DAWN trial: a prospective, multicenter, single-arm phase II study of neoadjuvant disitamab vedotin (RC48) in combination with adebrelimab, apatinib, and S-1 for locally advanced HER2-positive gastric cancer

Abstract

Background

Gastric cancer is the fifth most common malignancy worldwide and a major cause of cancer-related mortality, with over 750,000 deaths annually. Neoadjuvant chemotherapy remains the standard treatment for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, but recent evidence suggests that incorporating immunotherapy could offer synergistic effects. However, clinical benefits are limited in patients with low HER2 expression or programmed death-ligand 1 (PD-L1) levels due to primary or acquired resistance. To address this, we are conducting a prospective study to evaluate the efficacy and safety of a four-drug neoadjuvant regimen combining RC48 [a HER2-targeted antibody-drug conjugate (ADC)], adebrelimab (a PD-L1 inhibitor), apatinib (a VEGFR2 inhibitor), and S-1 (an oral fluoropyrimidine) in patients with locally advanced HER2-positive gastric cancer.

Methods

The DAWN trial is a prospective, open-label, phase II clinical trial designed to enroll 32 treatment-naïve patients with resectable, locally advanced HER2-positive gastric adenocarcinoma. Eligible patients will receive 3–4 cycles of neoadjuvant therapy, with each cycle lasting 21 days. The treatment regimen includes: RC48: 2.5 mg/kg, intravenous (iv), day 1, every 3 weeks (q3w). Adebrelimab: 1,200 mg, iv, day 1, q3w. S-1: For patients with a body surface area (BSA) ≤1.5 m², 50 mg orally, twice daily (bid), days 1–14, q3w; for BSA >1.5 m², 60 mg orally, bid, days 1–14, q3w. Apatinib: 250 mg orally, once daily (qd), q3w. The primary endpoint is the pathological complete response (pCR) rate. Secondary endpoints include major pathological response (MPR) rate, R0 resection rate, disease-free survival (DFS), overall survival (OS), and safety. All patients must provide written informed consent before enrollment. The study protocol was approved by the independent ethics committee at each participating institution.

Discussion

Previous preclinical and clinical studies have demonstrated the synergistic effects among chemotherapy, immunotherapy, anti-angiogenic therapy, and anti-HER2 antibody-drug conjugates (ADCs). We hypothesize that the combination of these four therapeutic strategies could significantly enhance treatment efficacy in HER2-positive gastric cancer, particularly in combined positive score (CPS) PD-L1-negative patients.

Trial Registration

This study was registered at ClinicalTrials.gov (Identifier: NCT06385873).

Introduction

Gastric cancer remains the fifth most prevalent malignancy and the third leading cause of cancer-related death worldwide, with over 750,000 deaths annually (1). For locally advanced gastric cancer (LAGC), neoadjuvant chemotherapy has significantly improved pathological complete response (pCR) rates, R0 resection rates, and overall survival (OS) compared to surgery alone (2). Regimens such as SOX (S-1 and oxaliplatin) and XELOX (capecitabine and oxaliplatin) are recommended as standard neoadjuvant treatments by the 2024 Chinese Society of Clinical Oncology (CSCO) guidelines, regardless of human epidermal growth factor receptor 2 (HER2) status, based on pivotal trials including RESOLVE and PRODIGY, which have raised the 5-year survival rate to 60–66.8% (3,4). Nevertheless, prognosis for many patients remains unsatisfactory, underscoring the urgent need for novel treatment strategies.

Recent years have seen substantial progress in combining chemotherapy with immunotherapy in advanced gastric cancer. Large phase III clinical trials [e.g., ORIENT-16 (5), CHECKMATE-649 (6), and GEMSTONE-303 (7)] have established chemoimmunotherapy as the preferred first-line option for advanced HER2-negative disease due to its significant progression-free survival (PFS) and OS benefits. Inspired by these outcomes, immunotherapy is being actively investigated in the neoadjuvant setting, with several phase II/III trials (e.g., DANTE, NEOSUMMIT-03) demonstrating encouraging efficacy and safety profiles (2,8,9). However, these studies have largely focused on HER2-negative or unstratified populations, leaving a critical gap in understanding optimal neoadjuvant strategies for HER2-positive LAGC.

