk after standard neoadjuvant therapy (NCT04595565) is currently recruiting.…”

“…DESTINY-Breast04 [26] 5-FU, 5-fluorouracil; PARP, Poly-adenosine diphosphate-ribose polymerase; SSB, single-strand break; DSB, doublestrand break; AKT, also called Protein kinase B; PD-L1, Programmed death-ligand 1; PD-1, Programmed death 1; MAB, monoclonal antibody; AR, androgen receptor; Trop-2, Human trophoblast cell-surface antigen 2; HER-2, Human epidermal growth factor receptor 2.…”

HER2-low-positive features a distinct subtype in estrogen receptor-positive breast cancer associated with endocrine therapy resistance

“…Regarding the response to different treatments, the NSABP-47 trial showed that breast cancer with HER2-low-positive status did not bene t from adjuvant trastuzumab treatment 14 . In contrast, other clinical trials showed that HER2 targeting antibody-drug conjugate, including trastuzumab deruxtecan (DS-8201) and trastuzumab duocarmazine, could bene t HER2-low-positive breast cancer patients but not patients with HER2-zero breast cancer 5,6,15 . In HR-positive breast cancer receiving neoadjuvant chemotherapy, HER2-low-positive tumors have signi cantly lower pathological complete response (pCR) ratio compared with HER2-zero tumors 9 , suggesting a role of chemotherapy resistance of HER2-low-positive status.…”