Surufatinib plus paclitaxel as second-line therapy for advanced gastric cancer: A single-arm, phase 2 clinical trial

Surufatinib plus paclitaxel as second-line therapy for advanced gastric cancer: A single-arm, phase 2 clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Surufatinib plus paclitaxel as second-line therapy for advanced gastric cancer: A single-arm, phase 2 clinical trial Ting Han, Meng Zhuo, Xinyi Zheng, Xiuqi Wu, Feng Jiao, Jiujie Cui, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6600621/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Nov, 2025 Read the published version in Cellular Oncology → Version 1 posted 15 You are reading this latest preprint version Abstract Purpose Combining paclitaxel with antiangiogenic agents has demonstrated improved efficacy as second-line treatment for advanced gastric cancer. Surufatinib, a multi-kinase inhibitor with antiangiogenic and immunomodulatory properties, has exhibited synergistic effects with chemotherapy in preclinical studies. Methods This single-arm phase 2 trial enrolled patients aged 18-75 with HER2-negative unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma who had failed first-line therapy. All received surufatinib 250mg once daily plus paclitaxel 150mg/m 2 every 3 weeks for up to 6 cycles, followed by maintenance surufatinib until progression, intolerable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results Thirty-five patients were enrolled. Among 32 tumor response-evaluable patients, the ORR and DCR were 25.0% (95% confidence interval [CI]: 11.5, 43.4) and 87.5% (95% CI: 71.0, 96.5), respectively. Median PFS was 5.7 (95% CI: 4.7, 6.9) months and median OS was 10.8 (95% CI: 7.0, 17.2) months. In 26 patients with prior immunotherapy exposure, the median OS was 14.4 (95% CI: 8.5, not estimable) months. Overall, treatment-related adverse events of grade ≥3 occurred in 19 (54.3%) patients, with neutropenia (40.0%), leukopenia (34.3%), and hypertension (11.4%) being the most commonly observed. Conclusions Surufatinib plus paclitaxel showed promising efficacy and manageable safety as second-line treatment for advanced gastric cancer, especially in patients who had failed prior immunotherapy. Clinical trial number: ChiCTR2200063336, registered in the Chinese Clinical Trial Registry on September 5, 2022. gastric cancer second-line surufatinib paclitaxel Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1 Background Gastric cancer is the third most common malignancy in China, with more than 40% of newly diagnosed cases and nearly half of all global deaths occurring in China.[ 1 , 2 ] Despite an increasing survival rate, the prognosis is still poor for Chinese patients, predominately attributed to a higher tumor burden, later stage at diagnosis, and a lower radical resection rate when compared to those from developed countries.[ 3 – 5 ] For unresectable or metastatic disease, chemotherapy-based systemic treatment is the standard-of-care.[ 6 ] In recent years, a plenty of studies have revealed the molecular pathogenesis and potential drivers of alterations in gastric cancer, and the advancement of targeted therapy and immunotherapy has significantly improved patient survival.[ 7 – 11 ] However, after the failure of first-line treatment, limited options are available.[ 6 , 12 , 13 ] Improved efficacy has been observed in the combination of paclitaxel and antiangiogenic agents as second-line treatment for advanced gastric cancer. Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play important roles in tumor proliferation and metastasis via angiogenesis and lymphangiogenesis.[ 14 ] Ramucirumab, a monoclonal VEGFR2 antibody, has been approved for the treatment of gastric cancer refractory to first-line treatment with proven efficacy and safety when combined with paclitaxel.[ 15 , 16 ] More recently, the FRUTIGA trial demonstrated significantly improved progression-free survival (PFS) by combining fruquintinib (a small-molecule inhibitor of VEGFRs) with weekly paclitaxel as compared with paclitaxel alone.[ 17 ] Surufatinib is a multi-kinase inhibitor of VEGFR1-3, fibroblast growth factor receptor 1 (FGFR1), and colony-stimulating factor-1 receptor (CSF-1R),[ 18 ] and therefore has both anti-angiogenetic activity through VEGFRs and FGFR1 inhibition, and immunomodulatory mechanism through the blockade of the colony-stimulating factor-1 (CSF-1) and CSF-1R axis.[ 19 – 22 ] This also endows surufatinib with the potential to be combined with chemotherapy or immunotherapy.[ 23 ] In a recent trial, surufatinib was combined with toripalimab, an anti-programmed death protein 1 (PD-1) monoclonal antibody, in treating patients with advanced gastric cancer refractory to first-line therapy. The objective response rate (ORR) was 31.6% and the median PFS and overall survival (OS) were 4.1 months and 13.7 months, respectively.[ 24 ] Based on these findings, we conducted this trial to evaluate the efficacy and safety of combining surufatinib with chemotherapy in patients with advanced gastric cancer who have disease progression after standard first-line treatment. 2 Materials and methods 1.1. Study design This is an investigator-initiated, open-label, single-arm, phase 2 trial conducted in China. With the approval of local institutional review board and ethics committee (KY2022-151-B), the trial was performed in accordance with the Declaration of Helsinki, Good Clinical Practice, and other applicable laws/regulations of China. All participants provided written informed consent prior to screening. This trial was registered in the Chinese Clinical Trial Registry (ChiCTR2200063336). 1.2. Patients Adult patients (aged 18–75 years) with histologically confirmed human epidermal growth factor receptor 2 (HER2)-negative metastatic or unresectable adenocarcinoma of the stomach or gastroesophageal junction (GEJ) who had failed first-line fluoropyrimidine-based doublet chemotherapy with or without an anti-PD-1 antibody, were eligible. Other inclusion criteria were: measurable lesions per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate bone marrow, hepatic and renal function. A full listing of eligibility is available in Supplementary Table S1 . 1.3. Treatments and assessments All patients received oral surufatinib (250 mg, once daily) plus intravenous paclitaxel (150 mg/m 2 , on day 1) or irinotecan (125 mg/m 2 , on days 1 and 8) in case paclitaxel had been included in the first-line regimen, with three weeks as one cycle for up to 6 cycles, followed by surufatinib maintenance (250 mg, once daily) until disease progression, intolerable toxicity, death, or patient withdrawal (whichever occurred first). Supportive care, dose interruption, and dose reduction were allowed in order to manage toxicity. Tumor response was assessed by investigators per RECIST v1.1 using computed tomography (CT) or magnetic resonance imaging (MRI) every 6 weeks after the first dose until disease progression, death, beginning of subsequent therapy, or patient withdrawal. Objective responses were confirmed 4 to 6 weeks after the first observation. After treatment discontinuation, patients were followed for survival every 12 weeks until death, loss to follow-up, withdrawal of informed consent, or end of study (whichever occurred first). Safety assessment included the incidence and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and relatedness judged by the investigator. Adverse events (AEs) were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 24.1, and the severity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. 1.4. Endpoints The primary endpoint for efficacy was the investigator-assessed ORR per RECIST v1.1. Secondary endpoints were disease control rate (DCR) and PFS per RECIST v1.1, and OS. Safety endpoints included treatment-related adverse events (TRAEs) and change from baseline in vital signs and laboratory test results. 1.5. Statistical analysis Sample size calculation was based on the superiority test for a one-group design. Thirty-five patients were required to provide 80% of power at a one-sided significance level of 0.05. The threshold ORR for historical control was set to 15% according to those with paclitaxel (14–24%)[ 12 , 15 , 16 , 25 ] or irinotecan (13.6%)[ 12 , 26 ] from previous studies. And the expected ORR was 35% as referred to previous finding with fruquintinib plus paclitaxel (35.7%) as second-line therapy for advanced gastric cancer in a phase 1b/2 trial.[ 27 ] Analyses for ORR and DCR were performed in patients who had received ≥ 1 dose of the study drug and had ≥ 1 post-baseline tumor assessment (the efficacy-evaluable analysis set [EEAS]), while analyses of PFS, OS, and safety data were performed in all patients who had received ≥ 1 dose of the study treatment (the full analysis set [FAS]). Duration of response (DoR) was analyzed for patients with confirmed objective responses. ORR, DCR, and the corresponding 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. The Kaplan-Meier method was used to estimate time-to-event endpoints including DoR, PFS and OS, and median and 95% CI values were provided. Data processing and analyses were performed using Microsoft Excel (version 2108) and the R software (version 4.4.0). 