HER2 overexpression, present in approximately 15–20% of gastric cancers, defines a biologically distinct subtype amenable to targeted therapy (10). The phase III ToGA trial in 2010 established trastuzumab plus chemotherapy as the first-line standard for HER2-positive advanced gastric cancer (11). However, progress in first-line treatment stagnated in the 2010s, as multiple phase III trials failed to improve OS: LOGIC explored replacing trastuzumab with lapatinib (12), HELOISE tested higher trastuzumab dosing (13), and JACOB added pertuzumab to standard therapy (14). These results suggest a therapeutic ceiling for conventional anti-HER2 approaches. One key explanation is the marked intratumoral heterogeneity of HER2 expression: under selective pressure from targeted therapy, HER2-negative subclones may expand, driving treatment resistance (15). Moreover, the ToGA trial showed that only patients with HER2 immunohistochemistry (IHC) 3+, but not those with IHC 2+, derived a survival benefit, indicating that patients with relatively low HER2 expression gain limited benefit from traditional anti-HER2 therapies.

A major advancement came with the phase III KEYNOTE-811 trial (16), which incorporated pembrolizumab into the trastuzumab and chemotherapy backbone. Based on this study, the current first-line standard for advanced HER2-positive gastric cancer now includes chemotherapy, immunotherapy, and trastuzumab. In the final analysis, the combination group showed improved median OS [20.0 vs. 16.8 months; hazard ratio (HR) 0.80, 95% confidence interval (CI): 0.67–0.94; P=0.004] and PFS (10.9 vs. 7.3 months; HR 0.72, 95% CI: 0.60–0.87) over chemotherapy plus trastuzumab alone. However, survival benefit was limited to patients with programmed death-ligand 1 (PD-L1) CPS >1, while those with CPS <1 saw no significant improvement (16). Further immune microenvironment analysis revealed that CPS <1 tumors had higher infiltration of immunosuppressive CXCR4⁺ M2 macrophages, suggesting the need for novel strategies to overcome resistance in this subgroup (17). This highlights an urgent need for alternative strategies to improve outcomes in PD-L1-negative populations.

Building upon the success of KEYNOTE-811, a recent phase II trial by Shen et al. translated the triplet regimen to the neoadjuvant setting. Patients with HER2-positive LAGC receiving XELOX plus atezolizumab and trastuzumab achieved a pCR rate of 38%, significantly higher than the 14% in the control arm without immunotherapy. Both regimens showed manageable safety profiles. Despite these promising results, the study’s limited sample size precluded subgroup analysis in PD-L1-negative patients, again leaving a clinically important population unaddressed (18).

To overcome resistance mechanisms and expand therapeutic benefit, particularly for patients with low HER2 expression and PD-L1 CPS <1, two promising strategies are being explored: the use of HER2-targeted antibody-drug conjugates (ADCs) and the incorporation of anti-angiogenic agents.

