T-DXd, trastuzumab deruxtecan, is an anti-HER2 ADC which showed activity for gastric cancer in multiple studies. For example, DG-01 as a third-line [??] treatment to compare cytotoxic chemotherapy and it showed a survival benefit. DG-02 is a second-line treatment in a non-Asian population which also showed activity. This trial showed a [??] indication in multiple countries. However, there is no randomised study to compare T-DXd and another global second-line standard of care, paclitaxel and ramucirumab, which is used regardless of HER2 status.

What was the methodology and what were the findings?

This DESTINY-Gastric04 is a global randomised open-label phase III trial to compare T-DXd and paclitaxel and ramucirumab as a second-line treatment. This is a phase III randomised study and the primary endpoint was overall survival. We also tested other secondary endpoints like progression free survival, confirmed response rate, duration of response, disease control rate and safety. Patient reported outcomes are also exploratory assessed.

What are the clinical implications of these findings?

This trial showed a statistically and clinically meaningful improvement of overall survival with T-DXd compared with paclitaxel and ramucirumab. The overall survival was 14.7 months with T-DXd and 11.4 months with paclitaxel and ramucirumab, showing a 3.3 months difference in median. The hazard ratio was 0.70 with a significant p-value.

I believe this median exceeded 14 months, it should be the longest median survival in a global second-line phase III study. This study also showed a PFS and response improvement. Actually, the confirmed response rate was 44% with T-DXd and 29% with Ram-Pac. So these results clearly support T-DXd as the preferred second-line treatment for HER2 positive gastric and GEJ cancers.

Is there anything else you would like to add?

I’ll also mention the toxicity profile of this treatment. Common toxicities with T-DXd include fatigue, myelosuppression and GI toxicity. Common toxicities with Ram-Pac include myelosuppression, fatigue, peripheral neuropathy and hypertension. Importantly, pneumonitis or ILD is more commonly observed in T-DXd , the same as previous studies, but most of these events were grade 1 and grade 2 and we could conclude this is a manageable treatment. Surely in clinical practice we should carefully manage patients but, based on these results, I believe T-DXd should be the preferred second-line treatment for the global population for gastric cancer.