3 Results 1.6. Patients From 27 September 2022 to 7 July 2024, 35 patients were enrolled and received ≥ 1 dose of the study treatment, and 14 (40.0%) patients completed all 6 cycles of combination therapy and received maintenance surufatinib. At data cutoff (20 December 2024), 30 (85.7%) patients had discontinued the study treatment, primarily due to radiographic disease progression (n = 19, 63.3%) (Fig. 1 ). After treatment discontinuation, 15 patients received subsequent systemic therapies, including apatinib (n = 8), monoclonal or bispecific antibodies targeting PD-1/L1 (n = 7), irinotecan (n = 4), and Claudin 18.2 antibody-drug conjugates (n = 3). More than half (n = 18, 51.4%) of patients were aged 65 or elder, 31 (88.6%) had an ECOG performance status of 1, and 26 (74.3%) were male. Primary tumor sites were stomach in 28 (80.0%) patients and GEJ in 7 (20.0%) patients. All patients had stage IV disease, with lymph nodes (n = 23, 65.7%), liver (n = 16, 45.7%), and peritoneum (n = 14, 40.0%) being the most common metastatic sites. Oxaliplatin (n = 29, 82.9%) and S-1 (n = 25, 71.4%) were predominantly used first-line chemo agents, and 26 (74.3%) had prior immunotherapy exposure, with sintilimab (n = 11, 31.4%) being the most frequently used. Other baseline characteristics were summarized in Table 1 . Table 1 Baseline demographic and clinical characteristics Characteristics All patients (n = 35) Age, years Median (range) <65 ≥65 65 (33–75) 17 (48.6) 18 (51.4) Sex Male Female 26 (74.3) 9 (25.7) ECOG performance status 0 1 4 (11.4) 31 (88.6) Primary site Stomach GEJ 28 (80.0) 7 (20.0) Tumor stage at screening IV 35 (100.0) Prior radical gastrectomy Yes No 21 (60.0) 14 (40.0) No. of involved organs 1 2 ≥3 7 (20.0) 13 (37.1) 15 (42.9) Site of metastases Lymph node Liver Peritoneum Abdominal/pelvic cavity Ovary Ureter 23 (65.7) 16 (45.7) 14 (40.0) 5 (14.3) 4 (11.4) 4 (11.4) PD-L1 expression a Positive Negative Unknown 12 (34.3) 19 (54.3) 4 (11.4) Chemo regimen in prior line Oxaliplatin S-1 Capecitabine Others b 29 (82.9) 25 (71.4) 8 (22.9) 6 (17.1) Immunotherapy in prior line Sintilimab SHR-1701 Nivolumab Toripalimab Others c None 11 (31.4) 4 (11.4) 3 (8.6) 3 (8.6) 5 (14.3) 9 (25.7) Data are n (%) otherwise indicated. CPS: combined positive score; ECOG: Eastern Cooperative Oncology Group; GEJ: gastroesophageal junction; PD-L1: programmed death-ligand 1; a. PD-L1 positive was defined as a combined positive score (CPS) ≥ 1; b. other chemo agents included cisplatin, 5-FU, and irinotecan; c. other immunotherapies included tislelizumab, pembrolizumab, and AK-104. 1.7. Efficacy The EEAS included 32 patients. The best overall response (BOR) was partial response (PR) in 8 (25.0%) patients, stable disease (SD) in 20 (62.5%) patients, and progressive disease (PD) in 4 (12.5%) patients (Fig. 2 and Fig. 3 ). The ORR was 25.0% (95% CI: 11.5, 43.4), and the DCR was 87.5% (95% CI: 71.0, 96.5). For the 8 patients who achieved PR, the median DoR was 3.2 (95% CI: 2.8, not estimable [NE]) months (Table 2 ). The ORR (25.0% [95% CI: 9.8, 46.7]) and DCR (91.7% [95% CI: 77.0, 99.0]) in patients with exposure to first-line immunotherapy (the prior IO subgroup) were consistent with the FAS population, and the median DoR was 3.1 (95% CI: 1.8, 10.9) months among the 6 patients who achieved objective responses. Table 2 Tumor responses according to RECIST v1.1 (EEAS, n = 32) EEAS (n = 32) Best overall response, n (%) Complete response Partial response Stable disease Progressive disease 0 (0) 8 (25.0) 20 (62.5) 4 (12.5) Objective response rate a n (%) 95% CI 8 (25.0) 11.5, 43.4 Disease control rate a n (%) 95% CI 28 (87.5) 71.0, 96.5 Duration of response b n (%) median (months) 95% CI 8 (25.0) 3.2 2.8, not estimable CI: confidential interval; EEAS: efficacy-evaluable analysis set; RECIST: Response Evaluation Criteria in Solid Tumors; a. 95%CIs were calculated with the Clopper-Pearson method; b. Median value and 95% CI were estimated using Kaplan-Meier method. Exploratory analyses suggested that none of the baseline characteristics, such as tumor PD-L1 expression, history of prior gastrectomy, or presence of lymph metastases, had a significant impact on response to the study treatment. However, patients with primary GEJ carcinoma (42.9% vs. 20.0%, P = 0.327) and the presence of liver metastases (40.0% vs. 11.8%, P = 0.106) tended to achieve a higher ORR, while baseline peritoneal metastases and multiple metastases appeared to be predictive factors of poorer ORR and DCR (Table 3 ). Table 3 Impact of baseline characteristics on tumor response (EEAS, n = 32) Clinical characteristics Objective response, n (%) P value a Disease control, n (%) P value a Yes No Yes No Primary tumor site GEJ Stomach 3 (42.9) 5 (20.0) 4 (57.1) 20 (80.0) 0.327 6 (85.7) 22 (88.0) 1 (14.3) 3 (12.0) 1.000 Baseline liver metastases Presence Absence 6 (40.0) 2 (11.8) 9 (60.0) 15 (88.2) 0.106 13 (86.7) 15 (88.2) 2 (13.3) 2 (11.8) 1.000 Baseline lymph metastases Presence Absence 4 (20.0) 4 (33.3) 16 (80.0) 8 (66.7) 0.433 17 (85.0) 11 (91.7) 3 (15.0) 1 (8.3) 1.000 Baseline peritoneal metastases Presence Absence 1 (8.3) 7 (35.0) 11 (91.7) 13 (65.0) 0.204 9 (75.0) 19 (95.0) 3 (25.0) 1 (5.0) 0.136 Number of metastatic sites ≤2 >2 6 (35.3) 2 (13.3) 11 (64.7) 13 (86.7) 0.229 12 (80.0) 16 (94.1) 3 (20.0) 1 (5.9) 0.319 Tumor PD-L1 expression Positive Negative Unknown 3 (25.0) 5 (27.8) 0 (0.0) 9 (75.0) 13 (72.2) 2 (100.0) 1.000 10 (83.3) 17 (94.4) 1 (50.0) 2 (16.7) 1 (5.6) 1 (50.0) 0.150 Prior gastrectomy Yes No 5 (25.0) 3 (25.0) 15 (75.0) 9 (75.0) 1.000 18 (90.0) 10 (83.3) 2 (10.0) 2 (16.7) 0.620 Prior immunotherapy Yes No 6 (25.0) 2 (25.0) 18 (75.0) 6 (75.0) 1.000 22 (91.7) 6 (75.0) 2 (8.3) 2 (25.0) 0.254 EEAS: efficacy-evaluable analysis set; GEJ: gastroesophageal junction; PD-L1: programmed death-ligand 1; a. Performed using two-side Fisher’s exact tests; b. PD-L1 positive was defined as a combined positive score (CPS) ≥ 1. At data cutoff, after 24 PFS events, the median PFS was 5.7 (95% CI: 4.7, 6.9) months (Fig. 4 A) and the 6-month PFS rate was 39.4%. With a median follow-up of 12.6 (95% CI: 10.4, 14.9) months, 19 patients had died, and the median OS was 10.8 (95% CI: 7.0, 17.2) months (Fig. 4 B), with a 12-month OS rate of 47.3%. In the prior IO subgroup, the median PFS was 5.9 (95% CI: 4.7, 10.5) months with a 6-month PFS rate of 44.9%, while the median OS was 14.4 (95% CI: 8.5, NE) months with a 12-month OS rate of 50.8%. Among 31 patients with baseline tumor PD-L1 testing results, 12 had positive PD-L1 expression (defined as a PD-L1 combined positive score [CPS] ≥ 1), and their PFS was significantly poorer than those with negative PD-L1 expression (median: 4.8 versus 6.9 months, log-rank P = 0.016) (Fig. 5 A). None of the other baseline factors demonstrated evident impact on PFS or OS, although a trend towards better OS was seen in patients with first-line immunotherapy exposure (median: 14.4 versus 5.9 months, log-rank P = 0.092) (Fig. 5 D), and those without peritoneal metastases (median: 13.8 versus 6.9 months, log-rank P = 0.080) (Fig. 5 F). 1.8. Safety TEAEs of any grade occurred in 33 (94.3%) patients, among which 30 (85.7%) were determined as treatment-related. Common TRAEs included neutrophil count decreased (n = 21, 60.0%), white blood cell decreased (n = 20, 57.1%), hypertension (n = 9, 25.7%), and proteinuria (n = 7, 20.0%). TRAEs of grade 3–4 occurred in 19 (54.3%) patients, with neutrophil count decreased (n = 14, 40.0%), white blood cell count decreased (n = 12, 34.3%), hypertension (n = 4, 11.4%), proteinuria (n = 2, 5.7%), and platelet count decreased (n = 2, 5.7%) being the most commonly observed (Table 4 ). Two patients experienced SAEs leading to hospitalization. Among whom, one had grade 4 intestinal obstruction and got relief after emergent surgery; the other had grade 3 acute kidney injury owing to bilateral ureteral stenosis. Neither event was related to the study treatment as judged by the investigator; however, both patients ultimately discontinued treatment because of deteriorated general condition. No treatment-related deaths occurred. Table 4 TRAEs occurring in more than 5% of all patients (FAS, n = 35) Adverse events by preferred term, n (%) Any grade Grade 3 ~ 4 Any TEAEs 33 (94.3) 20 (57.1) TEAEs related to study treatment 30 (85.7) 19 (54.3) Neutrophil count decreased 21 (60.0) 14 (40.0) White blood cell decreased 20 (57.1) 12 (34.3) Hypertension 9 (25.7) 4 (11.4) Proteinuria 7 (20.0) 2 (5.7) Paresthesia 6 (17.1) 0 (0.0) Platelet count decreased 3 (8.6) 2 (5.7) Lymphocyte count decreased 3 (8.6) 1 (2.9) Abdominal pain 2 (5.7) 0 (0.0) Asthenia 2 (5.7) 1 (2.9) Anemia 2 (5.7) 0 (0.0) FAS: full analysis set; TEAE: treatment-emergent adverse event; TRAE: treatment-related adverse event. The median treatment duration with surufatinib was 4.7 (95% CI: 3.4, 5.9) months, and the median number of treatment cycles with paclitaxel was 6 (range: 1–6). Dose reductions of surufatinib and paclitaxel were recorded in 11 (31.4%) and 13 (37.1%) patients, respectively, with leading causes being neutropenia (n = 10, 28.6%), leukopenia (n = 9, 25.7%), hypertension (n = 2, 5.7%), and paresthesia (n = 2, 5.7%). 