ADCs consist of a monoclonal antibody linked to a cytotoxic payload. These agents offer several advantages: targeted delivery, bystander killing of neighboring tumor cells (19), and upregulation of PD-L1 expression (20), which may enhance efficacy in HER2-low tumors and potentially re-sensitize tumors to immunotherapy. The primary ADCs targeting HER2 in gastric cancer are trastuzumab deruxtecan (T-DXd) and disitamab vedotin (RC48). T-DXd has shown efficacy in Western populations with an objective response rate (ORR) of 38% and pCR of 4% in the DESTINY-Gastric02 trial (21), but its use is limited by an 11.2% incidence of interstitial lung disease (ILD), with a 9% fatality rate (22), especially concerning in Asian populations (21). In contrast, RC48 has shown favorable efficacy and a more tolerable safety profile in Chinese patients, with no reported ILD. In a 2024 Chinese phase I trial involving previously treated patients with advanced gastric cancer, RC48 combined with toripalimab achieved an ORR of 43% and median OS of 16.8 months (23). In the setting of first-line treatment for advanced gastric cancer, the ongoing phase II RCTS study reported an ORR of 95.0% and a 20.0% clinical CR rate using a combination of RC48, tislelizumab, and S-1. Impressively, efficacy was consistent across HER2 IHC 3+, IHC 2+/fluorescence in situ hybridization (FISH)+, and even IHC 2+/FISH– subgroups, as well as in PD-L1 CPS <1 patients (ORR: 92.9%) (24). Based on these findings, the present study does not require FISH confirmation for patients with HER2 IHC 2+, thereby allowing the inclusion of a broader population, including selected IHC 2+/FISH– patients, with the aim of expanding the therapeutic applicability of RC48. In the neoadjuvant setting, a prospective, single-arm phase II study conducted in China evaluated RC48 combined with camrelizumab and S-1 in patients with locally advanced HER2-overexpressing gastric cancer. Among 12 patients who underwent D2 resection, 6 (50%) achieved MPR, including 4 (33.3%) with pCR (ypT0N0M0), and the R0 resection rate was 100%. Median DFS and OS were not reached. The most common grade ≥3 adverse events (AEs) were neutropenia (10%), bowel obstruction (5%), and elevated alanine transaminase (ALT)/aspartate transaminase (AST) (5% each), with no treatment-related mortality reported. These findings support the neoadjuvant use of RC48 in combination with camrelizumab and S-1 as a promising and well-tolerated strategy for locally advanced, resectable HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (25). Additionally, RC48 has demonstrated encouraging results in the neoadjuvant setting of other malignancies, including bladder cancer (26-29) and upper tract urothelial carcinoma (30).

Anti-angiogenic therapy offers another avenue for synergy. Agents like apatinib can normalize tumor vasculature, enhance immune cell infiltration, and reduce immunosuppressive cells, thereby sensitizing tumors to both chemotherapy and immunotherapy (31-34). Clinical studies have demonstrated that anti-angiogenic agents can potentiate chemo-immunotherapy, even in PD-L1 CPS-negative populations (35-37). Our group has actively contributed to this field: in advanced HER2-negative gastric cancer, the SPACE trial (35) and our unpublished TALENT study have shown that adding anti-angiogenic therapy to chemo-immunotherapy significantly improves ORRs in both CPS-positive and CPS-negative patients. Furthermore, a case report of primary trastuzumab-resistant HER2-positive gastric cancer showed that apatinib combined with anti-HER2 therapy and camrelizumab overcame resistance, reinforcing the rationale for incorporating anti-angiogenic agents into HER2-positive treatment regimens (38).

Taken together, these findings suggest that a rationally designed, multi-agent combination therapy has the potential to address the unmet needs in HER2-positive LAGC, especially among PD-L1-negative patients. Therefore, we designed the phase II DAWN trial to evaluate the efficacy and safety of a four-drug neoadjuvant regimen comprising the HER2-targeted ADC RC48, the immune checkpoint inhibitor adebrelimab, the anti-angiogenic agent apatinib, and chemotherapy (S-1). By leveraging the complementary mechanisms of these agents, this study aims to broaden the scope of benefit and improve outcomes in a population that has historically demonstrated poor responsiveness to immunotherapy.

Methods

This prospective, multicenter, single-arm, phase II study (DAWN trial) is designed to evaluate the therapeutic efficacy and safety profile of RC48 in combination with adebrelimab, apatinib, and S-1 as a neoadjuvant regimen for patients with HER2-positive, locally advanced G/GEJ adenocarcinoma. This study was approved by Jiangsu Provincial People’s Hospital (The First Affiliated Hospital of Nanjing Medical University) on April 9, 2024, with the approval No. 2024-SR-233. The study will be performed in accordance with the Declaration of Helsinki and its subsequent amendments, and Good Clinical Practice (GCP) Guidelines. Informed consent will be obtained from all participants, and all data will be handled with strict confidentiality. This study is prospectively registered under ClinicalTrials.gov (NCT06385873). A schematic overview of the study design is presented in Figure 1.

