On June 27, the world-renowned oncology journal Journal of Clinical Oncology (JCO) published the full research paper from a Phase II RCTS trial online. The study evaluated the combination of Disitamab Vedotin, Tislelizumab, and S-1 as a first-line therapy for patients with advanced gastric cancer showing moderate to high HER2 expression.
Published by the American Society of Clinical Oncology (ASCO) and boasting a stellar impact factor of 44.7, JCO is a world-renowned top journal in oncology, dedicated to fast-tracking groundbreaking clinical research and offering doctors high-grade evidence. The RCTS study, led by Professor Liu Lian from Qilu Hospital of Shandong University, had already been featured at the ASCO Annual Meeting for three consecutive years. Its efficacy data achieved remarkable milestones: an objective response rate (ORR) of 89.5%, a median progression-free survival (PFS) of 13.8 months, and a median overall survival (OS) of 31.9 months. Now, with its full-text publication in JCO, the RCTS study has once again earned the highest recognition from an elite international academic platform.
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Median overall survival (OS) hit 31.9 months
Targeting patients with medium to high HER2 expression
Benefit remained consistent across all PD-L1 subgroups
The RCTS study is a Phase II clinical trial designed as a single-arm, multi-center investigation to evaluate the effectiveness and safety of a novel combination therapy—Disitamab vedotin plus Tislelizumab and S-1—as a first-line treatment for advanced gastric cancer or gastroesophageal junction cancer (G/GEJ) with medium to high HER2 expression, all delivered without the need for intravenous chemotherapy. The study's primary goal was to measure the objective response rate (ORR), with secondary goals including progression-free survival (PFS), overall survival (OS), and safety profiles. Exploratory analyses involved dynamic sequencing of peripheral T-cell receptors (TCR) and whole-genome analysis of cell-free DNA (cfDNA).
What makes this treatment approach particularly relevant to real-world practice is its inclusive patient selection: among the 57 participants, the study enrolled not only those with high HER2 expression (IHC 3+ or IHC2+/FISH+) but also 10.5% of patients with medium HER2 expression (IHC2+/FISH-), a group typically excluded from earlier anti-HER2 trials. Moreover, about 54.4% of patients had a PD-L1 CPS score below 1, a subgroup that generally derives limited benefit from conventional immunotherapy.
Despite the patients' challenging baseline conditions, this treatment regimen achieved breakthrough results. As of December 31, 2025, after a median follow-up of 28.2 months:
●Tumor response: In the intention-to-treat (ITT) population, the confirmed objective response rate (ORR) reached an impressive 89.5% (51 out of 57 patients, 95% CI: 78.5-96.0), with a complete response (CR) rate of 8.8%. The disease control rate (DCR) was as high as 98.2%.
●Long-term survival: The median progression-free survival (PFS) was 13.8 months (95% CI: 10.3-24.0); median overall survival (OS) was 31.9 months (95% CI: 22.1-not reached); and the median duration of response (DoR) was 13.3 months (95% CI: 9.6-not reached).
●Consistent benefit across PD-L1 subgroups: Subgroup analysis revealed that patients benefited from the regimen regardless of their PD-L1 expression level. The ORR was 92.3% in the CPS ≥1 subgroup versus 87.1% in the CPS <1 subgroup; median PFS was 16.7 months versus 10.0 months; and median OS was 31.9 months versus 25.4 months. Notably, among patients with CPS ≥5, the median PFS extended to 24.0 months.
●HER2 subgroup analysis: In the HER2-high (IHC 3+ or IHC 2+/ISH+) and HER2-intermediate (IHC 2+/ISH-) subgroups, the ORR was 92.2% and 66.7%, respectively; median PFS was 13.8 months and 18.3 months; and median OS was 31.9 months and not reached, respectively.
●Safety: The regimen was well tolerated with a manageable safety profile, and no new safety signals emerged.
A comprehensive analysis reveals that the triple therapy combining disitamab vedotin, tislelizumab, and S-1 is highly effective and well-tolerated as a first-line treatment for gastric or gastroesophageal junction cancers with moderate to high HER2 expression. Notably, this regimen also provides substantial benefits for patients with a PD-L1 CPS score below 1.
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Three Breakthroughs That Define Clinical Value:
Efficacy Breakthrough, Synergistic Mechanism, and Precision-Driven Innovation
As the world's first "ADC + PD-1 + S-1" regimen that eliminates the need for intravenous chemotherapy, the RCTS study's long-term survival data and biomarker findings offer crucial insights for clinical practice and trial design. It marks breakthroughs in three key dimensions, with the potential to reshape first-line treatment for advanced gastric cancer:
Dimension 1: Efficacy breakthrough—pushing the survival limits of advanced gastric cancer. Historically, first-line treatment for HER2-positive advanced gastric cancer centered on "trastuzumab plus chemotherapy." Although adding PD-1 inhibitors has recently improved median overall survival (OS), unmet needs persist. The RCTS study achieved an impressive overall response rate (ORR) of 89.5% and a median OS of 31.9 months, setting a new benchmark. This underscores how the ADC drug Disitamab Vedotin can drive deeper tumor shrinkage and longer disease control, even in patients with moderate HER2 expression or low PD-L1 levels, where clear efficacy signals were also detected.
Dimension 2: Mechanistic synergy—validating the "ADC + immunotherapy + chemotherapy" triple action. The triple regimen's outstanding survival stems from deep synergy at the molecular level. Disitamab Vedotin, a leading ADC, carries the toxin MMAE, which not only kills cancer cells directly via cytotoxicity and the "bystander effect" but also triggers immunogenic cell death. By precisely targeting tumors, the drug transforms the tumor microenvironment from "cold" to "hot," releasing T cells from immune suppression and boosting PD-1 inhibitor efficacy. Combined with S-1 oral chemotherapy as a backbone, this creates a "1+1+1>3" synergy with manageable side effects.
Dimension 3: Precision guidance—TCR and cfDNA enable dynamic tumor monitoring. Identifying which patients benefit and tracking early response remain clinical challenges. Traditional methods rely heavily on PD-L1 CPS scores, but the RCTS study offers a fresh approach: the clonal expansion score (CEscore), derived from TCR sequencing, predicts progression-free survival (PFS) and OS independently of PD-L1, potentially serving as a better immune activation marker. Additionally, longitudinal cfDNA analysis detects tumor progression 1.4 months earlier than imaging, providing a powerful "liquid biopsy" tool for timely treatment adjustments.
Professor Liu Lian commented: "The combination of Disitamab Vedotin, Tislelizumab, and S-1 delivers remarkably high ORR, a groundbreaking median OS exceeding 30 months, and a manageable safety profile. It offers an inspiring, innovative first-line treatment for HER2-positive advanced gastric cancer, showcasing 'Chinese wisdom' in clinical trial design. Moving forward, we will continue advancing precision therapies to bring superior treatment options to gastric cancer patients."