4 Discussion To our knowledge, this is the first trial to evaluate the efficacy and safety of surufatinib combined with standard chemotherapy as second-line treatment for advanced gastric cancer. Theoretically, surufatinib’s mechanism on both antiangiogenic and immunomodulatory activities could provide better therapeutic activity than other antiangiogenic agents, such as ramucirumab and fruquintinib. However, the response rate did not meet the expected threshold of 35%. Several factors may have contributed to this finding. First, the dose intensity of paclitaxel in our trial (150 mg/m 2 , every 3 weeks) was lower than the standard triweekly regimen (175–225 mg/m 2 , every 3 weeks)[ 28 – 31 ] and the weekly regimen (80 mg/m 2 , d1, 8, 15, every 4 weeks)[ 15 – 17 ], thus decreasing the tumor-shrinking effect. Second, 80% of patients in our trial had multiple metastases and 42.9% had > 2 metastatic sites, both of which were higher than those in the recent RAINBOW-Asia and FRUTIGA trials.[ 16 , 17 ] Our analysis had suggested that ORR was 35.3% in patients with ≤ 2 metastatic sites but was only 13.3% in those with > 2 metastatic sites. Third, 51.8% of patients in our trial were aged ≥ 65 years, and nearly 90% had an ECOG performance status of 1. A poorer tolerance might indirectly increase the difficulty of achieving tumor relief. In fact, just after the first treatment cycle, 5 (14.3%) patients had to discontinue due to performance deterioration, and another 12 (34.3%) had dose reductions within the first 2 treatment cycles. Despite a moderate response, the survival benefit was more encouraging. The median PFS and OS were 5.7 months and 10.8 months, respectively, which were numerically superior to those from recent trials incorporating antiangiogenic therapies.[ 15 – 17 ] It is worth noting that much fewer patients in our trial (42.9%) received subsequent therapies than in the FRUTIGA trial (52.7%) and the RAINBOW-Asia trial (54%). Poorer baseline characteristics, as described above, might be a possible explanation. Subsequent antitumor treatment could have a remarkable impact on OS. The investigators of the FRUTIGA trial proposed that a much higher proportion of patients receiving subsequent antitumor therapies in the control group (72.2%) confounded the between-group OS comparison and led to a non-significant result.[ 17 ] Our supplementary analysis suggested that patients who received subsequent treatment tended to have prolonged OS compared to those who did not (median: 14.4 versus 8.5 months, log-rank P = 0.140). More noteworthy is the survival results in the prior IO subgroup. In the past decade, antiangiogenic therapy has established its standard-of-care position in the second-line treatment of advanced gastric cancer. Upon the arrival of the immunotherapy era, there is a need to clarify whether patients who have failed prior immunotherapy can also benefit from subsequent antiangiogenic therapy. Several recent retrospective studies have concluded that anti-PD-1-exposed patients benefitted more than anti-PD-1-naïve patients from second-line ramucirumab plus paclitaxel.[ 32 – 34 ] In prospective studies, the FRUTIGA trial included approximately 10% of patients with prior immunotherapy exposure. These patients seemed to derive a greater magnitude of PFS benefit from fruquintinib plus paclitaxel treatment than the intent-to-treat (ITT) population, but such a trend was not observed in the OS analysis.[ 17 ] In our trial, nearly four-fifths of patients were anti-PD-1-exposed. Although PFS results seemed comparable to those in the ITT population and in anti-PD-1-naïve patients, the median OS in this subpopulation reached 14.4 months, and the 12-month OS rate exceeded 50%. In contrast, the 9 patients with no prior anti-PD-1 exposure had a median OS of only 5.9 months with a 12-month OS rate of 16.7%. These results align with previous retrospective reports, suggesting that prior immunotherapy may predispose patients to better efficacy with subsequent antiangiogenic therapy.[ 32 – 34 ] Yet the clear mechanism of this effect remains unknown. Remodeling of the tumor microenvironment (TME) after immunotherapy might be one of the answers, while the potential of reprograming tumor-associated macrophages (TAMs) of surufatinib may also have provided extra effect on improving antitumor efficacy.[ 23 , 33 , 35 – 37 ] These results, however, should be interpreted with caution because of confounding factors. Compared with the ITT population, patients from the prior IO subgroup had a comparable proportion of presenting baseline liver metastases (46.2%), lymph metastases (65.4%), and metastatic sites > 2 (42.3%), a slightly lower proportion of baseline peritoneal metastases (34.6%) and positive PD-L1 expression (30.8%), whereas the proportion of patients receiving subsequent antitumor therapy (46.2%) was slightly higher. Such subtle differences in these factors may have contributed to the improved OS in this subgroup. In terms of safety, this treatment combination was generally well tolerated despite in a relatively elderly population. There were no unexpected adverse events, and the most frequently observed TRAEs were neutropenia and leukopenia with paclitaxel, and hypertension and proteinuria with surufatinib, consistent with those of previous reports. The single-arm, single-center design was the main limitation of our study. Moreover, the sample size of our trial was relatively small, which led to insufficient statistical power, particularly when performing inter-subgroup comparisons. Therefore, large multicenter randomized trials are warranted to validate our findings. 5 Conclusions Surufatinib plus paclitaxel demonstrated encouraging efficacy and favorable safety as second-line treatment for advanced gastric cancer. Notably, the survival benefit was especially promising in patients with prior exposure to immunotherapy. These results suggest an alternative position of surufatinib combined with paclitaxel for patients with advanced gastric cancer who have failed standard first-line immunochemotherapy. Declarations Human Ethics and Consent to Participate This study was approved by the Institutional Review Board and Ethics Committee (Approval letter No. : KY2022-151-B) of Renji Hospital, and was performed in accordance with the Declaration of Helsinki, Good Clinical Practice, and other applicable laws/regulations of China. All participants provided written informed consent prior to screening. Conflict of interest All authors declare no competing interests. Funding This investigator-initiated-trial was supported by HUTCHMED Limited (Protocol Code: 2022-012-CH01 IIT-GC) to Xiuying. Xiao, including study funding and supply of investigational surufatinib. Author Contribution X.X. and X.L. provided study conceptualization and led the execution of the project; T.H. enrolled patients, performed data curation and the final analyses; M.Z. enrolled patients and collected data; T.H., M.Z., and X.Z. interpretated the data and drafted the manuscript in collaboration; X.W., J.C. and F.J. helped to perform patient enrolment, data acquisition, data analysis, and data interpretation; X.Q., T.W. and Y.S. provided project administration and guaranteed the supply of study resources. All authors have reviewed and agreed to the published version of the manuscript. Acknowledgement The authors would like to thank the patients and their families for making this study possible, as well as all staff involved in this study. Data availability All data relevant to the study are included in the article, and are available from the corresponding authors upon reasonable request. References F. Bray, M. Laversanne, H. Sung, J. Ferlay, R.L. Siegel, I. 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Sci. 20 (9), 2106 (2019). https://doi.org/10.3390/ijms20092106 H. Wilke, K. Muro, E. Van Cutsem, S.-C. Oh, G. Bodoky, Y. Shimada et al., Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 15 (11), 1224–1235 (2014). https://doi.org/10.1016/S1470-2045(14)70420-6 R.-H. Xu, Y. Zhang, H. Pan, J. Feng, T. Zhang, T. Liu et al., Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-asia): a randomised, multicentre, double-blind, phase 3 trial. Lancet Gastroenterol. Hepatol. 6 (12), 1015–1024 (2021). https://doi.org/10.1016/S2468-1253(21)00313-7 F. Wang, L. Shen, W. Guo, T. Liu, J. Li, S. 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MacDonald, Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood. 119 (8), 1810–1820 (2012). https://doi.org/10.1182/blood-2011-09-379214 S.M. Pyonteck, L. Akkari, A.J. Schuhmacher, R.L. Bowman, L. Sevenich, D.F. Quail et al., CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19 (10), 1264–1272 (2013). https://doi.org/10.1038/nm.3337 M. Cheng, S. Fan, R. Tang, W. Zhang, J. Hu, J. Yu et al., Evaluation of surufatinib, an orally available VEGFR, FGFR1 and CSF-1R inhibitor, in combination with immune checkpoint blockade or chemotherapy in preclinical tumor models. Eur. J. Cancer. 138 , S25 (2020). https://doi.org/10.1016/S0959-8049(20)31132-1 P. Zhang, Z. Chen, S. Shi, Z. Li, F. Ye, L. Song et al., Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer. Cancer Immunol. Immunother. 73 (7), 119 (2024). https://doi.org/10.1007/s00262-024-03677-7 K. Shitara, M. Özgüroğlu, Y.-J. Bang, M. Di Bartolomeo, M. Mandalà, M.-H. Ryu et al., Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 392 (10142), 123–133 (2018). https://doi.org/10.1016/S0140-6736(18)31257-1 K. Lee, C.H. Maeng, T. Kim, D.Y. Zang, Y.H. Kim, I.G. Hwang et al., A phase III study to compare the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer who failed in first-line therapy (KCSG ST10‐01). Oncologist. 