First-Line Disitamab Vedotin, Tislelizumab, and S-1 in HER2-Overexpressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: A Single-Arm, Phase II Trial
Song Li, Zimin Liu, Yanguo Liu, Kainan Li, Lei Cong, Fangli Cao, Aina Liu, Haiyan Liu, Ling Li, Linli Qu, Yi Zhai, Feng Wang, Dongmei Zhou, Qijun Yi, Ping Wang, Jisheng Li, Duanbo Shi, Jiahui Chu, Di Zhang, Qian Xu, Shulun Nie, Mingchi Ma, Shuyi Song, Pei Wang, Lian LiuPURPOSE
Clinical data for first-line combination of antibody-drug conjugates (ADC) and immune checkpoint inhibitors in human epidermal growth factor receptor 2 (HER2)–overexpressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma remain limited. We evaluated the efficacy and safety of disitamab vedotin (a HER2-directed ADC) combined with tislelizumab (a PD-1 inhibitor) and oral fluoropyrimidine S-1 as first-line therapy for patients with advanced HER2-overexpressing (immunohistochemistry [IHC] 3+ or 2+, regardless of in situ hybridization [ISH] status) G/GEJ adenocarcinoma.
METHODS
In this single-arm, multicenter, phase II trial, patients received disitamab vedotin (2.5 mg/kg, once on day 1), tislelizumab (200 mg, once on day 1), and S-1 (40-60 mg, twice daily, days 1-14) in 21-day cycles. The primary end point was confirmed objective response rate (ORR) by independent central review (RECIST v1.1). Secondary end points included progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety.
RESULTS
Fifty-seven patients (median age 65; IHC 3+ 71.9%, IHC 2+/ISH+ 17.5%, IHC 2+/ISH− 10.5%; PD-L1 combined positive score [CPS] <1 54.4%) were enrolled. The confirmed ORR was 89.5% (95% CI, 78.5 to 96.0). At a median follow-up of 28.2 months, the median PFS (mPFS) was 13.8 months (95% CI, 10.3 to 24.0), the median OS (mOS) reached 31.9 months (95% CI, 22.1 to not reached), and the median DoR was 13.3 months (95% CI, 9.6 to not reached). Patients with CPS ≥1 achieved an ORR of 92.3%, mPFS of 16.7 months, and mOS of 31.9 months; in the CPS <1 subgroup, the ORR was 87.1% with an mPFS of 10.0 months, and mOS of 25.4 months. Grade ≥3 treatment-related adverse events occurred in 64.9% of patients, primarily hematologic and peripheral neuropathy.
CONCLUSION
First-line disitamab vedotin with tislelizumab and S-1 demonstrated remarkable antitumor activity and a manageable safety profile in HER2-overexpressing advanced G/GEJ adenocarcinoma, warranting validation in randomized controlled trials.