This article is more than 5 years old. Information may no longer be current.
T-DM1 significantly extends OS in HER-2–positive metastatic breast cancer
Click Here to Manage Email Alerts
SAN ANTONIO — Trastuzumab emtansine significantly prolonged OS compared with treatment of physician’s choice among women with HER-2–positive metastatic breast cancer that had progressed after treatment with two or more HER-2–targeted therapies, according to results of the phase 3 TH3RESA study presented at the San Antonio Breast Cancer Symposium.
Further, trastuzumab emtansine (Kadcyla, Genentech) — or T-DM1, an antibody-drug conjugate of trastuzumab (Herceptin, Genentech) linked to the cytotoxic microtubule inhibitor DM1 — appeared well tolerated.
The phase 3 EMILIA study showed T-DM1 significantly improved PFS (median, 9.6 months vs. 6.4 months; HR = 0.65; P ˂ .001) and OS (median, 30.9 months vs. 25.1 months; HR = 0.68; P ˂ .001) compared with lapatinib (Tykerb, Novartis) plus capecitabine. Based on these data, the FDA approved T-DM1 as monotherapy for women with HER-2–positive metastatic breast cancer who had previously received trastuzumab and a taxane.
“The goal of the TH3RESA study was to investigate T-DM1 in a more advanced population compared with the EMILIA study,” Hans Wildiers, MD, PhD, professor of medical oncology at KU Leuven in Belgium, said during a press conference.
Wildiers and colleagues evaluated data from 602 women with HER-2–positive metastatic breast cancer who had received a taxane in any setting and trastuzumab and lapatinib in an advanced setting. Patients had received a median of four prior regimens for advanced breast cancer.
Researchers randomly assigned patients 2:1 to 3.6 mg/kg T-DM1 every 3 weeks (n = 404) or physician’s choice (n = 198), which included trastuzumab-containing regimens (83%) or single-agent chemotherapy (17%).
After the EMILIA study demonstrated a significant OS benefit, researchers of the TH3RESA study amended their study in Sept. 2012 to enable patients on the control arm to cross over to the T-DM1 arm. At the time of the data cutoff in Feb. 2015, 93 patients (47%) assigned physician’s choice crossed over to the experimental arm.
OS and PFS served as the co-primary endpoints of the study. At the time of the primary PFS analysis in Feb. 2013, T-DM1 appeared to significantly improve PFS (median, 6.2 months vs. 3.3 months; HR = 0.528; P ˂ .0001). At this time, 105 of 492 targeted OS events had occurred. T-DM1 demonstrated a trend toward improved OS, but this did not reach statistical significance.
After a median follow-up of 30.5 months and the occurrence of 338 events, researchers conducted the second interim OS analysis.
Median OS in the T-DM1 arm was 22.7 months, which represented a statistically significant improvement compared with the 15.8-month median OS in the physician’s choice arm (HR = 0.68; 95% CI, 0.54-0.85). The P value of .0007 met the prespecified boundary (P ˂ .012) for stopping the trial.
The OS benefits persisted across subgroups defined by age, visceral involvement, hormone receptor status, number of prior regimens and physician’s choice treatment type. Patients outside of the U.S. tended to achieve more favorable outcomes with T-DM1, but this finding should be interpreted carefully, Wildiers said.
“We should be cautious because these are small numbers and the confidence intervals are wide,” he said.
Mean treatment duration was 7.9 months (range, 0.03-38) on the T-DM1 arm and 4.1 months (range, 0.03-31.2) on the physician’s choice arm.
Grade 3 or worse adverse events occurred in 47.3% of the control arm and 40% of the experimental arm. A greater proportion of patients assigned physician’s choice experienced grade 3 or worse neutropenia (15.8% vs. 2.5%), febrile neutropenia (3.8% vs. 0.2%), dyspnea (3.8% vs. 2.5%), diarrhea (4.3% vs. 0.7%) and asthenia (3.3% vs. 1%); however, more patients assigned T-DM1 experienced thrombocytopenia (6% vs. 2.7%) and anemia (3.5% vs. 3.3%).
“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in OS compared with physician’s choice in patients with HER-2–positive metastatic breast cancer previously treated with taxane, trastuzumab and lapatinib,” Wildiers said. “This result was reached despite at least 50% crossover, and about 80% of patients in the control arm receiving trastuzumab-containing regimens. … The TH3RESA results, together with the EMILIA OS benefit, which was updated and presented at [this meeting], solidify the role of T-DM1 with previously treated HER-2–positive advanced breast cancer.” – by Alexandra Todak
References:
- Wildiers H, et al. Abstract S5-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.
- Krop IE, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70178-0.
- Verma S, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1209124.
Disclosure: The study was funded by Roche. Wildiers reports his institution has received a research grant and consulting and speaker fees from Roche.
Perspective
Back to Top
Kent Osborne, MD
We used to think, and still do in a way, that HER-2–positive breast cancer was one of the more aggressive forms of the disease, and we hated to see a patient come in with a HER-2–positive tumor. Now with our treatments, based on HER-2 and the identification of targeted therapy, it’s actually turned out to be a good tumor to have. This is just another example with the effectiveness of this drug.
Treatment length is an interesting question. All of us have a patient who is on trastuzumab (Herceptin, Genentech) by itself, and some of those patients are out many years. We don’t know if we should stop it or not, and we are getting to the point where we should start asking the question of how long they need to be on it if they are in complete remission.
This treatment had far fewer side effects, and most of those side effects come from the cancer anyway at this stage. If you are putting patients into remission and they’re staying there for a long period of time, their symptoms are markedly improved.
Click Here to Manage Email Alerts