Long-Term Follow-up Supports Postneoadjuvant T-DM1 Over Trastuzumab in Early, High-Risk, HER2-Positive Breast Cancer

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At a median follow-up of 8.4 years, adjuvant use of ado-trastuzumab emtansine (T-DM1) continued to improve invasive disease–free survival and overall survival compared with trastuzumab in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy. These updated results of the phase III KATHERINE trial were presented at the 2023 San Antonio Breast Cancer Symposium (SABCS).1

The absolute invasive disease–free survival benefit with T-DM1 was 13.7% compared with the former standard of care, trastuzumab (80.9% vs 67.1%, respectively), for a highly statistically significant 46% risk reduction (P < .0001). At a median follow-up of 8.4 years, T-DM1 achieved a 34% improvement in overall survival compared with trastuzumab: 89.1% vs 84.4%, respectively. All subgroups derived a survival benefit from T-DM1 as well, including hormonal status and nodal status.

“T-DM1 is the first therapy to show a significant overall survival benefit in people with a high risk of recurrence due to residual invasive disease in the surgical specimen following neoadjuvant therapy for HER2-positive early breast cancer,” stated lead study author, Sibylle Loibl, MD, PhD. Dr. Loibl is Chair of the German Breast Group (GBG) and Chief Executive Officer of the GBG Forschungs GmbH, as well as Associate Professor of Obstetrics and Gynecology at the Goethe University of Frankfurt.

Sibylle Loibl, MD, PhD

Sibylle Loibl, MD, PhD

“The invasive disease–free survival benefit of T-DM1 was sustained in the intent-to-treat analysis and in key subgroups. There were no new safety signals, especially since cardiotoxicity was less than 1% in both treatment arms,” she added.

These longer-term results extend the promising data from KATHERINE reported previously.2 “About 5 years back in 2018, the interim analysis for invasive disease–free survival was presented at SABCS [and] demonstrated a large, clinically meaningful, and statistically significant benefit for T-DM1 over trastuzumab…, with a highly statistically significant P value of .01, and a 3-year invasive disease–free survival rate of 88%. That was an absolute difference of 11%. At that time, with a short follow-up, overall survival was immature,” Dr. Loibl told listeners.

Study Details

The prospective, randomized KATHERINE trial enrolled 1,486 patients with HER2-positive early breast cancer treated with six cycles of chemotherapy and a minimum of 9 weeks of trastuzumab as neoadjuvant therapy; they had residual invasive tumor in the breast and nodes after surgery. A second HER2-targeted agent was also permitted. Patients were randomly assigned within 12 weeks of surgery in a 1:1 ratio to receive 14 cycles of either T-DM1 (n = 740) or trastuzumab (n = 720). Radiation therapy and endocrine therapy were permitted at the investigator’s discretion, and crossover to trastuzumab was permitted if patients experienced adverse events on T-DM1.

At the 8.4-year timepoint, 521 patients (70.1%) given T-DM1 and 461 patients (62.0%) given trastuzumab were still alive.

Baseline characteristics were well balanced between the two treatment arms. About two-thirds had primary resectable disease, two-thirds had hormone receptor–positive disease, 80% had received previous trastuzumab, 46% had node-positive disease, and 53% had node-negative disease (1% unknown).

A higher percentage of patients in the trastuzumab arm experienced an invasive disease–free survival event compared with those in the T-DM1 arm: 32.2% vs 19.7%, respectively (P < .0001). The rates of distant recurrence were 21.5% and 14.7% with trastuzumab and T-DM1, respectively, including central nervous system metastases in 5.1% and 7.0%, respectively. The rate of locoregional recurrence was 6.2% vs 2.2%, respectively. Contralateral breast cancer was found in 2.6% vs 0.9%, respectively. Deaths without a prior event were reported in 1.9% of patients in each arm.

