All of the women in the study had progressed on two or more HER2-targeted therapies, including Herceptin (trastuzumab) and Tykerb (lapatinib).
Kadcyla (ado-trastuzumab emtansine; T-DM1) reduced the risk of death by 32 percent and improved median overall survival (OS) by almost seven months compared with physician's choice of therapy in heavily pretreated patients with HER2-positive advanced breast cancer. These updated data from the phase 3 TH3RESA study were presented at the 2015 San Antonio Breast Cancer Symposium (SABCS), a gathering of over 7,500 oncologists and oncology professionals.1
All of the women in the study had progressed on two or more HER2-targeted therapies, including Herceptin (trastuzumab) and Tykerb (lapatinib) in the advanced setting, and a taxane in any setting.
“[Kadcyla] 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, [Herceptin], and [Tykerb],” lead author Hans Wildiers, 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 3 TH3RESA trial included 602 women with progressive HER2-positive advanced breast cancer (ECOG performance status from 0 to 2). Patients were randomized from September 14, 2011, to November 19, 2012, in a two-to-one ratio to Kadcyla (404 patients) at 3.6 mg/kg IV every three weeks or physician's choice of treatment (198 patients).
About half of patients in each arm were estrogen receptor (ER) and/or progesterone receptor (PR)-positive, and about three-fourths of patients in each arm had visceral involvement. In the Kadcyla arm, 96.8 percent of patients had metastatic disease at baseline versus 94.4 percent of patients in the control arm. The remainder of patients in each arm had unresectable locally advanced/recurrent disease.
In the Kadcyla arm, 9.9 percent of patients had brain metastasis at baseline, compared with 13.6 percent of patients in the physician's choice group. Wildiers also noted that, “More than half of patients [in both arms] received four or more prior regimens for advanced breast cancer.”
In the physician’s choice arm, 83.2 percent of patients received HER2-directed therapies, including Herceptin-containing regimens for 80.4 percent of patients: chemotherapy/Herceptin (68.5 percent), Tykerb/Herceptin (10.3 percent), and hormonal therapy/Herceptin (1.6 percent). The other patients receiving HER2-targeted therapy were treated with chemotherapy/Tykerb (2.7 percent).
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 Kadcyla. “Importantly, 44.9 percent of the patients in the treatment of physician’s choice arm crossed over to [Kadcyla] at progression within the study. Another 6.6 percent in that arm crossed over to [Kadcyla] as a non-study treatment. So at least 50 percent of patients in the control arm received [Kadcyla] after 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 Kadcyla versus 15.8 months with physician’s choice. 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 Kadcyla versus 3.3 months in the control arm.2
“This is an important trial because it demonstrates that even in patients whose cancer has progressed on multiple other HER2-targeted therapies, treatment with [Kadcyla] substantially extends patient survival compared to other drugs,” senior TH3RESA author, Ian Krop, 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, [Kadcyla] 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, [Kadcyla] had a favorable safety profile which was consistent with prior studies.”
The median duration of treatment was 7.9 months (ranging from 0.03 to 38.0) with Kadcyla versus 4.1 months (ranging from 0.03 to 31.2) with physician’s choice. All-grade adverse events (AEs) occurred in 95.8 percent in the Kadcyla arm versus 89.1 percent in the control arm. Incidences of AEs of at least grade 3 were lower in the Kadcyla arm: 40 percent versus 47.3 percent.
AEs led to discontinuation in 14.6 percent of patents receiving Kadcyla versus 10.9 percent of patients treated with physician’s choice. Dose reductions due to AEs occurred in 13.4 percent and 20.7 percent of the two arms, respectively.
The most frequently occurring all-grade AEs in the Kadcyla arm included fatigue (30.8 percent) thrombocytopenia (20.6 percent), asthenia (19.1 percent), diarrhea (12.7 percent), and increased AST (12.4 percent). In the physician’s choice arm, the most common all-grade AEs included fatigue (26.1 percent), diarrhea (22.3 percent), neutropenia (21.7 percent), asthenia (17.9 percent) and dyspnea (13.0 percent).
AEs of at least grade 3 occurring at the highest rates in the Kadcyla arm included thrombocytopenia (6.0 percent) and anemia (3.5 percent), and neutropenia, increased AST, and dyspnea (each at 2.5 percent). The most frequently occurring AEs of at least grade 3 in the physician’s choice arm were neutropenia (15.8 percent), diarrhea (4.3 percent), febrile neutropenia (3.8 percent), dyspnea (3.8 percent) and anemia (3.3 percent).
Kadcyla is currently approved by the FDA for the treatment of patients with HER2-positive, metastatic breast cancer previously treated with a taxane and Herceptin. The approval was based on the phase 3 EMILIA trial, in which Kadcyla significantly improved survival versus Tykerb/capecitabine, with a median OS of 30.9 months versus 25.1 months, respectively.3
“The TH3RESA results, together with the EMILIA overall survival benefit, solidify the role of [Kadcyla] in the treatment of patients with previously treated HER2-positive advanced breast cancer,” said Wildiers.