Around 20% of advanced-stage gastric cancers express HER2, and the HER2-targeted therapy trastuzumab, plus chemotherapy, is an approved first-line therapy in this setting. However, other HER2-targeted therapies (including pertuzumab, lapatinib and trastuzumab emtansine) are ineffective following disease progression on trastuzumab. Now, data from the DESTINY-Gastric01 trial demonstrate that the antibody–drug conjugate trastuzumab deruxtecan (T-DXd) is superior to chemotherapy in this setting.
In this phase II trial, investigators randomized 187 patients with HER2+, locally advanced or metastatic gastric or gastroesophageal junction cancer with disease progression on ≥2 prior lines of therapy, including trastuzumab in all patients, (2:1) to receive either T-DXd or chemotherapy with irinotecan or paclitaxel. Objective response was the primary outcome.
Patients receiving T-DXd had significantly improved confirmed objective response rates (ORRs), as determined by independent central review, compared with those receiving chemotherapy (51% versus 14%; P < 0.001). T-DXd also resulted in longer median duration of response (11.3 months versus 3.9 months) among those with objective responses lasting ≥4 weeks. These improvements in ORR and duration of response are reflected in a significant improvement in the median overall survival duration: 12.5 months versus 8.4 months (HR 0.59, 95% CI 0.39– 0.88; P = 0.01).
Patients receiving T-DXd had a higher risk of grade ≥3 adverse events, including reduced neutrophil counts (51% versus 24%), anaemia (38% versus 23%) and reductions in white blood cell count (21% versus 11%). A higher percentage of patients receiving T-DXd discontinued treatment owing to adverse events (15% versus 6%).
These findings support T-DXd as a new targeted approach for patients with HER2+ advanced-stage gastric cancer. Nonetheless, this approach is more toxic than chemotherapy, and adverse events remain an important consideration.
Shitara, K. et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2004413 (2020)
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Sidaway, P. Trastuzumab deruxtecan improves survival. Nat Rev Clin Oncol 17, 521 (2020). https://doi.org/10.1038/s41571-020-0406-y