Prediction of survival after de-escalated neoadjuvant therapy in HER2+ early breast cancer: A pooled analysis of three WSG trials.

502 Background: Current treatment de-escalation strategies in HER2+ early breast cancer (eBC) aim to mitigate acute and late toxicities by reducing or entirely omitting systemic chemotherapy (sCTx). We analyzed the outcomes and investigated predictors of survival in three randomized de-escalation trials investigating short (12-week) neoadjuvant treatments (NAT) with and without sCTx (paclitaxel, pac) in HER2+ eBC. Methods: In total, 713 patients (pts) were analyzed. WSG-ADAPT-HR-/HER2+ (NCT01817452) compared trastuzumab and pertuzumab (T + P, n=92) vs. T +P + pac (n=42); WSG-ADAPT-HR+/HER2+ (NCT01779206) compared trastuzumab emtansine (T-DM1, n=118) vs. T-DM1 + standard endocrine therapy (ET, n=125) vs. T + ET (n=129); WSG-TP-II (NCT03272477) compared neoadjuvant/adjuvant T + P + ET (n=100) vs. T + P + pac (n=107). Omission of further sCTx was allowed in pts with pathological complete response (pCR, ypT0/is ypN0); sCTx was mandatory for non-pCR pts. pCR was the primary endpoint of each trial; survival was a secondary endpoint. Kaplan-Meier method and Cox regression were applied for survival analysis. Results: Median follow-up of 60.7 months was available for 713 pts (sCTx: n=149; sCTx-free NAT: n=564). 395 tumors (55%) were cT2-4, 414 (58%) were grade 3, and 223 pts (31%) were clinically node-positive. Ten (7%) and 74 (13%) pts had iDFS events, 8 (5%) and 51 (9%) had dDFS events, and 6 (4%) and 34 (6%) pts died in the sCTx and sCTx-free NAT groups, respectively. In the sCTx and sCTx-free NAT groups, the respective 5-year survival rates were 98% (95%CI 93, 99) and 97% (95%CI 95, 98) for OS (HR 0.88; 95%CI 0.36, 2.11; p=0.775) and 96% (95%CI 91, 98) and 88% (95%CI 85, 91) for iDFS (HR 0.56; 95%CI 0.29, 1.08; p=0.083). 95 (66%) and 171 (31%) pts had a pCR after sCTx and sCTx-free NAT, respectively. iDFS events occurred in 5 (5%) pts with pCR and 5 (10%) without pCR after sCTx and in 14 (8%) with pCR and 59 (16%) pts without pCR after sCTx-free NAT. 5-year iDFS rates in pts with pCR were 98% (95%CI 91, 99) after sCTx and 94% (95%CI 89, 97) after sCTx-free NAT (HR 0.76; 95%CI 0.27, 2.14; p=0.609). In univariate analysis, iDFS was associated with pCR (HR 0.18; 95%CI 0.04, 0.77) in the sCTx group and with cT (3-4 vs 1: HR 2.54; 95%CI 1.22, 5.28) and cN stage (cN+ vs cN-: HR 2.27; 95%CI 1.44, 3.58), grade (3 vs 1-2: HR 1.79; 95%CI 0.86, 3.74) and pCR (HR 0.47; 95%CI 0.26; 0.84) in the sCTx-free NAT group. Detailed subgroup analyses including the impact of standard chemotherapy on outcome will be presented at the meeting. Conclusions: This pooled analysis demonstrates that de-escalation trials in HER2+ eBC are feasible and safe for patients. 12× weekly paclitaxel + HER2 blockade is an effective and well-tolerated regimen with excellent 5-year survival. The favorable survival after pCR to sCTx-free NAT lays the groundwork for further de-escalation strategies, such as the currently ongoing WSG-ADAPT-HER2-IV evaluating T-DXd as NAT. Clinical trial information: NCT01817452 , NCT01779206 , NCT03272477 .