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Trastuzumab deruxtecan improves survival

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.


Original article

  1. Shitara, K. et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N. Engl. J. Med. (2020)

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Correspondence to Peter Sidaway.

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Sidaway, P. Trastuzumab deruxtecan improves survival. Nat Rev Clin Oncol 17, 521 (2020).

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