Frontline Disitamab Vedotin Yields Responses in Gastric/GEJ Cancer With Various HER2 Expression Levels

Disitamab Vedotin in HER2-Expressing

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The combination of first-line disitamab vedotin (Aidixi), toripalimab (Loqtorzi), and trastuzumab (Herceptin) generated favorable efficacy outcomes vs toripalimab plus trastuzumab and CAPOX (capecitabine and oxaliplatin) in patients with HER2-overexpressing locally advanced or metastatic gastric or gastroesophageal junction (GEJ) cancer, according to data from the phase 2 portion of a phase 2/3 trial (NCT05980481).

Furthermore, first-line disitamab vedotin plus toripalimab and CAPOX produced superior efficacy outcomes vs toripalimab plus CAPOX alone in patients with HER2-median/low–expressing locally advanced/metastatic gastric/GEJ cancer.

The data, which were presented at the 2025 ASCO Annual Meeting, showed that among patients with HER2-overexpressing tumors (n = 51), the confirmed objective response rate (cORR) was 82.4% in the disitamab vedotin/toripalimab/trastuzumab arm compared with 68.8% in the control arm after a median follow-up of 13.2 months. Notably, the median progression-free survival (PFS) was not reached (NR) in the treatment arm vs 14.1 months in the control arm (HR, 0.59; 95% CI, 0.20-1.70).

For patients with HER2-median/low–expressing tumors (n = 48), stage 1 results at a median follow-up of 10.4 months showed a cORR of 72.0% for patients who received DV plus toripalimab and CAPOX vs 47.8% in patients who received toripalimab plus CAPOX. The triplet regimen also extended the median PFS to 9.9 months vs 7.2 months for the doublet (HR, 0.69; 95% CI, 0.32-1.47).

In stage 2 for the same cohort, dose optimization further reinforced these trends. Patients receiving disitamab vedotin at 2.5 mg/kg with toripalimab and CAPOX achieved a cORR of 71.4%, whereas those who received disitamab vedotin at 2.0 mg/kg with the same combination had a 66.7% cORR. Patients in the control arm had a cORR of 58.3%. The median PFS in each of these populations was was NR, 8.3 months, and NR, respectively.

Summarizing the efficacy data for each cohort, lead author Lin Shen, MD, said, “For the HER2-overexpressing patients, the disitamab vedotin at 2.5 mg/kg, toripalimab, and trastuzumab combination demonstrated the strongest efficacy. In the HER2-median/low cohort, the disitamab vedotin at 2.5 mg/kg, toripalimab, and CAPOX regimen emerged as the preferred option.” Shen is the vice president of clinical oncology at Beijing Cancer Hospital and Peking University and deputy director of the Beijing Institute for Cancer Research in China.

Study Design

Patients in the HER2-overexpressing cohort were randomly assigned to 1 of 3 arms. Patients in arm 1 received 2.5 mg of disitamab vedotin plus toripalimab and CAPOX. Those in arm 2 received disitamab vedotin at 2.5 mg/kg plus toripalimab and trastuzumab. Those in arm 3 received toripalimab plus trastuzumab and CAPOX.

The HER2-median/low cohort compared disitamab vedotin at 2.5 mg/kg plus toripalimab and CAPOX (arm 1) vs toripalimab plus CAPOX (arm 2) in stage 1, followed by disitamab vedotin dose optimization in stage 2.

To be eligible, patients had to be naive to systemic chemotherapy for locally advanced/metastatic gastric/GEJ cancer, have histologically or cytologically confirmed unresectable locally advanced/metastatic gastric/GEJ cancer, and have an ECOG performance status of 0 or 1. For each cohort, the primary end point was ORR, and secondary end points were overall survival, PFS, duration of response, and safety.

Across both cohorts, most patients were male, the median age was consistent, and the dominant primary cancer was GEJ, with the exception of patients in the stage 2 dose-optimization arm, in which the numbers of patients with gastric and GEJ cancer were equal.

Safety Data and Next Steps

Overall, among patients in the HER2-overexpressing cohort, safety findings suggested that those in arm 2 had the most favorable safety outcomes. Among patients in the HER2-median/low-expressing cohort, those who received disitamab vedotin at 2.5 mg/kg plus toripalimab and CAPOX in the stage 2 dose-optimization portion had the most favorable outcomes.

Regarding specific grade 3 to 5 treatment-related adverse effects (TRAEs), the most common among patients in arm 1 of the HER2-overexpressing cohort were decreased neutrophil counts (61.1%), diarrhea (44.4%), and decreased platelet counts (27.8%). Among those in arm 2, the most common TRAEs were decreased neutrophil counts (47.1%), anemia (17.6%), and hypokalemia (11.8%). Among those in arm 3, the most common TRAEs were decreased platelet counts (43.8%), anemia (18.8%), and decreased neutrophil counts (12.5%).

Among patients in the stage 1 HER2-median/low-expressing cohort, the most common grade 3 to 5 TRAEs in arm 1 were decreased neutrophil counts (48%), diarrhea (44.0%), and decreased platelet counts (28.0%). In arm 2, the most common TRAEs were decreased platelet counts (34.8%), decreased neutrophil counts (26.1%), and decreased lymphocyte counts (13.0%).

In the stage 2 dose-optimization portion, the most common TRAEs among patients who received disitamab vedotin at 2.5 mg/kg plus toripalimab and CAPOX were decreased neutrophil counts (42.9%), hypokalemia (21.4%), and decreased appetite (21.4%). Among patients who received disitamab vedotin DV at 2.0 mg/kg arm plus toripalimab and CAPOX, the most common TRAEs were decreased neutrophil counts (20.0%), diarrhea (13.3%), and hypokalemia (13.3%). For patients in the toripalimab/CAPOX arm, the most common TRAEs were decreased platelet counts (18.8%), anemia (18.8%), and decreased neutrophil counts (12.5%).

“An ongoing phase 3 study [NCT06944496] is evaluating disitamab vedotin [plus] PD-1 [inhibition] and CAPOX vs PD-1 [inhibition] and CAPOX [alone] in patients with HER2-median/low-expressing locally advanced/metastatic gastric/GEJ cancer and will further validate these findings,” Shen concluded.

Reference

Shen L, Peng Z, Li, C, et al. Disitamab vedotin (DV) plus toripalimab (tor) and chemotherapy (C)/trastuzumab (tra) as first-line (1L) treatment of patients (pts) with HER2-expressing locally advanced or metastatic (la/m) gastric cancer. J Clin Oncol. 2025;43(suppl 17):LBA4012. doi:10.1200/JCO.2025.43.17_suppl.LBA4012