Figure 1.

Study design. BID, twice daily; BSA, body surface area; D, day; DFS, disease-free survival; ECOG PS, Eastern Cooperative Oncology Group performance score; IV, intravenous; M, metastasis; MPR, major pathological response; N, node; ORR, objective response rate; OS, overall survival; pCR, pathological complete response; PO, orally; QD, once daily; RC48, disitamab vedotin; T, tumor.

Endpoints

The primary endpoint of the DAWN trial is the pCR rate, which is defined as the absence of any viable tumor cells on histopathological assessment following neoadjuvant treatment. Secondary endpoints comprise the MPR rate (defined as ≤10% residual viable tumor cells in the resected specimen), the R0 resection rate (referring to the proportion of patients achieving complete surgical removal of all residual cancer cells), PFS (measured from study enrollment to the occurrence of radiologically confirmed disease recurrence or death, whichever occurs earlier), OS (calculated from enrollment to death from any cause), as well as the overall safety profile. AEs will be systematically recorded and graded based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE, version 5.0). Serious adverse events (SAEs) are defined as events leading to death, hospitalization or prolonged hospitalization, permanent or severe disability, teratogenesis, or other medically important conditions. Exploratory endpoints include the identification of predictive biomarkers of immunotherapy response in tumor tissue, peripheral blood, and feces.

Study population and eligibility criteria

Patients with endoscopic biopsy-confirmed HER2 overexpression, defined as IHC score of 2+ or 3+, and a clinical tumor-node-metastasis (cTNM) stage of >T2N0-3 or T0-4N+M0 for locally advanced G/GEJ adenocarcinoma, who have not received any prior systemic therapy for the current disease, are eligible for inclusion in this study. The presence of any other previously diagnosed malignancy constitutes the primary exclusion criterion. Comprehensive inclusion and exclusion criteria are detailed in Table 1. The informed consent document is provided in Appendix 1.

Table 1. Eligibility criteria.

