The late gastric cancer after the line "every life", DS-8201 strong effect to overcome front-line drug resistance! New advances in drugs.

In May 2020, trastuzumab deruxtecan (ds-8201) was awarded the title of orphan drug in gastric cancer by FDA. Before that, ds-8201 had been recognized as a breakthrough therapy by FDA in the field of gastric cancer.at this year's ASCO conference, ds-8201 updated the data of back-line treatment for HER2 positive gastric cancer, breast cancer, lung cancer and colorectal cancer.the destiny-gastric01 study is a multicenter, phase II open label study to further evaluate the efficacy and safety of ds-8201 in patients with advanced HER2 expression who have progressed through at least two treatments. The results of the study were recently published in the journal NEJM.1 background the incidence of gastric cancer and gastroesophageal junction cancer is high in East Asia. According to statistics, HER2 overexpression or amplification occurs in 15% - 20% of advanced patients.based on the phase III toga study (median OS 13.8 months and 11.1 months), chemotherapy plus trastuzumab is currently the recommended first-line treatment.a study showed that the median OS of paclitaxel plus ramorumab and paclitaxel monotherapy were 9.6 months and 7.4 months, respectively, and the median progression free survival (PFS) was 4.4 months and 2.9 months, respectively, and the remission rates were 28% and 16%, respectively.based on this, regardless of HER2 expression, paclitaxel + ramorumab is recommended for second-line treatment of advanced gastric cancer.for posterior line therapy, irinotecan, taxanes, trifluridine – tipiracil (3.6 months vs 5.7 months) and immunosuppressive checkpoint inhibitors (4.1 months vs 5.3 months) for posterior line therapy, with limited improvement in OS compared with placebo.in addition, several HER2 targeted drugs did not prolong OS in patients with gastric cancer.ds-8201 is a novel antibody drug conjugate consisting of humanized anti HER2 monoclonal antibody trastuzumab, cleavable peptide linker and topoisomerase I inhibitor. It has been approved for the treatment of metastatic HER2 positive breast cancer in the United States and Japan.in the phase I study of ds-8201 (ds8201-a-j101), the efficacy of 5.4mg or 6.4mg/kg was evaluated in 44 patients with her positive gastric cancer or gastroesophageal junction cancer after trastuzumab treatment. The orr was 43.2%, the median duration of remission was 7.0 months, and the median PFS was 5.6 months In patients, Orr was 41.7%, which indicated that the cross resistance with ds8201 payload was the least.destiny-gastric01 is a multicenter, phase II open label study to further evaluate the efficacy and safety of ds-8201 in patients with advanced HER2 expression who have progressed through at least two treatments.this year ASCO also released the latest data of this study.2 study methods patients with HER2 positive gastric cancer or gastroesophageal junction cancer confirmed by histology and who had received at least two treatments were included in the study. The enrolled patients were randomized to receive ds-8201 or the chemotherapy regimen selected by the researchers in a 2:1 ratio. The primary endpoint was orr assessed by the independent review committee, and the secondary endpoints included overall survival (OS), PFS, etc.3 results a total of 188 patients from Japan and South Korea were included from 2017 to 2019, with 187 patients receiving treatment. There were 125 patients in ds-8201 group and 62 patients in chemotherapy group.as of November 8, 2019, 22% and 5% of patients in the two groups continued to receive treatment, and the median duration of treatment was 4.6 months. The orr of ds-8201 group was significantly higher, 51% and 14% respectively (P < 0.001).of the 119 patients in the ds-8201 group, 10 patients achieved complete remission, while 56 patients in the chemotherapy group did not. The median duration of remission was 11.3 months and 3.9 months in the ds-8201 group and 3.9 months in the chemotherapy group. The disease control rates were 86% and 62% in the ds-8201 group. The median OS was 12.5 months and 8.4 months in the ds-8201 group (P = 0.01). The OS rates at 6 months and 12 months were 80% vs 66% and 52% respectively The median PFS was 5.6 months and 3.5 months.4 conclusion and discussion results further confirm the efficacy of ds-8201 in advanced HER2 positive gastric cancer or gastric esophageal junction cancer.ds-8201 significantly increased orr (51% vs 14%) in late stage patients compared with other three line therapy or posterior line therapy.acquired resistance to trastuzumab is very common. Studies have suggested a variety of possible drug resistance mechanisms, including the activation of PI3K-Akt signaling pathway and other growth factor receptor signaling pathways. In addition, the down-regulation of HER2 expression and the change of HER2 expression after trastuzumab treatment, together with the heterogeneity of HER2 expression in gastric cancer patients, may limit the efficacy of HER2 targeted therapy 01 showed activity in breast cancer cells with low HER2 expression and tumor cells with different HER2 expression. Its high drug antibody ratio and membrane permeability of payload may make it less dependent on HER2 high expression.different from metastatic breast cancer, HER2 positive gastric cancer patients have no other HER2 targeted drugs except trastuzumab.continued trastuzumab versus paclitaxel did not prolong survival in patients with advanced gastric cancer.chemotherapy plus PD-1 inhibitors showed limited and moderate survival benefits and low efficiency. PD-L1 inhibitors did not improve the survival of patients compared with chemotherapy. Br / > 20 20: English Trevi n doi:10.1056/NEJMoa2004413