Most patients who experienced an invasive disease–free survival event went on to receive at least one subsequent treatment (most commonly HER2-directed therapies, platinum compounds, taxanes, and capecitabine). With longer-term follow-up of overall survival, a total of 89 patients (12%) experienced an overall survival event in the T-DM1 arm, compared with 126 patients (17%) in the trastuzumab arm. Use of T-DM1 led to an absolute overall survival benefit of 4.7% at 7 years, reflecting a 34% reduction in the risk of death.

Breast cancer–specific cause of death occurred in 9.5% of the T-DM1 arm vs 15% of the trastuzumab arm. Death attributed to adverse events was reported in 0.1% vs 0%; other causes of death were reported in 2.4% vs 2.5%, respectively.

“Subgroup analysis underlined the treatment effect of T-DM1,” Dr. Loibl said. Patients with hormone receptor–positive and –negative disease, as well as those with measurable residual disease–positive and –negative disease, all had a benefit in invasive disease–free survival.


No new safety signals emerged with longer follow-up from the KATHERINE trial. Any-grade adverse events were reported in 24 patients (3.2%) in the T-DM1 group and 12 patients (1.7%) in the trastuzumab arm; these adverse events included cardiac disorders (0.7% in both arms), nervous system disorders (0.5% vs 0% with T-DM1 and trastuzumab, respectively), hepatobiliary disorders (0.3% vs 0%, respectively); and metabolism and nutrition disorders, skin, and subcutaneous tissue disorders (< 1% of both arms).

Serious adverse events occurred in 0.3% and 0.6% of patients in the T-DM1 and trastuzumab groups, respectively. Cardiac toxicity, hepatobiliary toxicity, and vascular toxicity were reported in less than 1% of each arm. Treatment discontinuation because of invasive disease–free survival events was reported in 105 patients (14.1%) and 159 patients (21.4%) in the T-DM1 and trastuzumab arms, respectively. An additional 117 patients (15.7%) and 123 patients (16.6%), respectively, discontinued treatment before an invasive disease–free survival event. 

Expert Point of View

Virginia Kaklamani, MD

Virginia Kaklamani, MD

Virginia Kaklamani, MD, Co-Director of the San Antonio Breast Cancer Symposium and press conference moderator, commented: “KATHERINE changed the standard of care when the data were first presented 5 years ago. We now treat patients with residual invasive disease following neoadjuvant chemotherapy with T-DM1, and we have better outcomes. Invasive disease–free survival is consistent with the original analysis. It is impressive that the curves remain separate after 7 years.” Dr. Kaklamani is Professor of Medicine, UT Health San Antonio, MD Anderson Cancer Center, Houston.

However, about 20% of patients still have a recurrence, Dr. Kaklamani noted. Dr. Sibylle Loibl responded to that comment: “Patients with large nodal disease and larger tumors really need better drugs.” Dr. Kaklamani asked about patients who convert to HER2-negative status after adjuvant therapy. “We looked at this and found no recurrences with T-DM1 and 11 with trastuzumab before the final analysis,” Dr. Loibl answered.

One subgroup that appeared to have no benefit from T-DM1 included those who developed brain metastases: 7% of patients given T-DM1 compared with 5.4% of those given trastuzumab. “Hopefully, newer targeted agents [such as tucatinib and fam-trastuzumab deruxtecan-nxki] will change that,” Dr. Loibl said.

DISCLOSURE: The KATHERINE study is sponsored by F. Hoffmann–La Roche Ltd. Dr. Loibl has received grants and other support from Roche, AstraZeneca, AbbVie, Amgen, DSI, Gilead Sciences, Celgene/BMS, Novartis, Pfizer, Molecular Health, Seagen, Sanofi, Relay, Olema, EirGenix, Merck KGaA, Eli Lilly, GSK, Pierre Fabre, and Eisai. Dr. Kaklamani has served as a consultant or speaker for Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, Novartis, AstraZeneca, Daiichi Sankyo, Seattle Genetics, Puma Biotechnology, Athenex, and Immunomedics.


1. Loibl S, Mano M, Untch M, et al: 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. 2023 San Antonio Breast Cancer Symposium. Abstract GS03-12. Presented December 8, 2023.

2. von Minckwitz G, Huang CS, Mano MS, et al: Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380:617-628, 2019.