The DESTINY-Gastric03 study (abstract number 14010), presented at the 2024 European Society for Medical Oncology (ESMO) Congress (September 13-17, Barcelona), evaluated the efficacy and safety of T-DXd combined with FP and anti-PD-1 as first-line treatment for adenocarcinoma of the esophagus, stomach, or gastroesophageal junction (GEJA). At the conference site, we specially invited the Principal Investigator, Dr. Yelena Janjigian from Memorial Sloan Kettering Cancer Center in the United States, to be interviewed by us on site.

1401O -Trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2-positive (HER2+) esophageal, gastric or gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03 (DG-03)

Dr Janjigian: It is exciting to be at the ESMO 2024 Congress. We presented the DESTINY-Gastric03 study, which is exploring T-DXd (trastuzumab deruxtecan) monotherapy in combination with capecitabine or pembrolizumab in first-line patients with HER2-positive gastric adenocarcinoma. This study was important to be able to bring antibody drug conjugates to the first-line setting. Of course, you know T-DXd is standardly used after trastuzumab failure in the second- and third-line settings. To bring it to first-line, we needed to demonstrate safety and feasibility with capecitabine, and we did that. Excitedly, it was shown that for the combination of T-DXd/capecitabine in the first-line setting, progression-free survival was 20 months. This was a global study including patients in Europe, the United States, and the rest of the world including Asia. We also looked at the combination with pembrolizumab. As KEYNOTE-811 taught us, a combination of dual immune checkpoint blockade with anti-HER2 therapies is important, so we studied the combination of pembrolizumab and T-DXd and capecitabine, and it appeared to be too toxic. The triplet combination with full doses was insufficient, so we are now exploring the lower dose of T-DXd at 5.4 mg/kg plus pembrolizumab and 750 mg/m2  of capecitabine. We know that the triplet regimen is feasible – we demonstrated that. The overall response rate looked favorable, and now we are waiting for updated survival data. In summary, DESTINY-Gastric03 looked at T-DXd monotherapy and the T-DXd combinations. It appears T-DXd in triplet combination is feasible. The phase III studies are exploring the combination of T-DXd 5.4 mg/kg with capecitabine and pembrolizumab or other immune checkpoint blockade for PD-L1 (CPS ≥1) and HER2-positive patients.