Abstract P3-14-01: Adjuvant trastuzumab emtansine (T-DM1) vs trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: KATHERINE subgroup analysis
Authors: Mano Max S , Loibl Sibylle , Mamounas Eleftherios P. , von Minckwitz Gunter , Huang Chiun-Sheng , Untch Michael , Wolmark Norman , Wapnir Irene L. , Yang Youngsen , Conlin Alison K. , Kümmel Sherko , Saghatchian Mahasti , DiGiovanna Michael P. , Strunk Claudia , Zimovjanova Martina , Song Chunyan , Liu Haying , Tesarowski David , Blotner Steven , Lam Lisa H. , Smitt Melanie , Geyer Charles E. 
Published: March 2020

Abstract
Background: Patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy (NACT) + HER2-targeted therapy have a higher risk of recurrence and death than those with pathologic complete response. In the phase III KATHERINE study, adjuvant T-DM1 reduced the risk of recurrence or death by 50% vs H in this population. Data from KATHERINE subgroups are reported here, including patients treated with non-anthracycline (AC) vs AC based NACT, patients with small tumors (cT1cN0) who typically do not receive neoadjuvant treatment, and patients with particularly higher-risk tumors defined by nodal involvement and hormone-receptor status. Methods: Eligible patients had HER2-positive early breast cancer, received taxane- and H-containing neoadjuvant therapy ± AC followed by surgery, and had residual invasive disease in the breast and/or axillary nodes. Patients received 14 cycles of adjuvant T-DM1 (3.6 mg/kg IV q3w) or H (6 mg/kg IV q3w) and endocrine and/or radiation therapy per local standards. The primary endpoint was invasive disease-free survival (IDFS), defined as time from randomization to the first occurrence of ipsilateral locoregional or contralateral invasive breast cancer recurrence, distant recurrence, or death from any cause. In this exploratory analysis, efficacy subpopulations were derived from the intent-to-treat population and safety data were reported for patients who received ≥1 dose of study treatment. Results: In the non-AC v AC based NACT analysis (N=1486), some patient characteristics were imbalanced. For non-AC/AC based NACT, respectively, these included: region (North America; 60.6% v 11.0%), race (Asian; 12.8% v 7.4%), ECOG PS 1 (28.0% v 15.7%); neoadjuvant HER2-based therapy (H + pertuzumab; 46.6% v 9.8%), and neoadjuvant carboplatin/cisplatin (78.7 v 2.3%). Benefit was observed with T-DM1 regardless of neoadjuvant AC use (Table). The all-grade incidence of selected AEs with T-DM1 including hepatotoxicity, peripheral neuropathy, hemorrhage, IRR/hypersensitivity, and cardiac dysfunction was similar between non-AC and AC NACT groups. There was a small increase in the non-AC group in all-grade thrombocytopenia (32.5% v 27.4%) and pulmonary toxicity (6.7% vs 1.7%). There was an increased incidence of grade ≥3 AEs (39.9% vs 21.7%) in the non-AC vs the AC group with T-DM1 which was likely driven by an increase in thrombocytopenia (10.4% v 4.3%) and peripheral sensory neuropathy (4.3% vs 0.5%). However, the percentage of patients with AEs leading to T-DM1 withdrawal in the non-AC vs AC groups (19.6% v 17.5%) was similar, as was the percentage with AEs leading to T-DM1 dose reduction (14.1% v 11.6%). In patients with cT1N0 tumors (n=77), baseline characteristics were well-balanced for H v T-DM1. There were only 6 IDFS events in this subgroup overall; none were observed with T-DM1 (Table). In the analysis of particularly higher-risk tumors, all subgroups showed a benefit with T-DM1; the number of patients was small in some subgroups (Table). Conclusions: T-DM1 provides clinical benefit regardless of prior non-AC vs AC based NACT, and in subgroups with small or particularly higher-risk tumors. There was an increased incidence of grade ≥3 AEs with T-DM1 in the non-AC vs the AC group but these did not result in increased treatment discontinuation and were likely driven by the imbalance in prior therapy.
Table 1. Risk of IDFS event in patients treated with non-AC versus AC based NACT, patients with small tumors, and patients with particularly higher-risk tumors.Unstratified hazard ratio of IDFS (95% confidence interval [CI])Patients treated with non-AC vs AC based NACT (N=1,486)Non-AC-based NACT: H (n=179) vs T-DM1 (n=164)0.43 (0.22–0.82)AC-based NACT: H (n=564) vs T-DM1 (n=579)0.51 (0.38–0.67)Patients with small (cT1cN0) tumors (N=77)H (n=32) vs T-DM1 (n=45)6 events with H; 0 events with T-DM1(hazard ratio not applicable due to zero events in T-DM1 arm)Tumor subgroups defined by nodal and HR status (N=957)Inoperable; any HR or ypN statusH (n=190)T-DM1 (n=185)3-year IDFS event-free rate, % (95% CI)60.2 (52.7–67.8)76.0 (70.0–82.4)Unstratified hazard ratio (95% CI)0.54 (0.37–0.80)Operable; ypN positive and HR negativeH (n=52)T-DM1 (n=58)3-year IDFS event-free rate, % (95% CI)69.5 (56.1–82.9)76.0 (64.5–87.5)Unstratified hazard ratio (95% CI)0.72 (0.35–1.50)Operable; ypN positive and HR positiveH (n=167)T-DM1 (n=168)3-year IDFS event-free rate, % (95% CI)77.2 (70.2–84.1)91.4 (86.6–96.2)Unstratified hazard ratio (95% CI)0.43 (0.25–0.75)Operable; ypN0 and HR negativeH (n=68)T-DM1 (n=69)3-year IDFS event-free rate, % (95% CI)77.2 (66.5–87.9)91.1 (84.3–97.9)Unstratified hazard ratio (95% CI)0.43 (0.17–1.06)
Citation Format: Max S Mano, Sibylle Loibl, Eleftherios P. Mamounas, Gunter von Minckwitz, Chiun-Sheng Huang, Michael Untch, Norman Wolmark, Irene L. Wapnir, Youngsen Yang, Alison K. Conlin, Sherko Kümmel, Mahasti Saghatchian, Michael P. DiGiovanna, Claudia Strunk, Martina Zimovjanova, Chunyan Song, Haying Liu, David Tesarowski, Steven Blotner, Lisa H. Lam, Melanie Smitt, Charles E. Geyer Jr. Adjuvant trastuzumab emtansine (T-DM1) vs trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: KATHERINE subgroup analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-14-01.