24 (1), 18–e24 (2019). https://doi.org/10.1634/theoncologist.2018-0142 R. Xu, D. Zhang, L. Shen, J. Li, J. Huang, J. Gong et al., A phase I/II trial of fruquintinib in combination with paclitaxel for second-line treatment in patients with advanced gastric cancer. J. Clin. Oncol. 35 (4suppl), 128–128 (2017). https://doi.org/10.1200/JCO.2017.35.4_suppl.128 S. Cascinu, F. Graziano, N. Cardarelli, M. Marcellini, P. Giordani, E.T. Menichetti et al., Phase II study of paclitaxel in pretreated advanced gastric cancer. Anticancer Drugs. 9 (4), 307–310 (1998). https://doi.org/10.1097/00001813-199804000-00003 Y. Yamada, K. Shirao, A. Ohtsu, N. Boku, I. Hyodo, H. Saitoh et al., Phase II trial of paclitaxel by three-hour infusion for advanced gastric cancer with short premedication for prophylaxis against paclitaxel-associated hypersensitivity reactions. Ann. Oncol. 12 (8), 1133–1137 (2001). https://doi.org/10.1023/A:1011680507956 K. Yamaguchi, M. Tada, N. Horikoshi, T. Otani, H. Takiuchi, S. Saitoh et al., Phase II study of paclitaxel with 3-h infusion in patients with advanced gastric cancer. Gastric Cancer. 5 (2), 90–95 (2002). https://doi.org/10.1007/s101200200015 Y.-K. Kang, M.-H. Ryu, S.H. Park, J.G. Kim, J.W. Kim, S.-H. Cho et al., Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy. Ann. Oncol. 29 (5), 1220–1226 (2018). https://doi.org/10.1093/annonc/mdy055 M. Masetti, S.-E. Al-Batran, T.O. Goetze, P. Thuss-Patience, J.R. Knorrenschild, E. Goekkurt et al., Efficacy of ramucirumab combination chemotherapy as second-line treatment in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction after exposure to checkpoint inhibitors and chemotherapy as first-line therapy. Int. J. Cancer. 154 (12), 2142–2150 (2024). https://doi.org/10.1002/ijc.34894 L.A. Kankeu Fonkoua, S. Chakrabarti, M.B. Sonbol, P.M. Kasi, J.S. Starr, A.J. Liu et al., Outcomes on anti-VEGFR-2/paclitaxel treatment after progression on immune checkpoint inhibition in patients with metastatic gastroesophageal adenocarcinoma. Int. J. Cancer. 149 (2), 378–386 (2021). https://doi.org/10.1002/ijc.33559 A. Sasaki, A. Kawazoe, T. Eto, M. Okunaka, S. Mishima, K. Sawada et al., Improved efficacy of taxanes and ramucirumab combination chemotherapy after exposure to anti-PD-1 therapy in advanced gastric cancer. ESMO Open. 4 (Suppl 2), e000775 (2020). https://doi.org/10.1136/esmoopen-2020-000775 Z. Ji, X. Wang, J. Xin, L. Ma, D. Zuo, H. Li et al., Multiomics reveals tumor microenvironment remodeling in locally advanced gastric and gastroesophageal junction cancer following neoadjuvant immunotherapy and chemotherapy. J. Immunother Cancer. 12 (12), e010041 (2024). https://doi.org/10.1136/jitc-2024-010041 A. Sasaki, Y. Nakamura, Y. Togashi, H. Kuno, H. Hojo, S. Kageyama et al., Enhanced tumor response to radiotherapy after PD-1 blockade in metastatic gastric cancer. Gastric Cancer Off J. Int. Gastric Cancer Assoc. Jpn Gastric Cancer Assoc. 23 (5), 893–903 (2020). https://doi.org/10.1007/s10120-020-01058-4 C. Huang, X. Wang, L. Wang, Y. Liu, Z. Xia, X. Wang et al., Targeting tumor associated macrophages (TAMs) reprograms tumor immune microenvironment to promote solid tumor immunotherapy. Cell. Oncol. 47 (5), 2011–2014 (2024). https://doi.org/10.1007/s13402-024-00987-x Additional Declarations No competing interests reported. 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2","display":"","copyAsset":false,"role":"figure","size":49129,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWaterfall plot for tumor response (EEAS, n=32)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6600621/v1/e7498da4d0c9a97880936114.png"},{"id":83199203,"identity":"28dcc013-43a4-4fea-9e94-d732a03aa79a","added_by":"auto","created_at":"2025-05-21 06:07:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":63734,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSwimming plot of treatment exposure and response (EEAS, n=32)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6600621/v1/cec543aa858b82ab23e529d9.png"},{"id":83199197,"identity":"036201d3-2160-4836-8a4e-fceeb1e4051b","added_by":"auto","created_at":"2025-05-21 06:07:20","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":141328,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curves of progression-free survival (A) and overall survival (B)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6600621/v1/22a2cd471dc343b8f54c8692.png"},{"id":83199195,"identity":"9a15a5a6-500f-4e68-9f9b-c2362a4bf633","added_by":"auto","created_at":"2025-05-21 06:07:20","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":669994,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExploratory subgroup analyses of progression-free survival and overall survival\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6600621/v1/69a99893300d68b1077ebcbf.png"},{"id":95564224,"identity":"fe49f7ce-390a-4e90-bb78-bf3ff05703a3","added_by":"auto","created_at":"2025-11-10 16:09:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2081897,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6600621/v1/581fe17c-e32c-46f4-ab76-2b4691d45339.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Surufatinib plus paclitaxel as second-line therapy for advanced gastric cancer: A single-arm, phase 2 clinical trial","fulltext":[{"header":"1 Background","content":"\u003cp\u003eGastric cancer is the third most common malignancy in China, with more than 40% of newly diagnosed cases and nearly half of all global deaths occurring in China.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Despite an increasing survival rate, the prognosis is still poor for Chinese patients, predominately attributed to a higher tumor burden, later stage at diagnosis, and a lower radical resection rate when compared to those from developed countries.[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] For unresectable or metastatic disease, chemotherapy-based systemic treatment is the standard-of-care.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] In recent years, a plenty of studies have revealed the molecular pathogenesis and potential drivers of alterations in gastric cancer, and the advancement of targeted therapy and immunotherapy has significantly improved patient survival.[\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] However, after the failure of first-line treatment, limited options are available.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eImproved efficacy has been observed in the combination of paclitaxel and antiangiogenic agents as second-line treatment for advanced gastric cancer. Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play important roles in tumor proliferation and metastasis via angiogenesis and lymphangiogenesis.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] Ramucirumab, a monoclonal VEGFR2 antibody, has been approved for the treatment of gastric cancer refractory to first-line treatment with proven efficacy and safety when combined with paclitaxel.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] More recently, the FRUTIGA trial demonstrated significantly improved progression-free survival (PFS) by combining fruquintinib (a small-molecule inhibitor of VEGFRs) with weekly paclitaxel as compared with paclitaxel alone.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eSurufatinib is a multi-kinase inhibitor of VEGFR1-3, fibroblast growth factor receptor 1 (FGFR1), and colony-stimulating factor-1 receptor (CSF-1R),[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and therefore has both anti-angiogenetic activity through VEGFRs and FGFR1 inhibition, and immunomodulatory mechanism through the blockade of the colony-stimulating factor-1 (CSF-1) and CSF-1R axis.[\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] This also endows surufatinib with the potential to be combined with chemotherapy or immunotherapy.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] In a recent trial, surufatinib was combined with toripalimab, an anti-programmed death protein 1 (PD-1) monoclonal antibody, in treating patients with advanced gastric cancer refractory to first-line therapy. The objective response rate (ORR) was 31.6% and the median PFS and overall survival (OS) were 4.1 months and 13.7 months, respectively.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eBased on these findings, we conducted this trial to evaluate the efficacy and safety of combining surufatinib with chemotherapy in patients with advanced gastric cancer who have disease progression after standard first-line treatment.\u003c/p\u003e"},{"header":"2 Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.1. Study design\u003c/h2\u003e \u003cp\u003eThis is an investigator-initiated, open-label, single-arm, phase 2 trial conducted in China. With the approval of local institutional review board and ethics committee (KY2022-151-B), the trial was performed in accordance with the Declaration of Helsinki, Good Clinical Practice, and other applicable laws/regulations of China. All participants provided written informed consent prior to screening. This trial was registered in the Chinese Clinical Trial Registry (ChiCTR2200063336).