NCT01401166.

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.

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503 Background: KEYNOTE-522 (NCT03036488) tested the benefit from adding pembrolizumab (pembro) to chemotherapy (chemo) in patients (pts) with early TNBC. The primary results showed statistically significant and clinically meaningful improvements in pCR and EFS with pembro.Prior studies have shown the prognostic value of the residual cancer burden (RCB) method to quantify the extent of residual disease after neoadjuvant chemo. In this exploratory analysis, we assessed EFS by RCB in KEYNOTE-522. Methods: 1174 pts with previously untreated, nonmetastatic, stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2:1 to pembro 200 mg Q3W or placebo (pbo) given with 4 cycles of paclitaxel + carboplatin, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After definitive surgery, pts received pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity. Dual primary endpoints are pCR and EFS. RCB was assessed by the local pathologist at the time of surgery. The association between RCB categories (RCB-0, -1, -2, -3, corresponding to increasingly larger residual cancer) and EFS was assessed based on a Cox regression model with treatment as a covariate. Results: Median follow-up was 39.1 months at data cutoff (23 MAR 2021). Pembro shifted RCB to lower categories across the entire spectrum (Table). The HRs (95% CI) for EFS were 0.70 (0.38 - 1.31) for RCB-0 (equivalent to pCR), 0.92 (0.39 - 2.20) for RCB-1, 0.52 (0.32 - 0.82) for RCB-2, and 1.24 (0.69 - 2.23) for RCB-3. The most common EFS event in both arms was distant recurrence, which occurred in fewer pts in the pembro arm in all RCB categories. Conclusions: Increased RCB score was associated with worse EFS. Pts with residual disease had lower RCB values in the pembro arm, including fewer pts with RCB-3. Pembro + chemo prolonged EFS vs chemo alone in the RCB-0, -1, and -2 categories; the small sample size limits interpretation in the RCB-3 category. The small subset of pts with extensive residual disease (RCB-3) in both arms, 5.1% and 6.7%, respectively, had a poor prognosis. These results highlight the importance of neoadjuvant treatment with pembro for improving survival in pts with early TNBC, and identified a subset of pts for whom additional therapies will be needed. Clinical trial information: NCT03036488. [Table: see text]