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
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.