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e1.2. Patients\u003c/h2\u003e \u003cp\u003eAdult patients (aged 18\u0026ndash;75 years) with histologically confirmed human epidermal growth factor receptor 2 (HER2)-negative metastatic or unresectable adenocarcinoma of the stomach or gastroesophageal junction (GEJ) who had failed first-line fluoropyrimidine-based doublet chemotherapy with or without an anti-PD-1 antibody, were eligible. Other inclusion criteria were: measurable lesions per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate bone marrow, hepatic and renal function. A full listing of eligibility is available in \u003cb\u003eSupplementary Table S1\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e1.3. Treatments and assessments\u003c/h2\u003e \u003cp\u003eAll patients received oral surufatinib (250 mg, once daily) plus intravenous paclitaxel (150 mg/m\u003csup\u003e2\u003c/sup\u003e, on day 1) or irinotecan (125 mg/m\u003csup\u003e2\u003c/sup\u003e, on days 1 and 8) in case paclitaxel had been included in the first-line regimen, with three weeks as one cycle for up to 6 cycles, followed by surufatinib maintenance (250 mg, once daily) until disease progression, intolerable toxicity, death, or patient withdrawal (whichever occurred first). Supportive care, dose interruption, and dose reduction were allowed in order to manage toxicity.\u003c/p\u003e \u003cp\u003eTumor response was assessed by investigators per RECIST v1.1 using computed tomography (CT) or magnetic resonance imaging (MRI) every 6 weeks after the first dose until disease progression, death, beginning of subsequent therapy, or patient withdrawal. Objective responses were confirmed 4 to 6 weeks after the first observation. After treatment discontinuation, patients were followed for survival every 12 weeks until death, loss to follow-up, withdrawal of informed consent, or end of study (whichever occurred first).\u003c/p\u003e \u003cp\u003eSafety assessment included the incidence and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and relatedness judged by the investigator. Adverse events (AEs) were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 24.1, and the severity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e1.4. Endpoints\u003c/h2\u003e \u003cp\u003eThe primary endpoint for efficacy was the investigator-assessed ORR per RECIST v1.1. Secondary endpoints were disease control rate (DCR) and PFS per RECIST v1.1, and OS. Safety endpoints included treatment-related adverse events (TRAEs) and change from baseline in vital signs and laboratory test results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e1.5. Statistical analysis\u003c/h2\u003e \u003cp\u003eSample size calculation was based on the superiority test for a one-group design. Thirty-five patients were required to provide 80% of power at a one-sided significance level of 0.05. The threshold ORR for historical control was set to 15% according to those with paclitaxel (14\u0026ndash;24%)[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] or irinotecan (13.6%)[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] from previous studies. And the expected ORR was 35% as referred to previous finding with fruquintinib plus paclitaxel (35.7%) as second-line therapy for advanced gastric cancer in a phase 1b/2 trial.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAnalyses for ORR and DCR were performed in patients who had received\u0026thinsp;\u0026ge;\u0026thinsp;1 dose of the study drug and had\u0026thinsp;\u0026ge;\u0026thinsp;1 post-baseline tumor assessment (the efficacy-evaluable analysis set [EEAS]), while analyses of PFS, OS, and safety data were performed in all patients who had received\u0026thinsp;\u0026ge;\u0026thinsp;1 dose of the study treatment (the full analysis set [FAS]). Duration of response (DoR) was analyzed for patients with confirmed objective responses. ORR, DCR, and the corresponding 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. The Kaplan-Meier method was used to estimate time-to-event endpoints including DoR, PFS and OS, and median and 95% CI values were provided. Data processing and analyses were performed using Microsoft Excel (version 2108) and the R software (version 4.4.0).\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e1.6. Patients\u003c/h2\u003e\n \u003cp\u003eFrom 27 September 2022 to 7 July 2024, 35 patients were enrolled and received\u0026thinsp;\u0026ge;\u0026thinsp;1 dose of the study treatment, and 14 (40.0%) patients completed all 6 cycles of combination therapy and received maintenance surufatinib. At data cutoff (20 December 2024), 30 (85.7%) patients had discontinued the study treatment, primarily due to radiographic disease progression (n\u0026thinsp;=\u0026thinsp;19, 63.3%) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). After treatment discontinuation, 15 patients received subsequent systemic therapies, including apatinib (n\u0026thinsp;=\u0026thinsp;8), monoclonal or bispecific antibodies targeting PD-1/L1 (n\u0026thinsp;=\u0026thinsp;7), irinotecan (n\u0026thinsp;=\u0026thinsp;4), and Claudin 18.2 antibody-drug conjugates (n\u0026thinsp;=\u0026thinsp;3).\u003c/p\u003e\n \u003cp\u003eMore than half (n\u0026thinsp;=\u0026thinsp;18, 51.4%) of patients were aged 65 or elder, 31 (88.6%) had an ECOG performance status of 1, and 26 (74.3%) were male. Primary tumor sites were stomach in 28 (80.0%) patients and GEJ in 7 (20.0%) patients. All patients had stage IV disease, with lymph nodes (n\u0026thinsp;=\u0026thinsp;23, 65.7%), liver (n\u0026thinsp;=\u0026thinsp;16, 45.7%), and peritoneum (n\u0026thinsp;=\u0026thinsp;14, 40.0%) being the most common metastatic sites. Oxaliplatin (n\u0026thinsp;=\u0026thinsp;29, 82.9%) and S-1 (n\u0026thinsp;=\u0026thinsp;25, 71.4%) were predominantly used first-line chemo agents, and 26 (74.3%) had prior immunotherapy exposure, with sintilimab (n\u0026thinsp;=\u0026thinsp;11, 31.4%) being the most frequently used. Other baseline characteristics were summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline demographic and clinical characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003eAll patients (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003cp\u003e\u0026lt;65\u003c/p\u003e\n \u003cp\u003e\u0026ge;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e65 (33\u0026ndash;75)\u003c/p\u003e\n \u003cp\u003e17 (48.6)\u003c/p\u003e\n \u003cp\u003e18 (51.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e26 (74.3)\u003c/p\u003e\n \u003cp\u003e9 (25.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003eECOG performance status\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e4 (11.4)\u003c/p\u003e\n \u003cp\u003e31 (88.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003ePrimary site\u003c/p\u003e\n \u003cp\u003eStomach\u003c/p\u003e\n \u003cp\u003eGEJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e28 (80.0)\u003c/p\u003e\n \u003cp\u003e7 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003eTumor stage at screening\u003c/p\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e35 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003ePrior radical gastrectomy\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e21 (60.0)\u003c/p\u003e\n \u003cp\u003e14 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003eNo. of involved organs\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e\u0026ge;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e7 (20.0)\u003c/p\u003e\n \u003cp\u003e13 (37.1)\u003c/p\u003e\n \u003cp\u003e15 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003eSite of metastases\u003c/p\u003e\n \u003cp\u003eLymph node\u003c/p\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003cp\u003ePeritoneum\u003c/p\u003e\n \u003cp\u003eAbdominal/pelvic cavity\u003c/p\u003e\n \u003cp\u003eOvary\u003c/p\u003e\n \u003cp\u003eUreter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e23 (65.7)\u003c/p\u003e\n \u003cp\u003e16 (45.7)\u003c/p\u003e\n \u003cp\u003e14 (40.0)\u003c/p\u003e\n \u003cp\u003e5 (14.3)\u003c/p\u003e\n \u003cp\u003e4 (11.4)\u003c/p\u003e\n \u003cp\u003e4 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003ePD-L1 expression \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e12 (34.3)\u003c/p\u003e\n \u003cp\u003e19 (54.3)\u003c/p\u003e\n \u003cp\u003e4 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003eChemo regimen in prior line\u003c/p\u003e\n \u003cp\u003eOxaliplatin\u003c/p\u003e\n \u003cp\u003eS-1\u003c/p\u003e\n \u003cp\u003eCapecitabine\u003c/p\u003e\n \u003cp\u003eOthers \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e29 (82.9)\u003c/p\u003e\n \u003cp\u003e25 (71.4)\u003c/p\u003e\n \u003cp\u003e8 (22.9)\u003c/p\u003e\n \u003cp\u003e6 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 57.6923%;\"\u003e\n \u003cp\u003eImmunotherapy in prior line\u003c/p\u003e\n \u003cp\u003eSintilimab\u003c/p\u003e\n \u003cp\u003eSHR-1701\u003c/p\u003e\n \u003cp\u003eNivolumab\u003c/p\u003e\n \u003cp\u003eToripalimab\u003c/p\u003e\n \u003cp\u003eOthers \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 42.3077%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e11 (31.4)\u003c/p\u003e\n \u003cp\u003e4 (11.4)\u003c/p\u003e\n \u003cp\u003e3 (8.6)\u003c/p\u003e\n \u003cp\u003e3 (8.6)\u003c/p\u003e\n \u003cp\u003e5 (14.3)\u003c/p\u003e\n \u003cp\u003e9 (25.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eData are n (%) otherwise indicated.