Criteria	Details
Inclusion criteria
1	Participants must voluntarily consent to the study, sign the informed consent form, and exhibit good compliance
2	Age 18–75 years
3	Histologically or cytologically confirmed diagnosis of locally advanced G/GEJ adenocarcinoma (>T2N0-3 or T0-4N+M0) as assessed by exploratory laparoscopic surgery, ultrasonography and/or CT/MRI
4	Resectable G/GEJ cancer, as assessed by experienced surgeons
5	No prior systemic therapy for the current disease, including chemotherapy, radiotherapy, or immunotherapy
6	IHC results confirming HER2-positive (IHC 2+ or 3+)
7	ECOG PS ≤1
8	Expected survival ≥6 months
9	Adequate organ function, including:
	(I) Hematologic: Hb ≥80 g/L, ANC ≥1.5×109/L, PLT ≥80×109/L
	(II) Biochemical: ALT and AST ≤2.5× ULN; TBIL ≤1.5× ULN; Cr ≤1.5× ULN or CrCl ≥60 mL/min
	(III) Coagulation: APTT, INR, PT ≤1.5× ULN
	(IV) Cardiac: LVEF ≥50% (assessed by Doppler ultrasound)
	(V) Clinically determined by the investigator to have sufficient organ function
10	Strict contraception
Exclusion criteria
1	Presence of malignancies other than gastric cancer (excluding curatively treated early-stage cancers)
2	Tumor lesions with a bleeding tendency (e.g., active ulcerative tumors with positive fecal occult blood test, history of hematemesis or melena within the last 2 months, or significant risk of gastrointestinal bleeding as judged by the investigator), or transfusion therapy within 4 weeks prior to study drug administration
3	Inability to take oral medications
4	Participation in an interventional clinical trial, or use of other investigational drugs or devices within 4 weeks prior to the first dose
5	Previous treatment with HER2 inhibitors, anti-PD-1, anti-PD-L1, anti-PD-L2, or any agents targeting T-cell receptor co-stimulation or co-inhibition (e.g., CTLA-4, OX-40, CD137, etc.)
6	Active autoimmune disease requiring systemic treatment (e.g., corticosteroids or immunosuppressive agents) within 2 years prior to the first dose (note: physiological doses of corticosteroids ≤10 mg/day of prednisone or equivalent are allowed; replacement therapies such as thyroid hormone or insulin are not considered systemic treatments)
7	Use of traditional Chinese medicine or immunomodulatory drugs with antitumor indications within 2 weeks prior to the first dose (including thymosin, interferons, interleukins, except for local use for pleural effusion)
8	History of organ transplantation (except corneal transplants) or allogeneic hematopoietic stem cell transplantation
9	Known hypersensitivity to any drug used in the study
10	Peripheral neuropathy ≥ Grade 2
11	Known HIV infection (HIV 1/2 antibody positive)
12	Active hepatitis B or C infection
13	Administration of live vaccines within 30 days before the first dose (note: inactivated seasonal influenza vaccine is allowed within 30 days before the first dose; nasal live attenuated influenza vaccines are not permitted)
14	Pregnant or breastfeeding women
15	Severe or uncontrolled systemic diseases, including:
	(I) Major and symptomatic abnormalities on resting ECG (e.g., complete left bundle branch block, ≥ Grade 2 heart block, ventricular arrhythmias, or atrial fibrillation)
	(II) Unstable angina, congestive heart failure, or NYHA ≥2 chronic heart failure
	(III) History of arterial thrombosis, embolism, or ischemia (e.g., myocardial infarction, stroke, transient ischemic attack) within the last 6 months
	(IV) Uncontrolled hypertension (systolic >140 mmHg, diastolic >90 mmHg)
	(V) History of non-infectious pneumonia requiring corticosteroid treatment within 1 year prior to the first dose or current active interstitial lung disease
	(VI) Active tuberculosis
	(VII) Any active or poorly controlled infections requiring systemic treatment
	(VIII) Active diverticulitis, abdominal abscess, or gastrointestinal obstruction
	(IX) Liver diseases such as cirrhosis, decompensated liver disease, or active hepatitis
	(X) Poorly controlled diabetes (e.g., fasting blood glucose >10 mmol/L)
	(XI) Proteinuria ≥ ++ on urine dipstick, with 24-hour urine protein >1.0 g
	(XII) Mental disorders that impair the patient’s ability to comply with study requirements
16	Any other conditions that may interfere with study results, prevent full participation, or pose an unacceptable risk as determined by the investigator

ALT, alanine aminotransferase; ANC, absolute neutrophil count; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; Cr, creatinine; CrCl, creatinine clearance; CT, computed tomography; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; ECG, electrocardiogram; ECOG PS, Eastern Cooperative Oncology Group performance score; G/GEJ, gastric/gastroesophageal junction; Hb, hemoglobin; HER2, human epidermal growth factor receptor 2; HIV, human immunodeficiency virus; IHC, immunohistochemistry; INR, international normalized ratio; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; N, node; NYHA, New York Heart Association; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2; PLT, platelets; PT, prothrombin time; T, tumor; TBIL, total bilirubin; ULN, upper limit of normal.

Intervention

The treatment regimen involves the combination of RC48, adebrelimab, apatinib, and S-1. The overall combination therapy follows a 3-week (21-day) cycle. RC48: 2.5 mg/kg, intravenous (iv), d1, q3w. Adebrelimab: 1,200 mg, iv, d1, q3w. S-1: For patients with a body surface area (BSA) ≤1.5 m², the dose is 50 mg, po, bid, d1–14, q3w; for BSA >1.5 m², the dose is 60 mg, po, bid, d1–14, q3w. Apatinib: 250 mg, po, qd, q3w.

