ASCO 2025 | DESTINY-Gastric04: T-DXd versus ramucirumab and paclitaxel in HER2+ GC/GEJA

DESTINY-Gastric04, or DG04 is a randomized Phase III trial to compare trastuzumab deruxtecan, or T-DXd versus ramucirumab plus paclitaxel or ram-pac in patients with HER2 positive after disease progression with first-line trastuzumab treatment. The HER2 status should be confirmed by a re-biopsy after disease progression with trastuzumab. And this study showed statistically and clinically meaningful improvement of overall survival with T-DXd over ram-pac. Actual median survival was 14.7 months with T-DXd and 11.4 months with ram-pac. So there was 3.3 months difference in median with a hazard ratio of 0.70. And PFS as a secondary endpoint as well as response rate was also improved actual response rate was 44% with T-DXd and 29% with ram-pac showing 15% improvement. Efficacy is confirmed and toxicity profile were in line with previous reports of these treatment especially T-DXd can induce pneumonitis or ILD and it was observed in 14% patient but most of them were with grade 1 and grade 2 and only one patient experienced great severity so most of the events were manageable and this study suggested T-DXd is a preferable or better a second-line treatment especially for patients with HER2-positive gastric cancer after first-line trastuzumab treatment and importantly this trial enrolled patient by fresh biopsy so it suggested the importance of confirmation of HER2 status after disease progression to select optimal treatment for patients. If HER2 was negative and if biopsy is not possible, I believe there is no one strategy. I think either T-DXd and ram-pac c is reasonable, but I personally prefer ram-pac if patients are HER2 negative because we can use T-DM1 in later line setting. Thank you.

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