Jason M. Broderick
Hans Wildiers, MD, PhD
T-DM1 (ado-trastuzumab emtansine; Kadcyla) reduced the risk of death by 32% and improved median overall survival (OS) by almost 7 months compared with physician's choice of therapy in heavily pretreated patients with HER2-positive advanced breast cancer, according to updated data from the phase III TH3RESA study presented at the 2015 San Antonio Breast Cancer Symposium (SABCS).1
All of the women in the study had progressed on 2 or more HER2-targeted therapies, including trastuzumab (Herceptin) and lapatinib (Tykerb) in the advanced setting, and a taxane in any setting.
“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival compared to a treatment of physician’s choice in patients with HER2-positive metastatic breast cancer previously treated with a taxane, trastuzumab, and lapatinib,” lead author Hans Wildiers, MD, PhD, a professor of Medical Oncology at KU Leuven in Belgium, said when presenting the data in a press briefing at SABCS.
The open-label phase III TH3RESA trial included 602 women with progressive HER2-positive advanced breast cancer (ECOG performance status, 0-2). Patients were randomized from September 14, 2011, to November 19, 2012, in a 2:1 ratio to T-DM1 (n = 404) at 3.6 mg/kg IV every 3 weeks or physician's choice of treatment (n = 198).
About half of patients in each arm were ER and/or PR-positive, and about three-fourths of patients in each arm had visceral involvement. In the T-DM1 arm, 96.8% of patients had metastatic disease at baseline versus 94.4% of patients in the control arm. The remainder of patients in each arm had unresectable locally advanced/recurrent disease.
In the T-DM1 arm, 9.9% of patients had brain metastasis at baseline, compared with 13.6% of patients in the physician's choice group. Wildiers also noted that, “More than half of patients [in both arms] received 4 or more prior regimens for advanced breast cancer.”
In the physician’s choice arm, 83.2% of patients received HER2-directed therapies, including trastuzumab-containing regimens for 80.4% of patients: chemotherapy/trastuzumab (68.5%), lapatinib/trastuzumab (10.3%), and hormonal therapy/trastuzumab (1.6%). The other patients receiving HER2-targeted therapy were treated with chemotherapy/lapatinib (2.7%).
The primary outcome measures for the trial were OS and progression-free survival (PFS). Following an interim analysis in September 2012, patients were allowed to cross over from the control arm at progression and receive T-DM1. “Importantly, 44.9% of the patients in the treatment of physician’s choice arm crossed over to T-DM1 at progression within the study. Another 6.6% in that arm crossed over to T-DM1 as a non-study treatment. So at least 50% of patients in the control arm received T-DM1after progression on their treatment of physician's choice," said Wildiers.
At a median follow-up of 30.5 months (338 events), median OS was 22.7 months with T-DM1 versus 15.8 months with physician’s choice (HR, 0.68; 95% CI, 0.54-0.85; P
= .0007). The OS benefit was observed regardless of age, visceral involvement, hormone receptor status, number of prior regimens, and physician’s selection of therapy.
Previously published data showed that PFS was also significantly improved with the antibody-drug conjugate. Median PFS was 6.2 months with T-DM1 versus 3.3 months in the control arm (HR, = 0.528; 95% CI, 0.422-0.661; P
“This is an important trial because it demonstrates that even in patients whose cancer has progressed on multiple other HER2-targeted therapies, treatment with T-DM1 substantially extends patient survival compared to other drugs,” senior TH3RESA author, Ian Krop, MD, PhD, senior physician in the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, said in a statement. “Based on this study and others, T-DM1 should be considered the standard of care for patients whose cancer has progressed on a HER2-targeted treatment."
Regarding toxicities in the study, Wildiers said, “Despite longer treatment duration relative to control, T-DM1 had a favorable safety profile which was consistent with prior studies.”
The median duration of treatment was 7.9 months (range, 0.03-38.0) with T-DM1 versus 4.1 months (range, 0.03-31.2) with physician’s choice. All-grade adverse events (AEs) occurred in 95.8% in the T-DM1 arm versus 89.1% in the control arm. Incidences of grade ≥3 AEs were lower in the T-DM1 arm: 40% versus 47.3%.
AEs led to discontinuation in 14.6% of patents receiving T-DM1 versus 10.9% of patients treated with physician’s choice. Dose reductions due to AEs occurred in 13.4% and 20.7% of the 2 arms, respectively.
The most frequently occurring all-grade AEs in the T-DM1 arm included fatigue (30.8%) thrombocytopenia (20.6%), asthenia (19.1%), diarrhea (12.7%), and increased AST (12.4%). In the physician’s choice arm, the most common all-grade AEs included fatigue (26.1%), diarrhea (22.3%), neutropenia (21.7%), asthenia (17.9%), and dyspnea (13.0%).
Grade ≥3 AEs occurring at the highest rates in the T-DM1 arm included thrombocytopenia (6.0%) and anemia (3.5%), and neutropenia, increased AST, and dyspnea (each at 2.5%). The most frequently occurring grade ≥3 AEs in the physician’s choice arm were neutropenia (15.8%), diarrhea (4.3%), febrile neutropenia (3.8%), dyspnea (3.8%), and anemia (3.3%).
T-DM1 is currently approved by the FDA for the treatment of patients with HER2-positive, metastatic breast cancer previously treated with a taxane and trastuzumab. The approval was based on the phase III EMILIA trial, in which T-DM1 significantly improved survival versus lapatinib/capecitabine, with a median OS of 30.9 months versus 25.1 months, respectively (HR, 0.68; P
“The TH3RESA results, together with the EMILIA overall survival benefit, solidify the role of T-DM1 in the treatment of patients with previously treated HER2-positive advanced breast cancer,” said Wildiers.
Wildiers H, Kim S-B, Gonzalez-Martin A, et al. Trastuzumab emtansine improves overall survival versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study. Presented at: 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract S5-05.
Krop IE, Kim SB, González-Martín A, et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(7):689-699.
Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791.
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