Kimberly L. Blackwell, MD
Trastuzumab emtansine (T-DM1, Genentech) extended progression-free survival (PFS) by 3.2 months in women with HER2
-positive locally advanced or metastatic breast cancer, according to data from a phase III trial presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting.
In a press briefing, lead study author Kimberly L. Blackwell, MD, professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University in Durham, North Carolina, said that T-DM1 is part of a new class of targeted therapies known as “antibody drug conjugates” that link antibodies with cytotoxic treatments.
T-DM1 combines the monoclonal antibody trastuzumab (Herceptin, Genentech) with the cytotoxic drug emtansine (DM1) using an MCC stable linker. By combining the treatments, T-DM1 both disrupts HER2 signaling and transports the cytotoxic agent DM1 directly into tumor cells.
In the phase III EMILIA trial, Blackwell et al randomized 978 patients with HER2
-positive breast cancer 1:1 to either T-DM1 or standard therapy with the FDA-approved “XL” doublet (capecitabine [Xeloda, Genentech] and lapatinib [Tykerb, GlaxoSmithKline]). All of the accrued patients had been previously treated with trastuzumab and a taxane.
T-DM1 was administered at a dose of 3.6 mg/kg once every 3 weeks. The XL regimen was also given on a 3-week cycle, with 1000 mg/m2
of capecitabine being administered twice a day on days 1-14, along with daily treatment with 1250 mg of lapatinib. Patients received treatment until disease progression or unmanageable toxicity, at which point patients were not allowed to cross over. The primary endpoints were PFS, overall survival (OS), and safety.
The trial met its PFS endpoint, with T-DM1 delaying disease progression for a median of 9.6 months, as compared with 6.4 months with XL (hazard ratio [HR] = 0.650; 95% CI, 0.549–0.771; P
With OS, the study approached, but did not meet, its primary endpoint. The 2-year OS for patients receiving T-DM1 was 65.4% versus 47.5% in the control arm (HR = 0.621; 95% CI, 0.475-0.813; P
= .0005). These data did not meet a predetermined statistical goal for OS.
At the press conference, Blackwell explained that the targeted P
value for statistical significance in OS was set “very high because of the coprimary endpoints [PFS and OS],” and that there is still “an apparent survival benefit in T-DM1 over the control arm.” A final OS analysis will be forthcoming, Blackwell added.
The safety data revealed that T-DM1 was better tolerated than XL, with fewer treatment-related toxicities and discontinuations. Grade ≥3 adverse events occurred in 57.0% of the XL arm, as compared with 40.8% of the T-DM1 group. Dose reductions were necessary in 53.4%, 27.3%, and 16.3% of patients receiving capecitabine, lapatinib, and T-DM1, respectively.
The most common grade ≥3 adverse events in the T-DM1 arm included thrombocytopenia (12.9%) and elevations in the liver enzymes aspartate transaminase (4.3%) and alanine transaminase (2.9%). Blackwell said that these side effects were manageable through interruptions in treatment.
Based on EMILIA’s efficacy and safety results, Blackwell said she considers the trial to be a success, but that she is uncertain how regulatory agencies will interpret the data.
“From a clinician’s standpoint and from a patient’s standpoint this is definitely a positive study. It’s continuing to be discussed as to whether or not meeting one of the efficacy endpoints, PFS, being extremely close on the second efficacy endpoint, OS, and having a really good safety profile is a positive study in the eyes of the regulatory agencies,” Blackwell said.
“The regulatory discussions are ongoing,” she added. “I will say that both the US and European regulatory authorities have been very considerate in their willingness to [discuss] the data.”
In the meantime, Blackwell said a manuscript of the EMILIA data is being prepared and will soon be submitted for publication in a peer-reviewed journal.