ESMO 2025 | DESTINY-Gastric04: T-DXd vs RAM plus PTX in 2L treatment of HER2+ unresectable/metastatic GC/GEJA

The DESTINY-Gastric04 study is a practice-changing trial. It’s a Phase III study enrolling patients with Gastric Cancer and Gastroesophageal Cancer adenocarcinoma and their HER2 positive status in the second-line setting. So all patients were pre-treated with a first-line trastuzumab-containing regimen and all patients were required to undergo a second biopsy after progression on trastuzumab to confirm HER2 positivity after trastuzumab and so this trial basically randomized patients to the previous standard of care with paclitaxel and ramucirumab versus trastuzumab deruxtecan at the dose of 6.4 milligrams per kg. The trial was positive and as a ratio for overall survival which was the primary endpoint was 0.7 and the median absolute gain was 3.3 months with 11.7 months, 14.7 months in the experimental arm. So this was really achieving the best results in the second-line setting for HER2-positive disease. And we know that trastuzumab deruxtecan is approved in several countries, more than 60 countries, I guess, in the second and third-line setting. But based on the DESTINY-Gastric04 study results, of course, this is more a second-line option. So this trial really established the place in therapy of trastuzumab deruxtecan in the second-line setting after failure of trastuzumab-based chemotherapy. And the additional data presented here basically compared local versus central testing over time, because at the end of the study, an amendment allowed the investigators to reassess HER2 status based on local testing. And so 133 patients at the end of the study had the option to undergo local testing and HER2 confirmation. And then the majority of these patients had also central testing. So if we compare the results of the general study of the overall results of the study with the patient population with both central and local testing, we see that the results are unchanged. So basically confirming that re-biopsying the patients in clinical practice is good. If feasible, of course, we should consider several factors such as worsening of the patient condition, feasibility of the biopsy, because it’s not mandatory to redo the biopsy in clinical practice it’s not in the drug label so we can decide on a patient-by-patient basis what to do in clinical practice however in the clinical trial which is important the concordance between local and central testing was 80 percent confirming that this is a high concordance rate and central confirmation initially required by the protocol can be useful for getting good trial results but in clinical practice we may rely on initial biopsies and on our local pathologists as well.

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