Gastric adenocarcinoma is the fifth most commonly diagnosed malignancy worldwide, with >1 million cases reported annually.1 It is the third leading cause of cancer mortality globally, with many patients being diagnosed at an advanced stage or experiencing relapse after surgery.1 In 15% to 20% of cases of gastric adenocarcinoma, HER2 is dysregulated.1 The ERBB2 gene encodes HER2 with HER2 mutations, amplifications, fusions, and overexpressions found in gastric and gastroesophageal cancers.1 HER2-targeted therapies have been developed to treat gastric adenocarcinoma with more therapies in ongoing development.1 The DESTINY-Gastric01 phase 2 study was a randomized study conducted in Asia to study the antibody–drug conjugate trastuzumab deruxtecan. The participants in this study had locally advanced or metastatic HER2-positive gastric or gastroesophageal cancers. The patients’ cancer progressed on ≥2 lines of therapy including therapy with trastuzumab.
Dr Eric Van Cutsem reported results from the single-arm, phase 2 DESTINY-Gastric02 trial of trastuzumab deruxtecan at the European Society for Medical Oncology Congress 2021. This trial is the first second-line study of trastuzumab deruxtecan in Western patients with HER2-positive gastric or gastroesophageal cancer. The trial included 79 patients from the United States and European Union with centrally confirmed HER2-positive unresectable, metastatic gastric or gastroesophageal junction cancer. These patients progressed while on or after receiving trastuzumab containing first-line therapy and were treated with 6.4 mg/kg trastuzumab deruxtecan intravenously every 3 weeks. Independent central review using RECIST v1.1, confirmed the primary end point, which was the objective response rate. Secondary study end points were progression-free survival, safety, and duration of response by independent central review.
Study participants had a median age of 61 years (range, 20-78 years) and were treated with trastuzumab deruxtecan for a median of 4.3 months (range, 0.7-15.9 months). The median follow-up duration was 5.7 months (range, 0.7-15.2 months). The median time to response was 1.4 months. When response rates were evaluated, it was determined that 3 patients had a complete response, and 27 patients had a partial response. The confirmed objective response rate was 30 (38%; 95% confidence interval, 27.3-49.6). Median progression-free response was 5.5 months, and the median duration of response was 8.1 months.
All patients experienced treatment-emergent adverse events (TEAEs) with 40 experiencing grade ≥3 TEAEs. The most common TEAEs were nausea, vomiting, and fatigue. Interstitial lung disease occurred in 6 patients, primarily grade 1-2, but 1 patient had grade 5 interstitial lung disease. Dose continuation occurred in 12 patients, 19 had dose reductions, and 17 had dose interruption. The overall safety profile was manageable in the participants.
Van Cutsem E, Di Bartolomeo M, Smyth E, et al. Primary analysis of a phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer who progressed on or after a trastuzumab-containing regimen. Ann Oncol. 2021;32(suppl_5):S1283-S1346.
- Ricci AD, Rizzo A, Rojas Llimpe FL, et al. Novel HER2-directed treatments in advanced gastric carcinoma: AnotHER paradigm shift? Cancers (Basel). 2021;13:1664.