Abstract GS03-12: Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis

Abstract Background: Patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant chemotherapy + HER2-targeted therapy have a high risk of recurrence and death. The standard of care when KATHERINE was designed was continuation of the same HER2-targeted therapy in the adjuvant setting for 1 year. The primary analysis of KATHERINE in 2018 showed that the risk of recurrence of invasive BC or death was 50% lower with adjuvant ado-trastuzumab emtansine (T-DM1) than with trastuzumab. Methods: KATHERINE (NCT01772472/BO27938/NSABP B-50-I/GBG 77) is a phase III, open-label, global study of patients with centrally confirmed, HER2-positive (immunohistochemistry 3+ or in situ hybridization-positive) primary BC (T1–4, N0–3, M0) who received neoadjuvant chemotherapy + HER2-targeted therapy, which had to include a taxane and trastuzumab, followed by surgery, with pathologically documented residual invasive disease in the breast and/or axillary lymph nodes. Within 12 weeks of surgery, patients were randomized 1:1 to T-DM1 (3.6 mg/kg intravenously [IV] every 3 weeks [q3w]) or trastuzumab (6 mg/kg IV q3w) for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single vs dual neoadjuvant HER2-targeted therapy, and pathologic nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint was invasive disease-free survival (IDFS). We report the final IDFS analysis, which was to occur after ~384 events had been reported, and the preplanned second interim analysis of overall survival (OS); specified to occur at the same time. Results: With a median follow-up of 8.4 years (101 months), T-DM1 sustained the improvement in IDFS over trastuzumab (unstratified hazard ratio [HR] 0.54; 95% confidence interval [CI] = 0.44, 0.66; p < 0.0001). Landmark 7-year IDFS rates were increased from 67.1% with trastuzumab to 80.8% with T-DM1; a difference of 13.7%. At clinical cutoff for the final IDFS analysis, 215 deaths had been reported. T-DM1 significantly reduced the risk of death by 34% compared with trastuzumab (unstratified HR 0.66; 95% CI = 0.51, 0.87; p = 0.0027). Deaths had occurred in 89/743 patients (12.0%) in the T-DM1 arm and 126/743 (17.0%) in the trastuzumab arm. Landmark 7-year OS rates were increased from 84.4% with trastuzumab to 89.1% with T-DM1; a difference of 4.7%. OS and IDFS benefits were seen across key subgroups. A low incidence of adverse events (AEs) related to study treatment or to study procedures was observed during the post-treatment period: Grade ≥3 related AEs occurred in 3/740 patients (0.4%) in the T-DM1 arm and 3/720 (0.4%) in the trastuzumab arm; serious related AEs, in 2/740 (0.3%) and 4/720 (0.6%), respectively. Related AEs classed as “cardiac disorders” were rare in both arms with extended follow-up. Conclusions: After 8.4 years (101 months) median follow-up, T-DM1 significantly improved OS in patients with HER2-positive EBC with residual invasive disease after neoadjuvant therapy. The IDFS benefit of T-DM1 was sustained in the intention-to-treat population with longer follow-up, and no new safety issues emerged. Cardiac toxicity was rare in both arms. T-DM1 is the first therapy to show improved survival post-surgery in patients with HER2-positive EBC with residual invasive disease after neoadjuvant therapy. Follow-up is ongoing for the final OS analysis. Citation Format: Sibylle Loibl, Max Mano, Michael Untch, Chiun-Shen Huang, Eleftherios Mamounas, Norman Wolmark, Adam Knott, Asna Siddiqui, Thomas Boulet, Beatrice Nyawira, Eleonora Restuccia, Charles Geyer. Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-12.