Adebrelimab should be administered intravenously first, followed by chemotherapy after at least a 30-minute interval. Preoperative neoadjuvant therapy consists of 3–4 cycles, with the final cycle of apatinib lasting only 14 days. Postoperatively, patients who demonstrate clinical benefit may continue treatment with RC48 combined with adebrelimab and S-1 for 4 additional cycles (starting approximately 4 weeks after surgery), or they may receive a standard postoperative adjuvant regimen as per clinical guidelines.

Statistical analysis

This is an exploratory study. Based on the PETRARCA phase III clinical trial (39), which reported a standard neoadjuvant pCR rate of 12%, the null hypothesis (P0) is set at 12%, with an expected increase to a pCR rate of 30%, thus P1 is 30%. A Simon two-stage design is applied, with α=0.05 and β=0.2, using the Minimax sample size approach. In the first stage, 18 patients will be enrolled, and if ≥2 patients respond, the study will proceed to the second stage, resulting in a total sample size of 29. Considering a 10% dropout rate, the final sample size will be 32 patients.

Descriptive statistics will be used to summarize baseline and clinicopathological characteristics. The pCR rate, major pathological response (MPR) rate, and R0 resection rate will be calculated, with corresponding confidence intervals (CIs) estimated using Blaker’s exact binomial method. Kaplan-Meier estimates of disease-free survival (DFS) and OS probabilities will be determined, along with their respective 95% CIs. Primary analyses will be conducted in the intention-to-treat (ITT) population.

AEs will be analyzed in the safety population, defined as patients who receive at least one dose of neoadjuvant treatment. Emergent AEs related to neoadjuvant or adjuvant treatments will be reported separately, given the different regimens involved. Surgery-related morbidity and mortality will be analyzed in the per-protocol population, which includes patients who adhere to the study protocol and proceed to surgery.

Discussion

Gastric cancer remains one of the most lethal malignancies worldwide, with the highest incidence observed in East Asia and Central Europe (40). HER2-positive gastric cancer, representing a distinct molecular subtype, is associated with aggressive tumor biology, including epithelial-mesenchymal transition (EMT), chemoresistance, and T-cell exhaustion (41). This highlights that HER2-positive gastric cancer exhibits fundamentally different tumor biology from HER2-negative disease, warranting the development of novel therapeutic approaches, particularly in the neoadjuvant context.

Currently, the 2024 CSCO guidelines still recommend chemotherapy alone as the standard neoadjuvant treatment for resectable, locally advanced HER2-positive gastric cancer. However, growing evidence suggests that integrating targeted agents, immunotherapy, and anti-angiogenic therapy into neoadjuvant chemotherapy may improve outcomes in this subgroup.

HER2-targeted strategies have demonstrated clinical promise in the neoadjuvant context. A 2021 phase II trial showed that trastuzumab plus FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy improved both pCR (21.4%) and 3-year OS (82.1%) (42). ADCs, such as T-Dxd and RC48, offer enhanced cytotoxicity with reduced systemic toxicity (21,23,43-51). In 2024, a prospective, single-arm phase II study in China evaluated RC48 in combination with camrelizumab and S-1 as neoadjuvant therapy for locally advanced HER2-overexpressing gastric cancer. Among 12 patients who underwent D2 resection, 6 (50%) achieved MPR, including 4 (33.3%) with pCR (ypT0N0M0), and the R0 resection rate was 100%, with a favorable safety profile (25).

Immunotherapy has emerged as a promising neoadjuvant approach. A 2025 randomized phase II trial from Peking University demonstrated that adding atezolizumab to trastuzumab plus XELOX significantly improved pCR rates (38% vs. 14%), including in patients with CPS <1 (18). The PANDA trial also showed encouraging pCR and MPR rates when incorporating atezolizumab into neoadjuvant chemotherapy, including responses in two HER2-positive cases (52). However, most neoadjuvant studies to date have not stratified by HER2 status, limiting the generalizability of these findings to HER2-positive patients (8,9,53).

