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The phase III DESTINY-Gastric04 trial randomized HER2+ metastatic gastric/GEJ adenocarcinoma progressing on trastuzumab to T-DXd versus RAM+PTX, showing a significant overall survival (OS) benefit with T-DXd (14.7 vs 11.4 months) and improved PFS (6.7 vs 5.6 months). Objective response rate (ORR) was higher with T-DXd (44.3% vs 29.1%), and duration of response was longer (7.4 vs 5.3 months). Grade ≥3 AE rates were comparable (50.0% vs 54.1%), though adjudicated ILD/pneumonitis was more frequent with T-DXd (13.9% vs 1.3%, mostly grade 1–2), underscoring the need for vigilant monitoring. Bottom line: T-DXd looks like the new second-line standard for HER2+ disease that stays HER2-positive post-trastuzumab—meaningful survival gains. Please make sure to plan for a repeat biopsy in this setting.

The DESTINY-Gastric04 trial compared trastuzumab deruxtecan (T-DXd) vs ramucirumab + paclitaxel as second-line therapy for HER2+ advanced gastric or gastroesophageal junction (GEJ) cancer, showing significant improvements in progression-free survival (PFS) (7.1 vs 5.7 months) and overall survival (OS) (13.6 vs 10.2 months). The antibody-drug conjugate (ADC) also achieved a higher objective response rate (43.6% vs 28.4%). This is no surprise as this T-DXd seems to be a game changer in many diseases. Toxicities were as expected.

The RINDBeRG phase III trial investigated Ram + IRI versus IRI alone in Ram-refractory advanced gastric cancer, showing a significant improvement in progression-free survival (PFS) (3.8 vs 2.8 months) but no significant difference in overall survival (OS) (9.4 vs 8.5 months). The combination therapy achieved a higher overall response rate (ORR) (22.1% vs 15.0%) and disease control rate (DCR) (64.4% vs 52.1%), indicating likely modest antitumor activity. This combo offers a slight edge in delaying progression, but the lack of overall survival (OS) benefit means we’ll need to carefully consider its role in practice.

This is another option for gastric cancer that is showing efficacy in non-HER-2 neutrophils, as Enhertu showed superiority in a recent study in the second line over taxol and cyramza (destiny gastric 4).

Preoperative chemoradiation added to perioperative chemotherapy (ECF/ECX or FLOT) was not beneficial. Of note this study was done in a non-US, predominantly caucasian population. It seems XRT has less and less of a role in gastroesophageal junction / gastroesophageal (GEJ/GE) cancers.

Fruquintinib was recently approved for colorectal cancer, advanced refractory stage. It is an oral VEGF inihibitor, now in combination with taxol, showing improved progression-free survival (PFS) and trends to improve overall survival (OS), another option for those patients for second line therapy. This PFS benefit was close to benefit of adding ramucirimab to taxol. This combination showed OS benefit, too. So, it is not surprising that adding VEGF to taxol showed superiority to taxol alone in those patients. In both trials, immunotherapy was not used in the first line setting.

Interesting correlation between H. Pylori infection and increased risk of gastric cancer in patients with pathogenic homologous-recombination mutations. The risk was additive and not multiplicative as many had thought.