Adjuvant regimen extends survival in early HER2-positive breast cancer
Click Here to Manage Email Alerts
Key takeaways:
- Adjuvant ado-trastuzumab emtansine improved survival compared with trastuzumab for early HER2-positive breast cancer.
- Long-term follow-up showed a continued DFS benefit with ado-trastuzumab emtansine, as well.
Adjuvant ado-trastuzumab emtansine significantly prolonged survival compared with trastuzumab for certain women with HER2-positive breast cancer, according to long-term results of a randomized phase 3 trial.
Ado-trastuzumab emtansine (Kadcyla, Genentech) — often referred to as T-DM1 — also continued to show durable benefit for reducing risk of invasive recurrence or death, long-term results of the randomized phase 3 KATHERINE trial showed.
“Prior to [the KATHERINE trial], HER2-directed drug treatments for early breast cancer were administered either before or after surgery since the outcomes were similar irrespective of the sequence. KATHERINE changed that paradigm,” Charles E. Geyer Jr., MD, chief scientific officer and breast committee chairman at National Surgical Adjuvant Breast and Bowel Project Foundation, and professor of medicine in the division of malignant hematology and oncology at University of Pittsburgh Hillman Cancer Center, told Healio.
“T-DM1 has been the standard of care for patients meeting the KATHERINE eligibility criteria since we reported the initial results at the 2018 San Antonio Breast Cancer Symposium and in The New England Journal of Medicine in 2019. The current publication adds 5 years of follow-up and provides long-term results that confirm and strengthen the initial results of KATHERINE.”
Background and methods
An estimated 45% to 66% of women with HER2-positive early breast cancer who receive neoadjuvant chemotherapy and HER2-targeted therapy still have residual invasive disease at surgery, according to study background.
“T-DM1 was the first antibody-drug conjugate to be developed and approved in HER2-positive metastatic breast cancer,” Geyer said. “The EMILIA study, published in 2012, compared T-DM1 with the standard combination of capecitabine and lapatinib [Tykerb, Novartis] in patients with metastatic, HER2-positive breast cancer previously treated with trastuzumab [Herceptin, Genentech] and a taxane, demonstrated substantial improvements in both progression-free survival and overall survival with a much better toxicity profile. These results generated intense interest in evaluating T-DM1 in early breast cancer.”
In the KATHERINE trial, Geyer and colleagues investigated the efficacy of T-DM1 vs. trastuzumab as adjuvant treatment for patients with HER2-positive earlier breast cancer found to have residual invasive breast cancer at surgery.
The trial included 1,486 women with HER2-positve early breast cancer who had residual disease following at least six cycles of neoadjuvant chemotherapy, 9 weeks of taxane-based therapy and 9 weeks of trastuzumab.
Researchers randomly assigned 743 women (median age, 49 years; range, 24-79; 74.2% white) to T-DM1 dosed at 3.6 mg/kg every 3 weeks for 14 cycles. The other 743 women (median age, 49 years; range, 23-80; 71.5% white) received trastuzumab 6 mg/kg via IV every 3 weeks for 14 cycles.
Invasive DFS served as the primary endpoint. OS served as a key secondary endpoint.
The initial analysis in 2018 showed T-DM1 reduced risk for invasive disease or death by 50% (P < .001) compared with trastuzumab.
“We had been hopeful that our selection of patients with tumors that had not responded completely to trastuzumab and chemotherapy might select a group that would benefit, but we were not expecting to see such a large improvement,” Geyer said. “The large difference in invasive DFS appeared relatively quickly, so we were interested in continuing follow-up to see if the improvement persisted over time and if the T-DM1 ultimately improved survival.”
Results and next steps
The updated results are based on median follow-up of 101.4 months (range, 0.1-123.3) in the T-DM1 group and 100.8 months (range, 0.1-122.8) in the trastuzumab group.
Findings showed a higher rate of estimated 7-year invasive DFS (80.8% vs. 67.1%; HR = 0.54; 95% CI, 0.44-0.66) in the T-DM1 group relative to the trastuzumab group.
The T-DM1 group also had a significantly improved estimated 7-year OS (89.1% vs. 84.4%; HR = 0.66; 95% CI, 0.51-0.87).
A higher percentage of patients assigned T-DM1 developed grade 3 or worse adverse events (26.1% vs. 15.7%) and serious adverse events (12.7% vs. 8.1%).
“When we saw the initial results of KATHERINE, all but one cohort in the study had a roughly 50% improvement in invasive DFS,” Geyer said. “However, we noted that the highest risk groups — such as those patients who had originally presented with such advanced cancer that surgery could not be performed, or who had residual cancer present in the axillary nodes removed at surgery, or had hormone-receptor negative residual disease — still had sufficient residual risk even with T-DM1 to warrant evaluation of newer therapies that might be more effective than T-DM1. We also saw that T-DM1 did not reduce the risk for developing brain metastases, so evaluation of newer drugs that might address this problem would also be warranted. Fortunately we have promising new agents such as fam-trastuzumab deruxtecan-nxki [Enhertu; AstraZeneca, Daiichi Sankyo], often called T-DXd, and tucatinib [Tukysa, Seagen], which are being evaluated in ongoing clinical trials in an effort to address these remaining unmet clinical needs.””
References:
- Geyer CE, et al. N Engl J Med. 2025;doi:10.1056/NEJMoa2406070.
- von Minckwitz G, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1814017.
For more information:
Charles E. Geyer Jr., MD, can be reached at charles.geyer@nsabp.org.
Collapse
Click Here to Manage Email Alerts