De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)–Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor–Positive Phase II Randomized Trial—Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET

Abstract

Purpose Human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor (HR)-positive breast cancer is a distinct subgroup associated with lower chemotherapy sensitivity and slightly better outcome than HER2-positive/HR-negative disease. Little is known about the efficacy of the combination of endocrine therapy (ET) with trastuzumab or with the potent antibody-cytotoxic, anti-HER2 compound trastuzumab emtansine (T-DM1) with or without ET for this subgroup. The West German Study Group trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) compares pathologic complete response (pCR) rates of T-DM1 versus trastuzumab with ET in early HER2-positive/HR-positive breast cancer. Patients and Methods In this prospective, neoadjuvant, phase II trial, 375 patients with early breast cancer with HER2-positive and HR-positive status (n = 463 screened) were randomly assigned to 12 weeks of T-DM1 with or without ET or to trastuzumab with ET. The primary end point was pCR (ypT0/is/ypN0). Early response was assessed in 3-week post-therapeutic core biopsies (proliferation decrease ≥ 30% Ki-67 or cellularity response). Secondary end points included safety and predictive impact of early response on pCR. Adjuvant therapy followed national standards. Results Baseline characteristics were well balanced among the arms. More than 90% of patients completed the therapy per protocol. pCR was observed in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and ET, and 15.1% with trastuzumab and ET ( P < .001). Early responders (67% of patients with assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio, 2.2; 95% CI, 1.24 to 4.19). T-DM1 was associated with a significantly higher prevalence of grade 1 to 2 toxicities, especially thrombocytopenia, nausea, and elevation of liver enzymes. Overall toxicity was low; seventeen therapy-related severe adverse events (T-DM1 arms v trastuzumab plus ET; 5.3% v 3.1%, respectively) were reported. Conclusion The ADAPT HER2-positive/HR-positive trial demonstrates that neoadjuvant T-DM1 (with or without ET) given for only 12 weeks results in a clinically meaningful pCR rate. Thus, a substantial number of patients are spared the adverse effects of systemic chemotherapy.

Optimal treatment of early stage HER2‐positive breast cancer

“…Results from 2 randomized studies in the neoadjuvant setting already have been reported (Table ), including the phase 3 KRISTINE trial . Although these data indicate that T‐DM1 may not be as effective as chemotherapy plus trastuzumab and pertuzumab for high‐risk patients, it is associated with less toxicity . Two phase 3 trials are ongoing to assess its potential use in the adjuvant setting: the KATHERINE trial (clinicaltrials.gov identifier NCT01772472), which is comparing 1 year of T‐DM1 versus trastuzumab in patients who have residual disease after neoadjuvant therapy; and the KAITLIN trial (clinicaltrials.gov identifier NCT01966471), which is evaluating the combination of T‐DM1 and pertuzumab versus trastuzumab, pertuzumab, and a taxane after anthracyclines in both arms.…”

“…48,49 T-DM1 is under active clinical investigation in early stage, HER2-positive breast cancer. Results from 2 randomized studies in the neoadjuvant setting already have been reported (Table 4), 50,51 including the phase 3 KRISTINE trial. 50 Although these data indicate that T-DM1 may not be as effective as chemotherapy plus trastuzumab and pertuzumab for high-risk patients, it is associated with less toxicity.…”

A randomized, 3-arm, neoadjuvant, phase 2 study comparing docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP), TCbHP followed by trastuzumab emtansine and pertuzumab (T-DM1+P), and T-DM1+P in HER2-positive primary breast cancer

“…Although direct comparisons cannot be made with other studies due to differences in study design, region, and treatment regimens, the TRYPHAENA study reported a pCR rate (ypT0-isypN0) of 50.7% with the FEC+H+P×3 → T+H+P×3 regimen, 45.3% with the FEC×3 → T+H+P×3 regimen, and 51.9% with the TCH+P×6 regimen, the only comparable arm, compared with 57% in group A of this study [8]. The pCR rates in the ADAPT study were 41.0% for the T-DM1×4 regimen and 41.5% for the T-DM1+ET×4 regimen in patients with early HER2+ HR+ breast cancer [20]. However, in ADAPT, patients received 4 treatment cycles unlike 6 in our study.…”

“…In pre-menopausal women with ER+, ovarian suppression is often engaged using HT. In the ADAPT study, pCR rates were 41.5% and 15.1% in patients with HER2+ HR+ breast cancer receiving concomitant HT with 12-week T-DM1 and trastuzumab, respectively [20], suggesting improved efficacy of anti-HER2 therapy without any detrimental effects with concomitant HT. In the Neo-LaTH study [25], patients receiving anti-HER2 therapy (with/without HT) before chemotherapy for longer duration (18 versus 6 weeks) tended to show more tumor shrinkage.…”

What is the best pharmacotherapeutic strategy for HER-2 positive breast cancer?

“…Superiority was confirmed by a significant p-value and chemotherapy plus double HER2 targeting remains the treatment of choice in the neoadjuvant setting. A similar pCR rate obtained with T-DM1 alone in the West German study ADAPT in women with HER2 positive and HR positive breast cancer (41%) [23], strongly suggests that T-DM1 might be a potentially less toxic and less expensive option for selected patients who need neoadjuvant therapy. While newer drugs will be always welcome, not using active drugs that we already have in a more rationale, biomarker-guided way will remain a missed opportunity to optimize the therapeutic strategy in HER2 positive breast cancer.…”