\u003c/p\u003e\n \u003cp\u003eCPS: combined positive score; ECOG: Eastern Cooperative Oncology Group; GEJ: gastroesophageal junction; PD-L1: programmed death-ligand 1;\u003c/p\u003e\n \u003cp\u003ea. PD-L1 positive was defined as a combined positive score (CPS)\u0026thinsp;\u0026ge;\u0026thinsp;1;\u003c/p\u003e\n \u003cp\u003eb. other chemo agents included cisplatin, 5-FU, and irinotecan;\u003c/p\u003e\n \u003cp\u003ec. other immunotherapies included tislelizumab, pembrolizumab, and AK-104.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e1.7. Efficacy\u003c/h2\u003e\n \u003cp\u003eThe EEAS included 32 patients. The best overall response (BOR) was partial response (PR) in 8 (25.0%) patients, stable disease (SD) in 20 (62.5%) patients, and progressive disease (PD) in 4 (12.5%) patients (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The ORR was 25.0% (95% CI: 11.5, 43.4), and the DCR was 87.5% (95% CI: 71.0, 96.5). For the 8 patients who achieved PR, the median DoR was 3.2 (95% CI: 2.8, not estimable [NE]) months (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eThe ORR (25.0% [95% CI: 9.8, 46.7]) and DCR (91.7% [95% CI: 77.0, 99.0]) in patients with exposure to first-line immunotherapy (the prior IO subgroup) were consistent with the FAS population, and the median DoR was 3.1 (95% CI: 1.8, 10.9) months among the 6 patients who achieved objective responses.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTumor responses according to RECIST v1.1 (EEAS, n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEEAS (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBest overall response, n (%)\u003c/p\u003e\n \u003cp\u003eComplete response\u003c/p\u003e\n \u003cp\u003ePartial response\u003c/p\u003e\n \u003cp\u003eStable disease\u003c/p\u003e\n \u003cp\u003eProgressive disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e8 (25.0)\u003c/p\u003e\n \u003cp\u003e20 (62.5)\u003c/p\u003e\n \u003cp\u003e4 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eObjective response rate \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e8 (25.0)\u003c/p\u003e\n \u003cp\u003e11.5, 43.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisease control rate \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e28 (87.5)\u003c/p\u003e\n \u003cp\u003e71.0, 96.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDuration of response \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003cp\u003emedian (months)\u003c/p\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e8 (25.0)\u003c/p\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003cp\u003e2.8, not estimable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eCI: confidential interval; EEAS: efficacy-evaluable analysis set; RECIST: Response Evaluation Criteria in Solid Tumors;\u003c/p\u003e\n \u003cp\u003ea. 95%CIs were calculated with the Clopper-Pearson method;\u003c/p\u003e\n \u003cp\u003eb. Median value and 95% CI were estimated using Kaplan-Meier method.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eExploratory analyses suggested that none of the baseline characteristics, such as tumor PD-L1 expression, history of prior gastrectomy, or presence of lymph metastases, had a significant impact on response to the study treatment. However, patients with primary GEJ carcinoma (42.9% vs. 20.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.327) and the presence of liver metastases (40.0% vs. 11.8%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.106) tended to achieve a higher ORR, while baseline peritoneal metastases and multiple metastases appeared to be predictive factors of poorer ORR and DCR (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eImpact of baseline characteristics on tumor response (EEAS, n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eClinical characteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eObjective response, n (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDisease control, n (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrimary tumor site\u003c/p\u003e\n \u003cp\u003eGEJ\u003c/p\u003e\n \u003cp\u003eStomach\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e3 (42.9)\u003c/p\u003e\n \u003cp\u003e5 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e4 (57.1)\u003c/p\u003e\n \u003cp\u003e20 (80.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.327\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e6 (85.7)\u003c/p\u003e\n \u003cp\u003e22 (88.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e1 (14.3)\u003c/p\u003e\n \u003cp\u003e3 (12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBaseline liver metastases\u003c/p\u003e\n \u003cp\u003ePresence\u003c/p\u003e\n \u003cp\u003eAbsence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e6 (40.0)\u003c/p\u003e\n \u003cp\u003e2 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e9 (60.0)\u003c/p\u003e\n \u003cp\u003e15 (88.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e13 (86.7)\u003c/p\u003e\n \u003cp\u003e15 (88.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e2 (13.3)\u003c/p\u003e\n \u003cp\u003e2 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBaseline lymph metastases\u003c/p\u003e\n \u003cp\u003ePresence\u003c/p\u003e\n \u003cp\u003eAbsence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e4 (20.0)\u003c/p\u003e\n \u003cp\u003e4 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e16 (80.0)\u003c/p\u003e\n \u003cp\u003e8 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.433\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e17 (85.0)\u003c/p\u003e\n \u003cp\u003e11 (91.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e3 (15.0)\u003c/p\u003e\n \u003cp\u003e1 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBaseline peritoneal metastases\u003c/p\u003e\n \u003cp\u003ePresence\u003c/p\u003e\n \u003cp\u003eAbsence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e1 (8.3)\u003c/p\u003e\n \u003cp\u003e7 (35.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e11 (91.7)\u003c/p\u003e\n \u003cp\u003e13 (65.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e9 (75.0)\u003c/p\u003e\n \u003cp\u003e19 (95.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e3 (25.0)\u003c/p\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of metastatic sites\u003c/p\u003e\n \u003cp\u003e\u0026le;2\u003c/p\u003e\n \u003cp\u003e\u0026gt;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e6 (35.3)\u003c/p\u003e\n \u003cp\u003e2 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e11 (64.7)\u003c/p\u003e\n \u003cp\u003e13 (86.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.229\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e12 (80.0)\u003c/p\u003e\n \u003cp\u003e16 (94.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e3 (20.0)\u003c/p\u003e\n \u003cp\u003e1 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.319\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor PD-L1 expression\u003c/p\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e3 (25.0)\u003c/p\u003e\n \u003cp\u003e5 (27.8)\u003c/p\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e9 (75.0)\u003c/p\u003e\n \u003cp\u003e13 (72.2)\u003c/p\u003e\n \u003cp\u003e2 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e10 (83.3)\u003c/p\u003e\n \u003cp\u003e17 (94.4)\u003c/p\u003e\n \u003cp\u003e1 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e2 (16.7)\u003c/p\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003cp\u003e1 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.150\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior gastrectomy\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e5 (25.0)\u003c/p\u003e\n \u003cp\u003e3 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e15 (75.0)\u003c/p\u003e\n \u003cp\u003e9 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e18 (90.0)\u003c/p\u003e\n \u003cp\u003e10 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e2 (10.0)\u003c/p\u003e\n \u003cp\u003e2 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.620\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior immunotherapy\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e6 (25.0)\u003c/p\u003e\n \u003cp\u003e2 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e18 (75.0)\u003c/p\u003e\n \u003cp\u003e6 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e22 (91.7)\u003c/p\u003e\n \u003cp\u003e6 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e2 (8.3)\u003c/p\u003e\n \u003cp\u003e2 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.254\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003eEEAS: efficacy-evaluable analysis set; GEJ: gastroesophageal junction; PD-L1: programmed death-ligand 1;\u003c/p\u003e\n \u003cp\u003ea. Performed using two-side Fisher\u0026rsquo;s exact tests;\u003c/p\u003e\n \u003cp\u003eb. PD-L1 positive was defined as a combined positive score (CPS)\u0026thinsp;\u0026ge;\u0026thinsp;1.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eAt data cutoff, after 24 PFS events, the median PFS was 5.7 (95% CI: 4.7, 6.9) months (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA) and the 6-month PFS rate was 39.4%. With a median follow-up of 12.6 (95% CI: 10.4, 14.9) months, 19 patients had died, and the median OS was 10.8 (95% CI: 7.0, 17.2) months (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eB), with a 12-month OS rate of 47.3%. In the prior IO subgroup, the median PFS was 5.9 (95% CI: 4.7, 10.5) months with a 6-month PFS rate of 44.9%, while the median OS was 14.4 (95% CI: 8.5, NE) months with a 12-month OS rate of 50.8%.