Anti-angiogenic therapy represents another promising strategy. Agents such as apatinib can remodel the tumor vasculature, enhance immune cell infiltration, and mitigate immunosuppressive components within the tumor microenvironment (TME) (54). Although evidence in the neoadjuvant setting remains limited, findings from the HER-RAM trial (trastuzumab plus ramucirumab and paclitaxel) and the INTEGRATE study (regorafenib in later-line treatment) suggest that anti-angiogenic agents may confer clinical benefit in previously treated HER2-positive populations (55,56).

Mechanistically, the rationale for multimodal therapy lies in their synergistic effects: chemotherapy increases antigen exposure; anti-angiogenic agents enhance drug delivery and promote immune cell infiltration; and immunotherapy amplifies anti-HER2 and ADC activity (54,57-59). Furthermore, apatinib has been shown to enhance RC48 efficacy through PI3K-AKT pathway inhibition (60), while ADC-induced deoxyribonucleic acid (DNA) damage may elevate PD-L1 expression, thereby sensitizing PD-L1-negative tumors to immunotherapy (20).

Safety considerations were paramount in the design of the present four-drug combination regimen. First, regarding the chemotherapy backbone, we selected S-1 monotherapy to minimize toxicity, avoiding platinum agents and taxanes which are associated with cumulative, often irreversible peripheral neurotoxicity (11,61,62) and substantial myelosuppression, respectively (62,63). S-1 offers a favorable balance of efficacy and tolerability, even in patients with poor performance status (64). Second, regarding the ADC component, RC48 possesses a favorable safety profile, particularly the absence of severe or fatal ILD commonly associated with T-DXd (21). The feasibility of combining RC48, immunotherapy, and S-1 has been supported by the Phase II RCTS study. Among 47 patients receiving this triplet regimen, grade 3/4 treatment-related adverse events (TRAEs), primarily neutropenia, fatigue, and diarrhea, occurred in 40.9% of patients, indicating a manageable toxicity profile (24).

Building on this foundation, the current DAWN trial incorporates apatinib, a standard VEGFR2 inhibitor for advanced gastric cancer. While apatinib monotherapy has been associated with grade 3/4 toxicities such as hand-foot syndrome, hypertension, and thrombocytopenia, fatal events are rare (65). Crucially, evidence suggests that adding apatinib to chemo-immunotherapy does not significantly exacerbate toxicity. In the phase II Arise-FJ-G 005 trial (apatinib plus camrelizumab and chemotherapy; n=51), grade 3/4 AEs were infrequent (e.g., 13.7% leukopenia, 9.8% neutropenia) (66). Although bleeding is a concern in the neoadjuvant setting, the Arise-FJ-G 005 study reported a low incidence of grade 3/4 bleeding (2.0%), with the majority of events being grade 1–2 (15.7%) (66). To further mitigate surgical risks, our protocol enforces a strictly defined washout period of at least 14 days between apatinib discontinuation and gastrectomy, consistent with the safety measures in the Arise-FJ-G 005 trial (66). Collectively, these data support the expectation that this four-drug neoadjuvant regimen will demonstrate an acceptable and manageable safety profile.

Based on these findings, we initiated a prospective, open-label, phase II DAWN trial to evaluate the efficacy and safety of a quadruple neoadjuvant regimen comprising RC48 (anti-HER2 ADC), adebrelimab (PD-L1 inhibitor), apatinib (anti-angiogenic agent), and S-1 (chemotherapy) in treatment-naïve patients with resectable, locally advanced HER2-positive gastric adenocarcinoma. To our knowledge, this is the first study globally to assess this four-drug combination in this setting. We hypothesize that this regimen will result in higher pCR and R0 resection rates, and potentially improve long-term survival, including in PD-L1-negative patients.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by Jiangsu Provincial People’s Hospital (The First Affiliated Hospital of Nanjing Medical University) on April 9, 2024, with the approval No. 2024-SR-233. The study will be performed in accordance with the Declaration of Helsinki and its subsequent amendments, and Good Clinical Practice (GCP) Guidelines. Written informed consent will be obtained from all participants prior to study initiation.