Trastuzumab emtansine

T-DM1 Prolongs Survival in Advanced HER2-Positive Breast Cancer.

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The drug-antibody conjugate was more effective and less toxic than lapatinib plus capecitabine in patients previously treated with trastuzumab and a taxane.

We can expect that the next breast cancer drug soon to be approved by the FDA will be trastuzumab emtansine (T-DM1), an antibody-drug conjugate combining trastuzumab with a derivative of the cytotoxic maytansine via a stable linker molecule (JW Oncol Hematol Oct 2 2012). T-DM1 is more than just another new agent. It represents vindication for those who have worked on fusion molecules for the last 2 decades. Previous efforts with such molecules were often derailed because the linker was either unstable (resulting in systemic exposure to the toxin) or cytotoxic (resulting in prohibitive adverse effects). With T-DM1, intracellular drug delivery only to human epidermal growth factor receptor 2 (HER2)–overexpressing tumor cells has been observed.

Now, investigators report the results of the EMILIA study, an industry-sponsored, phase III, randomized, open-label trial involving 991 patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane. Patients received either T-DM1 or lapatinib plus capecitabine (LC) and were stratified by world region, number of prior chemotherapy regimens for advanced disease, and presence or absence of visceral disease. Primary endpoints were progression-free survival (PFS), overall survival (OS), and safety; secondary endpoints included objective response rate, duration of response, and time to symptom progression.

Median PFS was significantly longer with T-DM1 versus LC (9.6 vs. 6.4 months; hazard ratio, 0.65; P<0.001), as was median OS (30.9 vs. 25.1 months; HR, 0.68; P<0.001). Overall response rate was also superior with T-DM1 versus LC (43.6% vs. 30.8%; P<0.001), as were results for all secondary endpoints. Rates of grade 3 or 4 adverse events were 40.8% with T-DM1 and 57.0% with LC.

Comment: The excitement surrounding the anticipated FDA approval of T-DM1 is justified given that the drug successfully targets HER2-overexpressing disease with potent antitumor activity minus the full complement of adverse effects associated with typical chemotherapy partnered with trastuzumab. Of course, the stage is set for exploring T-DM1 in combination with other anti-HER2 agents, including pertuzumab (JW Oncol Hematol Jan 24 2012). Because the toxicity of T-DM1 is quite modest, adjuvant trials are under way to compare the use of this compound with standard trastuzumab-based regimens.

Source: Journal Watch Oncology and Hematology

 

The Next Big Thing for Metastatic Breast Cancer.

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The drug-antibody conjugate trastuzumab emtansine demonstrated single-agent activity in patients with previously treated HER2-positive disease.

Even with the recent approval of pertuzumab as a component (along with trastuzumab and docetaxel) of a first-line regimen for patients with human epidermal growth factor receptor 2 (HER2)–positive, metastatic breast cancer, the anticipated approval of trastuzumab emtansine (T-DM1) is eagerly awaited by oncologists as a treatment for patients with progressive HER2-positive breast cancer following treatment with trastuzumab. Indeed, clinical experience with T-DM1 — a fusion molecule combining trastuzumab with a cytotoxic (maytansine) utilizing a stable linker (see illustration) — has shown robust clinical activity following prior anti-HER2 therapy with relatively modest toxicity (J Clin Oncol 2011 Feb; 29:398).

Now, investigators have conducted an industry-supported, single-arm, phase II clinical trial to evaluate the effectiveness of T-DM1 (3.6 mg/kg intravenously, every 3 weeks) in 110 patients with metastatic HER-2-positive breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. Patients had previously received a median of seven prior nonendocrine agents.

At median follow-up of 17.4 months, the objective response rate (the primary objective) was 34.5%, the clinical benefit rate (inclusive of stable disease) was 48.2%, and median progression-free survival (PFS) was 6.9 months. T-DM1 was well tolerated. Most adverse events were grade 1 or 2. The most common events of any grade were fatigue, nausea, and thrombocytopenia. Grade 3 or 4 thrombocytopenia occurred in 9.1% of patients, and grade 3 fatigue occurred in 4.5%.

Comment: T-DM1 was recently shown to be superior to combination capecitabine and lapatinib in metastatic breast cancer patients who were not as heavily pretreated as those in the current study (JW Oncol Hematol Jul 3 2012). T-DM1 will be rapidly embraced by clinical oncologists once it is approved, and the future development of this agent will likely move to earlier-stage breast cancer and be used in combination with other HER2-targeted agents such as pertuzumab.

Source:Journal Watch Oncology and Hematology