\u003c/p\u003e\n \u003cp\u003eAmong 31 patients with baseline tumor PD-L1 testing results, 12 had positive PD-L1 expression (defined as a PD-L1 combined positive score [CPS]\u0026thinsp;\u0026ge;\u0026thinsp;1), and their PFS was significantly poorer than those with negative PD-L1 expression (median: 4.8 versus 6.9 months, log-rank \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eA). None of the other baseline factors demonstrated evident impact on PFS or OS, although a trend towards better OS was seen in patients with first-line immunotherapy exposure (median: 14.4 versus 5.9 months, log-rank \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.092) (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eD), and those without peritoneal metastases (median: 13.8 versus 6.9 months, log-rank \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.080) (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eF).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e1.8. Safety\u003c/h2\u003e\n \u003cp\u003eTEAEs of any grade occurred in 33 (94.3%) patients, among which 30 (85.7%) were determined as treatment-related. Common TRAEs included neutrophil count decreased (n\u0026thinsp;=\u0026thinsp;21, 60.0%), white blood cell decreased (n\u0026thinsp;=\u0026thinsp;20, 57.1%), hypertension (n\u0026thinsp;=\u0026thinsp;9, 25.7%), and proteinuria (n\u0026thinsp;=\u0026thinsp;7, 20.0%). TRAEs of grade 3\u0026ndash;4 occurred in 19 (54.3%) patients, with neutrophil count decreased (n\u0026thinsp;=\u0026thinsp;14, 40.0%), white blood cell count decreased (n\u0026thinsp;=\u0026thinsp;12, 34.3%), hypertension (n\u0026thinsp;=\u0026thinsp;4, 11.4%), proteinuria (n\u0026thinsp;=\u0026thinsp;2, 5.7%), and platelet count decreased (n\u0026thinsp;=\u0026thinsp;2, 5.7%) being the most commonly observed (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Two patients experienced SAEs leading to hospitalization. Among whom, one had grade 4 intestinal obstruction and got relief after emergent surgery; the other had grade 3 acute kidney injury owing to bilateral ureteral stenosis. Neither event was related to the study treatment as judged by the investigator; however, both patients ultimately discontinued treatment because of deteriorated general condition. No treatment-related deaths occurred.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTRAEs occurring in more than 5% of all patients (FAS, n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAdverse events by preferred term, n (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAny grade\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGrade 3\u0026thinsp;~\u0026thinsp;4\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny TEAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (94.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTEAEs related to study treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (85.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (54.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeutrophil count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWhite blood cell decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (34.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (25.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProteinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eParesthesia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelet count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLymphocyte count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsthenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eFAS: full analysis set; TEAE: treatment-emergent adverse event; TRAE: treatment-related adverse event.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eThe median treatment duration with surufatinib was 4.7 (95% CI: 3.4, 5.9) months, and the median number of treatment cycles with paclitaxel was 6 (range: 1\u0026ndash;6). Dose reductions of surufatinib and paclitaxel were recorded in 11 (31.4%) and 13 (37.1%) patients, respectively, with leading causes being neutropenia (n\u0026thinsp;=\u0026thinsp;10, 28.6%), leukopenia (n\u0026thinsp;=\u0026thinsp;9, 25.7%), hypertension (n\u0026thinsp;=\u0026thinsp;2, 5.7%), and paresthesia (n\u0026thinsp;=\u0026thinsp;2, 5.7%).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eTo our knowledge, this is the first trial to evaluate the efficacy and safety of surufatinib combined with standard chemotherapy as second-line treatment for advanced gastric cancer. Theoretically, surufatinib\u0026rsquo;s mechanism on both antiangiogenic and immunomodulatory activities could provide better therapeutic activity than other antiangiogenic agents, such as ramucirumab and fruquintinib. However, the response rate did not meet the expected threshold of 35%. Several factors may have contributed to this finding. First, the dose intensity of paclitaxel in our trial (150 mg/m\u003csup\u003e2\u003c/sup\u003e, every 3 weeks) was lower than the standard triweekly regimen (175\u0026ndash;225 mg/m\u003csup\u003e2\u003c/sup\u003e, every 3 weeks)[\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and the weekly regimen (80 mg/m\u003csup\u003e2\u003c/sup\u003e, d1, 8, 15, every 4 weeks)[\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], thus decreasing the tumor-shrinking effect. Second, 80% of patients in our trial had multiple metastases and 42.9% had\u0026thinsp;\u0026gt;\u0026thinsp;2 metastatic sites, both of which were higher than those in the recent RAINBOW-Asia and FRUTIGA trials.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Our analysis had suggested that ORR was 35.3% in patients with \u0026le;\u0026thinsp;2 metastatic sites but was only 13.3% in those with \u0026gt;\u0026thinsp;2 metastatic sites. Third, 51.8% of patients in our trial were aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years, and nearly 90% had an ECOG performance status of 1. A poorer tolerance might indirectly increase the difficulty of achieving tumor relief. In fact, just after the first treatment cycle, 5 (14.3%) patients had to discontinue due to performance deterioration, and another 12 (34.3%) had dose reductions within the first 2 treatment cycles.\u003c/p\u003e \u003cp\u003eDespite a moderate response, the survival benefit was more encouraging. The median PFS and OS were 5.7 months and 10.8 months, respectively, which were numerically superior to those from recent trials incorporating antiangiogenic therapies.[\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] It is worth noting that much fewer patients in our trial (42.9%) received subsequent therapies than in the FRUTIGA trial (52.7%) and the RAINBOW-Asia trial (54%). Poorer baseline characteristics, as described above, might be a possible explanation. Subsequent antitumor treatment could have a remarkable impact on OS. The investigators of the FRUTIGA trial proposed that a much higher proportion of patients receiving subsequent antitumor therapies in the control group (72.2%) confounded the between-group OS comparison and led to a non-significant result.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Our supplementary analysis suggested that patients who received subsequent treatment tended to have prolonged OS compared to those who did not (median: 14.4 versus 8.5 months, log-rank \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.140).\u003c/p\u003e \u003cp\u003eMore noteworthy is the survival results in the prior IO subgroup. In the past decade, antiangiogenic therapy has established its standard-of-care position in the second-line treatment of advanced gastric cancer. Upon the arrival of the immunotherapy era, there is a need to clarify whether patients who have failed prior immunotherapy can also benefit from subsequent antiangiogenic therapy. Several recent retrospective studies have concluded that anti-PD-1-exposed patients benefitted more than anti-PD-1-na\u0026iuml;ve patients from second-line ramucirumab plus paclitaxel.[\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] In prospective studies, the FRUTIGA trial included approximately 10% of patients with prior immunotherapy exposure. These patients seemed to derive a greater magnitude of PFS benefit from fruquintinib plus paclitaxel treatment than the intent-to-treat (ITT) population, but such a trend was not observed in the OS analysis.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] In our trial, nearly four-fifths of patients were anti-PD-1-exposed. Although PFS results seemed comparable to those in the ITT population and in anti-PD-1-na\u0026iuml;ve patients, the median OS in this subpopulation reached 14.4 months, and the 12-month OS rate exceeded 50%. In contrast, the 9 patients with no prior anti-PD-1 exposure had a median OS of only 5.9 months with a 12-month OS rate of 16.7%. These results align with previous retrospective reports, suggesting that prior immunotherapy may predispose patients to better efficacy with subsequent antiangiogenic therapy.