Topo its game.

Top Line: 15-20% of gastric cancers are HER2+ creating a fertile ground for HER2 manipulation.

The Study: Trastuzumab-deruxtecan (aka Enhertu) is a topoisomerase I inhibitor bound to an anti-HER2 monoclonal antibody (think Kadcyla without the taxane). The topoisomerase inhibitor is potent, and the conjugate is cleaved when it binds cells leading to high membrane permeability. DESTINY-Gastric01 was a randomized phase 2 trial that compared this drug to the choice of irinotecan or paclitaxel in over 180 patients with HER2+ advanced gastric or EG junction cancer progressing after two prior lines of therapy that included platinum, fluoropyrimidine, and trastuzumab. This publication includes analysis of only patients with high level, 3+ HER2 expression or 2+ expression with FISH-amplification. In the end, the primary endpoint of objective response was way higher with trastuzumab-deruxtecan (51%) than with chemo (14%). Of these, 43% and 12%, respectively, had a confirmed response lasting more than 4 weeks. And the median duration of response was almost 3 times higher with trastuzumab-deruxtecan (11 months) than with chemo (4 months). This resulted in a significant improvement in the secondary outcome of median overall survival from >8 → >12 months and in 12-month overall survival from 29 → 52%. An important side effect of trastuzumab-deruxtecan is pneumonitis at a rate of 10%.

TBL: Trastuzumab-deruxtecan could be a new breakthrough for HER2+ gastric cancer. | Shitara, N Eng J Med 2020