Neoadjuvant trastuzumab deruxtecan shows clinical activity in patients with HER2-low breast cancer
Results from the phase II TRIO-US B-12 TALENT trial demonstrated preliminary evidence of neoadjuvant clinical activity of trastuzumab deruxtecan (T-DXd) in HER2-low, HR+ localised breast cancer. With T-DXd, an overall response rate of 68% was achieved. The addition of endocrine therapy to T-DXd did not appear to enhance efficacy.
Although patients with hormone receptor-positive (HR+)/HER2-negative breast cancer (BC) frequently experience disease response to neoadjuvant therapy, fewer than 10% achieve a pathologic complete response (pCR) with standard chemotherapy or endocrine therapy, even in combination with CDK4/6 inhibitors. Thus, finding more effective therapies for this disease remains an unmet need. HER2 is expressed at a low level (IHC 1+ or 2+) in approximately 60-70% of HR+ BC. Trastuzumab deruxtecan (T-DXd) is a novel HER2-targeting antibody drug conjugate (ADC) that has demonstrated impressive efficacy in metastatic HER2-low BC. However, efficacy in localised HER2-low BC is not known. The primary objective of TALENT (TRIO-US B-12) is to evaluate the clinical activity and safety of neoadjuvant T-DXd alone or in combination with endocrine therapy in patients with HR+/HER2-low early BC.
Study design
Men and women with previously untreated, operable invasive early stage, non-recurrent, HR+, HER2-low (IHC 1+ or 2+/ISH- by local or central review) breast cancer measuring > 2 cm were eligible. In stage 1 of the clinical trial, participants were randomised 1:1 to receive T-DXd (5.4 mg/kg IV q21 days) alone, Arm A, or in combination with anastrozole (1 mg PO QD), Arm B. Originally, 6 cycles of treatment were given but in 02/2022, an amendment increased the number of treatment cycles from 6 to 8. Men and pre/peri-menopausal women randomised to Arm B also received a GnRH agonist. Stratification factors were HER2 expression (1+ vs. 2+) and menopausal status (men as postmenopausal). Tumour tissue was collected at baseline, cycle 1 day 17-21, and at surgery. Breast imaging was performed at baseline, cycle 2 and pre-surgery/EOT. Primary endpoint is pCR rate (ypT0/is ypN0) at surgery. In stage 1, the intent was to randomise 58 patients (if at least 2 pCR occurred in an arm, arm progresses to Stage 2 and an additional 15 patients to be enrolled).
Results
In stage 1 of the trial, 58 patients were enrolled and treated (29 in arm A and 29 in arm B). Seven patients came off study before completing protocol-specified therapy, one of them had disease progression. 27 patients completed 6 cycles and 15 completed 8 cycles. Baseline characteristics were well balanced between the two arms. About half of the patients had lymph node positive disease. In Arm A, 2/25 patients (8%) had pCR and the ORR was 68%. In Arm B, 2/24 patients had a CR (8%) and the ORR was 58%. In total, 48.6% (17/35) had a change in HER2 IHC after T-DXd treatment. Of those who had a change, the majority (88.2%) had a decrease in HER2 IHC expression. As of the data cut-off on November 25th 2022, surgical outcomes were pending for 24% (7/29) of patients being treated in Arm A and for 31% (9/29) in Arm B. The RCB 0/1 rate was 15% in both arms.
In total, 5.2% of patients (3/58) had dose-reductions due to adverse events (AEs). Interstitial lung disease (ILD) occurred in 1 patient (1.7%), was of grade 2 and resolved 11 days after stopping therapy. Most common treatment-related grade ≥ 3 AEs in Arms A and B, respectively, include hypokalaemia (1.7%, 5.2%), diarrhoea (3.4%, 3.4%), neutropenia (3.4%, 1.7%), fatigue (1.7%, 3.4%), headache (3.4%, 1.7%), vomiting (3.4%, 1.7%), dehydration (1.7%, 1.7%) and nausea (3.4%, 0%). There was one death due to myocardial infarction after severe gastro-intestinal toxicity, possible related to T-DXd. The incidence of gastro-intestinal adverse events appeared to decrease over time, possible due to better supportive therapy.
Conclusion
Neoadjuvant T-DXd demonstrated preliminary evidence of clinical activity in HER2-low, HR+ localised breast cancer with a toxicity profile consistent with previous reports. The addition of endocrine therapy to T-DXd did not appear to enhance efficacy but caution needs to be exerted in strong conclusions given small numbers. This is the first report of neoadjuvant T-DXd for patients with HR+/HER2 low breast cancer and provides groundwork for future studies with ADCs for patients with early-stage breast cancer.
Reference
Hurvitz S, et al. TRIO-US B-12 TALENT: Neoadjuvant trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer. Presented at SABCS 2022; Abstract GS2-03.