[\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] Yet the clear mechanism of this effect remains unknown. Remodeling of the tumor microenvironment (TME) after immunotherapy might be one of the answers, while the potential of reprograming tumor-associated macrophages (TAMs) of surufatinib may also have provided extra effect on improving antitumor efficacy.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThese results, however, should be interpreted with caution because of confounding factors. Compared with the ITT population, patients from the prior IO subgroup had a comparable proportion of presenting baseline liver metastases (46.2%), lymph metastases (65.4%), and metastatic sites\u0026thinsp;\u0026gt;\u0026thinsp;2 (42.3%), a slightly lower proportion of baseline peritoneal metastases (34.6%) and positive PD-L1 expression (30.8%), whereas the proportion of patients receiving subsequent antitumor therapy (46.2%) was slightly higher. Such subtle differences in these factors may have contributed to the improved OS in this subgroup.\u003c/p\u003e \u003cp\u003eIn terms of safety, this treatment combination was generally well tolerated despite in a relatively elderly population. There were no unexpected adverse events, and the most frequently observed TRAEs were neutropenia and leukopenia with paclitaxel, and hypertension and proteinuria with surufatinib, consistent with those of previous reports.\u003c/p\u003e \u003cp\u003eThe single-arm, single-center design was the main limitation of our study. Moreover, the sample size of our trial was relatively small, which led to insufficient statistical power, particularly when performing inter-subgroup comparisons. Therefore, large multicenter randomized trials are warranted to validate our findings.\u003c/p\u003e"},{"header":"5 Conclusions","content":"\u003cp\u003eSurufatinib plus paclitaxel demonstrated encouraging efficacy and favorable safety as second-line treatment for advanced gastric cancer. Notably, the survival benefit was especially promising in patients with prior exposure to immunotherapy. These results suggest an alternative position of surufatinib combined with paclitaxel for patients with advanced gastric cancer who have failed standard first-line immunochemotherapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cb\u003eHuman Ethics and Consent to Participate\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThis study was approved by the Institutional Review Board and Ethics Committee (Approval letter No. : KY2022-151-B) of Renji Hospital, and was performed in accordance with the Declaration of Helsinki, Good Clinical Practice, and other applicable laws/regulations of China. All participants provided written informed consent prior to screening.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConflict of interest\u003c/strong\u003e \u003cp\u003eAll authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis investigator-initiated-trial was supported by HUTCHMED Limited (Protocol Code: 2022-012-CH01 IIT-GC) to Xiuying. Xiao, including study funding and supply of investigational surufatinib.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eX.X. and X.L. provided study conceptualization and led the execution of the project; T.H. enrolled patients, performed data curation and the final analyses; M.Z. enrolled patients and collected data; T.H., M.Z., and X.Z. interpretated the data and drafted the manuscript in collaboration; X.W., J.C. and F.J. helped to perform patient enrolment, data acquisition, data analysis, and data interpretation; X.Q., T.W. and Y.S. provided project administration and guaranteed the supply of study resources. All authors have reviewed and agreed to the published version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to thank the patients and their families for making this study possible, as well as all staff involved in this study.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eAll data relevant to the study are included in the article, and are available from the corresponding authors upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eF. Bray, M. Laversanne, H. Sung, J. Ferlay, R.L. Siegel, I. Soerjomataram et al., Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. 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Oncol. \u003cb\u003e47\u003c/b\u003e(5), 2011\u0026ndash;2014 (2024). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s13402-024-00987-x\u003c/span\u003e\u003cspan address=\"10.1007/s13402-024-00987-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cellular-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ceon","sideBox":"Learn more about [Cellular Oncology](http://link.springer.com/journal/13402)","snPcode":"13402","submissionUrl":"https://submission.nature.com/new-submission/13402/3","title":"Cellular Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"gastric cancer, second-line, surufatinib, paclitaxel","lastPublishedDoi":"10.21203/rs.3.rs-6600621/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6600621/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose \u003c/strong\u003eCombining paclitaxel with antiangiogenic agents has demonstrated improved efficacy as second-line treatment for advanced gastric cancer. Surufatinib, a multi-kinase inhibitor with antiangiogenic and immunomodulatory properties, has exhibited synergistic effects with chemotherapy in preclinical studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eThis single-arm phase 2 trial enrolled patients aged 18-75 with HER2-negative unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma who had failed first-line therapy. All received surufatinib 250mg once daily plus paclitaxel 150mg/m\u003csup\u003e2\u003c/sup\u003e every 3 weeks for up to 6 cycles, followed by maintenance surufatinib until progression, intolerable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eThirty-five patients were enrolled. Among 32 tumor response-evaluable patients, the ORR and DCR were 25.0% (95% confidence interval [CI]: 11.5, 43.4) and 87.5% (95% CI: 71.0, 96.5), respectively. Median PFS was 5.7 (95% CI: 4.7, 6.9) months and median OS was 10.8 (95% CI: 7.0, 17.2) months. In 26 patients with prior immunotherapy exposure, the median OS was 14.4 (95% CI: 8.5, not estimable) months. Overall, treatment-related adverse events of grade ≥3 occurred in 19 (54.3%) patients, with neutropenia (40.0%), leukopenia (34.3%), and hypertension (11.4%) being the most commonly observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e Surufatinib plus paclitaxel showed promising efficacy and manageable safety as second-line treatment for advanced gastric cancer, especially in patients who had failed prior immunotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e ChiCTR2200063336, registered in the Chinese Clinical Trial Registry on September 5, 2022.\u003c/p\u003e","manuscriptTitle":"Surufatinib plus paclitaxel as second-line therapy for advanced gastric cancer: A single-arm, phase 2 clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-21 06:07:15","doi":"10.21203/rs.3.rs-6600621/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-05T04:34:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-30T00:10:11+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-21T04:20:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-20T07:24:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-18T09:50:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"24344770623242675223417810751645922386","date":"2025-06-18T08:00:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"21432636397079218993304847637344012244","date":"2025-06-16T23:38:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"300810527146385085843132122263199494463","date":"2025-06-16T02:44:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"272238710969974207762003494276651873207","date":"2025-06-13T22:23:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-29T06:36:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"283252940620831817832714849954589797357","date":"2025-05-18T22:35:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-16T07:20:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-09T09:47:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-09T09:43:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cellular Oncology","date":"2025-05-06T08:15:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cellular-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ceon","sideBox":"Learn more about [Cellular Oncology](http://link.springer.com/journal/13402)","snPcode":"13402","submissionUrl":"https://submission.nature.com/new-submission/13402/3","title":"Cellular Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"81dc5521-fe9f-44f1-9fbd-bca8dda9b121","owner":[],"postedDate":"May 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-10T16:05:52+00:00","versionOfRecord":{"articleIdentity":"rs-6600621","link":"https://doi.org/10.1007/s13402-025-01127-9","journal":{"identity":"cellular-oncology","isVorOnly":false,"title":"Cellular Oncology"},"publishedOn":"2025-11-03 15:58:07","publishedOnDateReadable":"November 3rd, 2025"},"versionCreatedAt":"2025-05-21 06:07:15","video":"","vorDoi":"10.1007/s13402-025-01127-9","vorDoiUrl":"https://doi.org/10.1007/s13402-025-01127-9","workflowStages":[]},"version":"v1","identity":"rs-6600621","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6600621","identity":"rs-6600621","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}