Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE

Eleftherios P Mamounas ,G Kunz,A Fontana,H Liu,B Kaufman,Charles E Geyer ,Juan Carlos Alcedo ,Michael Untch ,Norman Wolmark ,Michael P Digiovanna ,Chiun‐Sheng Huang ,Thomas Boulet ,Thorsten Kuehn ,Xavier Pivot ,Irene Wapnir ,David Tesarowski ,Gϋnter Von Minckwitz ,Alison Conlin ,Youngsen Yang ,Max Senna Mano ,Lisa H Lam ,John Hackmann ,Melanie C Smitt ,Adam Brufsky ,Jonathan Polikoff ,Martina Zimovjanová ,Mahasti Saghatchian ,Sherko Küemmel ,Chunyan Song ,Sibylle Loibl

doi:10.1016/j.annonc.2021.04.011

Abstract

In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n= 743) or trastuzumab (n= 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR)= 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR= 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Highlights

These include an analysis of factors potentially associated with the higher rates of peripheral neuropathy (PN) and thrombocytopenia observed with T-DM1; the efficacy implications of the numerically higher rate of central nervous system (CNS) recurrence as the first invasive disease-free survival (IDFS) event observed in the T-DM1 arm; efficacy in patients treated with non-anthracycline (AC) versus AC-based neoadjuvant chemotherapy (NACT); and in mutually exclusive, high-risk patient cohorts
Differences in the Adverse events (AEs) profile between T-DM1 and trastuzumab were observed in the primary analysis of KATHERINE, including higher rates of all-grade and grade !3 PN and thrombocytopenia.[8]
PN has been reported in clinical trials of T-DM1.9,10 Previous studies have shown that baseline neuropathy is a risk factor for chemotherapyinduced peripheral sensory neuropathy.[11]

Summary

Introduction

The addition of human epidermal growth factor receptor 2 (HER2)-targeted therapy to standard treatment regimens for HER2-positive early breast cancer (EBC) has dramatically improved survival in this patient population.[1,2,3] the risk of recurrence and death is substantially higher in patients with residual invasive disease after neoadjuvant chemotherapy (NACT) plus HER2-targeted therapy compared with those with a pathologic complete response.[3,4,5,6,7] The phase III KATHERINE study compared the efficacy and safety of adjuvant therapy with trastuzumab versus trastuzumab emtansine (T-DM1) in patients with residual invasive disease after NACT plus trastuzumab, with or without a second HER2-targeted agent, generally pertuzumab (NCT01772472/BO27938/NSABP B-50-I/GBG 77).[8]. We present the results of multiple exploratory analyses from KATHERINE aimed at gaining further insight into the safety and efficacy of T-DM1 in the EBC setting These include an analysis of factors potentially associated with the higher rates of peripheral neuropathy (PN) and thrombocytopenia observed with T-DM1; the efficacy implications of the numerically higher rate of central nervous system (CNS) recurrence as the first invasive disease-free survival (IDFS) event observed in the T-DM1 arm; efficacy in patients treated with non-anthracycline (AC) versus AC-based NACT; and in mutually exclusive, high-risk patient cohorts.

Methods

Results

Conclusion