Trastuzumab Deruxtecan Is Safe and Active in HER2-Expressing Tumors

HER2 is overexpressed in multiple tumor types including a subset of patients with breast cancer or gastric cancer. Several HER2-targeting therapies have been evaluated including the anti-HER2 antibody trastuzumab, and the antibody–drug conjugate trastuzumab emtansine (T-DM1), which links trastuzumab to a microtubule inhibitor payload. Although T-DM1 extends survival in patients with breast cancer, the microtubule inhibitor is associated with dose-limiting toxicities. The antibody–drug conjugate trastuzumab deruxtecan links an anti-HER2 antibody to a topoisomerase I inhibitor payload and was designed to overcome the limitations of trastuzumab and T-DM1. In preclinical studies trastuzumab deruxtecan had activity in tumors expressing both high and low levels of HER2, including tumors resistant to T-DM1. Based on the preclinical efficacy, Doi and colleagues evaluated the safety, tolerability, and activity of trastuzumab deruxtecan in a first-in-human, open-label, phase I dose-escalation study. In total, 24 patients with refractory breast, gastric, or gastroesophageal carcinomas were treated with trastuzumab deruxtecan. The primary objectives were assessment of the safety and tolerability of trastuzumab deruxtecan and determination of the maximum tolerated or recommended phase II dose. Secondary outcomes included assessment of antitumor activity. Overall, 10 of 23 evaluable patients (43%) achieved an objective response, including 6 patients with tumors expressing low levels of HER2 and 9 patients who had previously been treated with trastuzumab. Further, 21 patients (91%) experienced disease control. Trastuzumab deruxtecan was well tolerated, and no patients experienced dose-limiting toxicities. Serious adverse events occurred in only 3 patients, who experienced febrile neutropenia, intestinal perforation, or cholangitis. Taken together, these findings suggest that trastuzumab deruxtecan is safe and exhibits antitumor activity in patients with both HER2^lo and HER2^hi breast and gastric cancers and may overcome the limitations of other antibody–drug conjugates. These findings support further clinical investigation of trastuzumab deruxtecan, which is ongoing in the dose-expansion phase of this study.

Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol 2017 Oct 13 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.