7.1.2 Application of Antibody Drug Coupling in the...
T-DM1（trastuzumab emtansine）is an antibody drug coupling consisting of trastuzumab，SMMC linkage and the chemotherapeutic drug maytansine derivative（DM1）.It is a new class of antitumor drugs.It consists of cytotoxic drugs，monoclonal antibodies and ligation structures with dual anti-tumor effects of targeting and cytotoxicity.It is the first antibody-drug conjugate（ADC）for solid tumors.
Dml was developed in the 1970s and 1980s.Tumor remission was observed in patients with breast cancer and lung cancer.Due to the narrow therapeutic index，no further development was performed.After coupling Dml and trastuzumab with a special linker，The drug（T-Dml）specifically binds to HER-2 overexpressing tumor cells，internalizes the drug，and releases Dm1 in the tumor cells.Therefore，T-Dm1 retains both trastuzumab and HER-2.The targeting of positive breast cancer，carrying a highly efficient cytotoxic drug（Dml）into tumor cells，inhibits tubulin polymerization and microtubule dynamics，and exerts anti-tumor effects.In theory，T-Dml can overcome trastuzumab resistance to drug resistance.(https://www.daowen.com)
Early clinical studies of T-DM1 showed good efficacy，with a single-agent effective rate of 26%to 44%in patients who failed trastuzumab treatment.Phase Ⅱ clinical study found that T-DM1 combined with trastuzumab and docetaxel can further prolong the PFS of patients with HER-2 positive advanced breast cancer for 5 months，and the tolerance and safety are significantly better than two.Medicine combination.The administration method used in the T-DM1 clinical trial was 3.6 mg/kg once every 3 weeks.Major adverse reactions included fatigue，nausea，thrombocytopenia，leukopenia，diarrhea，edema，and hair loss，but most were mild.The 2012 ASCO meeting reported the results of a Phase Ⅲ randomized controlled clinical study（EMILIA）.The purpose of the EMILIA study was to evaluate the safety and efficacy of T-DM1 versus lapatinib plus capecitabine in the treatment of patients with HER-2 positive MBC who had failed paclitaxel and trastuzumab therapy.In recurrent metastatic breast cancer with trastuzumab and taxane therapy failure，T-DM1 is superior to the current standard selection of lapatinib+capecitabine in terms of remission rate，PFS，and OS.And less toxic，it is likely to replace the latter as a new standard of care.T-DM1 was approved by the US FDA in 2013 for the second-line treatment of patients with HER-2 positive MBC who had previously received trastuzumab and paclitaxel failure.
The CTNeoBC meta-analysis confirmed that HER2-positive breast cancer is highly responsive to neoadjuvant therapy and that patients with pCR have a better prognosis.However，there is no evidence of large clinical studies for patients who have residual disease in neoadjuvant therapy.KATHERINE is the first study to optimize treatment of HER-2-positive breast cancer with residual lesions after neoadjuvant therapy.The median follow-up of 41 months showed that the KATHERINE study reached the primary end point of the study.The iDFS was 88.3%in the T-DM1 group（no invasive disease survival）and 77.0%in the trastuzumab group.The absolute difference between the two groups was 11.3.%，HR was 0.5（95%CI，0.39-0.64），P＜0.0001，which means that for patients with HER2-positive breast cancer who still have residual lesions after neoadjuvant therapy，treatment with T-DM1 can further reduce recurrence and risk of death by 50%.In terms of safety，there was no new adverse event in T-DM1 compared with previous studies.The incidence of peripheral neuropathy，elevated alanine aminotransferase，elevated aspartate aminotransferase，and thrombocytopenia was higher than that of trastuzumab group.