De-Escalated Neoadjuvant Trastuzumab-Emtansine With or Without Endocrine Therapy Versus Trastuzumab With Endocrine Therapy in HR+/HER2+ Early Breast Cancer: 5-Year Survival in the WSG-ADAPT-TP Trial

Abstract

PURPOSE Neoadjuvant chemotherapy is standard of care in human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC), irrespective of the hormone receptor status. Trastuzumab-emtansine (T-DM1), antibody-drug conjugate, is highly effective in HER2+ EBC; however, no survival data are available for de-escalated antibody-drug conjugate–based neoadjuvant therapy without conventional chemotherapy. PATIENTS AND METHODS In the WSG-ADAPT-TP (ClinicalTrials.gov identifier: NCT01779206 ) phase II trial, 375 centrally reviewed patients with hormone receptor-positive (HR+)/HER2+ EBC (clinical stage I-III) were randomly assigned to 12 weeks of T-DM1 with or without endocrine therapy (ET) or trastuzumab + ET once every 3 weeks (ratio 1:1:1). Adjuvant chemotherapy (ACT) omission was allowed in patients with pathologic complete response (pCR). In this study, we report the secondary survival end points and biomarker analysis. Patients who received at least one dose of study treatment were analyzed. Survival was analyzed using the Kaplan-Meier method, two-sided log-rank statistics, and Cox regression models stratified for nodal and menopausal status. P values < .05 were considered statistically significant. RESULTS T-DM1, T-DM1 + ET, and trastuzumab + ET induced similar 5-year invasive disease-free survival (iDFS; 88.9%, 85.3%, 84.6%; Plog-rank = .608) and overall survival rates (97.2%, 96.4%, 96.3%; Plog-rank = .534). Patients with pCR versus non-pCR had improved 5-year iDFS rates (92.7% v 82.7%; hazard ratio, 0.40; 95% CI, 0.18 to 0.85). Among the 117 patients with pCR, 41 did not receive ACT; 5-year iDFS rates were similar in those with (93.0%; 95% CI, 84.0 to 97.0) and without ACT (92.1%; 95% CI, 77.5 to 97.4; Plog-rank = .848). Translational research revealed that tumors with PIK3CA wild type, high immune marker expression, and luminal-A tumors (by PAM50) had an excellent prognosis with de-escalated anti-HER2 therapy. CONCLUSION The WSG-ADAPT-TP trial demonstrated that pCR after 12 weeks of chemotherapy-free de-escalated neoadjuvant therapy was associated with excellent survival in HR+/HER2+ EBC without further ACT. Despite higher pCR rates for T-DM1 ± ET versus trastuzumab + ET, all trial arms had similar outcomes because of mandatory standard chemotherapy after non-pCR. WSG-ADAPT-TP demonstrated that such de-escalation trials in HER2+ EBC are feasible and safe for patients. Patient selection on the basis of biomarkers or molecular subtypes may increase the efficacy of systemic chemotherapy-free HER2-targeted approaches.

Tamoxifen Dose De-Escalation: An Effective Strategy for Reducing Adverse Effects?

“…If the value is already below 10% before the start of treatment, no reliable conclusion can be drawn as to whether or not the endocrine therapy is effective. Since then, this surrogate endpoint has been widely used in preoperative endocrine therapy studies (both tamoxifen and aromatase inhibitors) to answer important clinically relevant research questions, of which the ADAPT study is a perfect example [ 84 , 85 ]. In that study, breast cancer patients who had an adequate decrease in Ki67 after a short duration of neoadjuvant endocrine therapy were spared adjuvant chemotherapy [ 84 ].…”

A review of the clinical efficacy of FDA-approved antibody‒drug conjugates in human cancers

“…In the WSG-ADAPT-TP phase II trial involving 375 hormone receptor-positive or HER2-positive patients, randomization into three groups (T-DM1, T-DM1 + endocrine therapy, trastuzumab + endocrine therapy) resulted in similar 5-year invasive DFS rates (88.9%, 85.3%, and 84.6%, respectively) and OS rates (97.2%, 96.4%, and 96.3%, respectively) [38].…”

Use of Antibody–Drug Conjugates in the Early Setting of Breast Cancer

“…This suggests that patients’ selection based on biomarkers or molecular subtypes may increase the efficacy of systemic de-escalated HER2-targeted approaches. 32 In addition, the PHERGain-2 trial (NCT04733118) is testing mAb/ADC-based therapies with a neoadjuvant chemotherapy-free regimen consisting of trastuzumab and pertuzumab ± ET, followed by the same regimen or T-DM1 ± ET as determined by pCR after the surgery. 33 Conventional chemotherapy is reserved for patients with disease progression after preoperative treatment.…”

“…Genomic profiling for luminal A tumors (by PAM50), PIK3CA mutation, BRCA status, and immune marker expression could refine the outcomes of systemic de-escalated treatments. 32 The identification of new targets with tumor-specific expression, such as Trop-2, LIV-1, and HER3, or improved conjugation technologies to optimize payload/release are certainly of paramount importance to improve ADC therapy and catalyze their development toward early breast cancer. High DAR and strong bystander effects may potentiate the efficacy of the new-generation ADCs against heterogeneous tumors or to those with low target expression.…”