5/9/2023 0 Comments T dm1 mechanism of action![]() Patients in the capecitabine/lapatinib arm with PIK3CA mutations had worse outcomes than those with wild-type PIK3CA, but the presence of PIK3CA mutations did not have any effect on progression-free or overall survival in patients treated with T-DM1. In the high expressors, median progression-free survival was 34.1 months on T-DM1 vs 24.8 months on capecitabine/lapatinib. However, patients with tumors that expressed high HER2 mRNA levels derived even more benefit from T-DM1 than those with lower levels of expression. In all biomarker subgroups, T-DM1 achieved superior progression-free and overall survival. Median HER2 mRNA concentration ratios and PIK3CA mutation frequencies were similar across all treatment arms. Progression-free and overall survival were analyzed for each biomarker subgroup according to amount of HER2 mRNA expression and PIK3CA mutation frequency. Tumor samples were collected prospectively from patients enrolled in EMILIA for analysis of EGFR, HER2 mRNA, and PIK3CA. At a median follow-up of 20 months, T-DM1 also improved overall survival by 32% median overall survival was 30.9 months with T-DM1 vs 25.1 months for capecitabine plus lapatinib. In that trial, T-DM1 significantly improved progression-free survival by 35% from a median of 6.4 months with capecitabine plus lapatinib vs 9.6 months for T-DM1 ( P < .001). The pivotal phase III EMILIA trial compared the effectiveness of TDM-1 vs lapatinib and capecitabine (Xeloda) in patients previously treated with trastuzumab plus taxane chemotherapy. “T-DM1 is 10,000 times more potent than vinorelbine, for example,” he noted. Baselga pointed out that emtansine is so potent that it cannot be given on its own. Trastuzumab homes in on the HER2 protein in HER2-positive breast cancers and releases emtansine into the tumor cells, thereby killing them. The compound attaches the antibody trastuzumab to a toxic chemotherapy called emtansine. T-DM1 is a novel antibody-drug conjugate with a mechanism of action that differs from that of classical anti-HER2 therapies. These data will help us as we identify a panel of molecular features that we can use to make informed treatment decisions,” stated Jos é Baselga, MD, Physician-in-Chief at Memorial Sloan-Kettering Cancer Center in New York. The findings are an important step toward identifying the best therapy for individual patients with HER2-positive breast cancer. “HER2-positive breast cancer is not a uniform disease. The study, which was presented at the Annual Meeting of the American Association for Cancer Research, 1 also suggests that the presence of PI3 kinase (PIK3CA) mutations in HER2-positive breast tumors does not compromise the effectiveness of T-DM1, but does lead to poorer responses to conventional HER2-targeted therapies such as trastuzumab (Herceptin) and lapatinib (Tykerb). A biomarker analysis of the pivotal EMILIA trial suggests that women with metastatic HER2-positive breast cancer with tumors that have high expression of HER2 derive the most robust benefit from treatment with the antibody-drug conjugate T-DM1 (also now known as ado-trastuzumab emtansine ).
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