Abstract GS1-10: Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE

Abstract

Background: Patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy have a high risk of recurrence and death. The current standard of care is continuation of the same HER2-targeted therapy in the adjuvant setting for one year. T-DM1 has shown activity and a favorable benefit-risk profile in metastatic patients with disease progression after prior chemotherapy plus HER2-targeted therapy. Thus, T-DM1 may also be active in patients with residual invasive disease after neoadjuvant HER2-targeted therapy. 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 (IHC3+ or ISH+) primary breast cancer (T1–4, N0–3, M0) who received neoadjuvant chemotherapy plus 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 IV q3w) or trastuzumab (6 mg/kg IV q3w), for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single versus dual neoadjuvant HER2-targeted therapy, and pathological nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint is invasive disease-free survival (IDFS). A single interim analysis (IA) was planned after approximately 67% of the IDFS events required for the primary analysis had occurred, with an efficacy stopping boundary of HR?0.732 or p<0.0124. The statistical plan stipulated an IA of OS if the IDFS IA boundary was crossed. Secondary endpoints include IDFS including second primary non-breast cancer, disease-free survival, distant recurrence-free interval, overall survival, and safety. Results:After review of the pre-specified IA, the IDMC recommended full analysis and disclosure of the results. With 256 IDFS events reported, administration of T-DM1 significantly improved IDFS compared with trastuzumab (unstratified HR=0.50; 95% CI: 0.39 to 0.64; p<0.0001). IDFS events occurred in 91 patients (12.2%) in the T-DM1 arm compared with 165 patients (22.2%) in the trastuzumab arm. T-DM1 treatment increased estimated three-year IDFS rates (88.3% vs 77.0% with trastuzumab). A consistent benefit was shown across all stratification subgroups. With 98 deaths reported, the OS analysis is immature (HR=0.70; 95% CI: 0.47 to 1.05; p=0.085). The safety data were consistent with the known safety profile of T-DM1, with expected increases in AEs associated with T-DM1 compared to trastuzumab alone. One grade 5 AE (0.1%) occurred in each arm. Conclusions: Adjuvant T-DM1 substantially improved IDFS in patients with HER2-positive early breast cancer with residual disease after completion of neoadjuvant therapy. Citation Format: Geyer, Jr. CE, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Fischer HH, Redondo A, Jackisch C, Jacot W, Conlin AK, Schneeweiss A, Wapnir IL, Fasching PA, DiGiovanna MP, Wuelfing P, Arce-Salinas C, Crown JP, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, von Minckwitz G. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS1-10.

ERBB2 mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer

“…In this context, HER2 3+ tumors have been reported to benefit more from T-DM1 than other IHC groups in retrospective and prospective studies [ 7 , 18 ]. Moreover, benefit associated with the use of post-neoadjuvant T-DM1 as compared to trastuzumab in the KATHERINE trial appeared to more marked in HER2 3+ than in HER2 2+ tumors [ 19 ]. Greater benefit to T-DM1 in HER2 3+ tumors has also been reported in the KATE2 trial [ 20 ] and other cancer types [ 21 , 22 ].…”

Update Breast Cancer 2019 Part 1 – Implementation of Study Results of Novel Study Designs in Clinical Practice in Patients with Early Breast Cancer

“…The phase III CREATE X study showed for the first time that, by adapting the postoperative therapy to the pathological response to the neoadjuvant therapy, the risk of recurrence and mortality can be significantly decreased 67 . While the CREATE X study included only patients with a HER2-negative breast cancer who did not achieve pCR through neoadjuvant chemotherapy, the KATHERINE study tested the same approach in patients with HER2-positive breast cancer 103 , 104 . This study included 1486 patients with primary HER2-positive breast cancer who had not achieved pCR following neoadjuvant standard therapy with at least one taxane and trastuzumab for at least 9 weeks.…”

“… Invasive disease-free survival when comparing the two randomisation arms of the Katherine study (modified according to 104 ). …”

Update Mammakarzinom 2019 Teil 1 – Implementierung der Ergebnisse neuer Studienkonzepte beim frühen Mammakarzinom in die klinische Praxis

“…▶ Fig. 4 Invasive disease-free survival when comparing the two randomisation arms of the Katherine study (modified according to [104]).…”

“…The phase III CREATE X study showed for the first time that, by adapting the postoperative therapy to the pathological response to the neoadjuvant therapy, the risk of recurrence and mortality can be significantly decreased [67]. While the CREATE X study included only patients with a HER2-negative breast cancer who did not achieve pCR through neoadjuvant chemotherapy, the KA-THERINE study tested the same approach in patients with HER2positive breast cancer [103,104]. This study included 1486 patients with primary HER2-positive breast cancer who had not achieved pCR following neoadjuvant standard therapy with at least one taxane and trastuzumab for at least 9 weeks.…”