e14023 Background: Leptomeningeal metastasis (LM) from malignant melanoma remains a catastrophic event with a historical median survival of <3 months. While intrathecal (IT) administration of PD-1 antibodies has shown preliminary efficacy, the potential synergy between radiotherapy-induced immunogenic cell death and compartmentalized checkpoint blockade remains unexplored. We investigated the safety and survival impact of combining WBRT with IT PD-1 antibody therapy in this high-risk population. Methods: We retrospectively analyzed consecutive patients with melanoma LM treated with IT PD-1 antibodies at a single center between June 2022 and December 2024. The cohort was stratified by treatment modality: IT Monotherapy vs. Combination Therapy (WBRT delivered within 30 days of IT PD-1 initiation). The primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS), assessed by Kaplan-Meier analysis and Log-rank tests. Safety was rigorously graded per NCI-CTCAE v5.0, with specific focus on neurotoxicity and immune-related adverse events (irAEs). Results: A total of 20 patients were enrolled (Combination: n=13; Monotherapy: n=7). Baseline characteristics were well-balanced. The Combination arm achieved a striking survival advantage, with a median OS of 45.3 weeks (95% CI 28.7–NR) compared to 20.1 weeks (95% CI 13.3–NR) in the Monotherapy arm (HR 0.30 [95% CI, 0.04-0.68]; P = 0.021). Similarly, median iPFS was more than doubled in the Combination group (23.0 vs. 10.0 weeks; P < 0.001). The regimen was well-tolerated; there was no statistically significant difference in the incidence of Grade ≥2 adverse events between groups, and no unexpected severe neurotoxicity was observed. Conclusions: Concurrent WBRT and IT PD-1 blockade demonstrates potent synergistic activity in melanoma LM, delivering unprecedented survival outcomes (median OS >10 months) without amplifying toxicity. These findings suggest that radiotherapy may prime the CSF microenvironment for enhanced immune checkpoint efficacy. This novel multimodal strategy warrants validation in prospective randomized trials as a potential new standard of care.

4079 Background: Borrmann type IV (Borrmann-IV) gastric cancer (GC), or linitis plastica, is marked by diffuse infiltration, early metastasis, and poor prognosis, with limited benefit from conventional therapies. This study evaluated the efficacy and safety of a total neoadjuvant regimen combining immunotherapy and chemotherapy in Borrmann-IV GC. Methods: This trial (NCT06451211) enrolled patients with Borrmagnn-IV gastric cancer without distant metastasis. Participants received a total neoadjuvant regimen consisting of tislelizumab (an anti–PD-1 antibody) combined with platinum-based chemotherapy (oxaliplatin plus capecitabine or S-1) for 6 cycles at 3-week intervals, followed by radical surgical resection. The prespecified primary endpoint was the pathological response rate, defined as tumor regression grade (TRG) 0/1. Results: A total of 56 patients were enrolled, all patients had no distant metastasis confirmed by laparoscopic exploration and ascitic fluid cytology. The median age was 58 years; all patients were pMMR. In the efficacy analysis population (n=47), 41 patients completed 5–6 cycles and 6 patients completed 3–4 cycles of preoperative chemotherapy plus immunotherapy, no patients experienced disease progression leading to tumor metastasis during preoperative treatment. 47 patients underwent radical surgical resection, including 42 total gastrectomy, with an R0 resection rate of 98% (46/47). The prespecified primary endpoint of TRG 0/1 was achieved in 32% of patients (15/47; 95% CI, 21%–48%). Notably, 17% (n = 8) achieved pCR (ypT0N0), and 53% (n =25) were ypN0. Pathological response (TRG 0/1) was significantly higher in Lauren intestinal/mixed versus diffuse types (53% vs. 21%; p < 0.05), while efficacy was comparable between PD-L1 CPS ≥5 and <5 (44% vs. 30%). Grade 3/4 treatment-related adverse events occurred in 32% of patients (n=18), mainly thrombocytopenia and liver function impairment. Surgical morbidity (Clavien–Dindo grade II/III) occurred in 10.6% of surgical patients (5/47), including 1 patient with postoperative bleeding and 3 patients with anastomotic leakage; no perioperative mortality was observed. Conclusions: Total neoadjuvant tislelizumab plus chemotherapy demonstrated promising efficacy and an acceptable safety profile in patients with Borrmann-IV gastric cancer. Lauren classification may serve as a potential predictive biomarker and warrants further study. Clinical trial information: NCT06451211 .

BackgroundLeptomeningeal metastases (LM) from melanoma are rare and associated with dismal outcomes. Intrathecal PD-1 antibody therapy has shown encouraging activity in LM. Radiotherapy may enhance tumor immunogenicity and potentially augment immune checkpoint blockade within the central nervous system. The efficacy and safety of combining intrathecal PD-1 antibodies with whole-brain radiotherapy (WBRT) in melanoma LM remain unclear.MethodsWe retrospectively reviewed melanoma patients with LM who received intrathecal PD-1 antibody therapy between June 2022 and December 2024. Patients were categorized according to whether WBRT was administered within 30 days of intrathecal PD-1 antibody therapy: intrathecal monotherapy and combination therapy. Overall survival (OS) and intracranial progression-free survival (iPFS) were descriptively evaluated by treatment exposure, with between-group analyses considered exploratory and hypothesis-generating. Adverse events were graded using CTCAE v5.0.Results20 patients were included, of whom 7 received intrathecal PD-1 antibody monotherapy and 13 received intrathecal PD-1 antibody therapy combined with WBRT. The observed median OS was 20.1 weeks (95% CI, 13.3-not reached) in the intrathecal monotherapy group and 45.3 weeks (95% CI, 28.7-not reached) in the combination group. The observed median iPFS was 10.0 weeks (95% CI, 6.1-not reached) and 23.0 weeks (95% CI, 18.4-not reached), respectively. Treatment-related adverse events were manageable, and no new safety signals were identified.ConclusionIntrathecal PD-1 antibody therapy combined with WBRT showed numerically longer OS and iPFS than intrathecal therapy alone in this small retrospective descriptive series of melanoma leptomeningeal metastasis. These hypothesis-generating findings warrant prospective investigation but do not establish comparative efficacy.

ABSTRACT While adjuvant immunotherapy and BRAF/MEK inhibitors improve the outcomes for BRAF V600‐mutant stage III melanoma, comparisons of long‐term survival and safety of these therapeutic modalities are currently lacking in Chinese patients. We retrospectively analyzed data from patients with resected stage III BRAF V600‐mutant melanoma who received adjuvant therapy between June 2013 and December 2023 across three centers in China. Note that 122 patients were included and categorized into interferon (n = 25), aPD‐1 (n = 18), D/T (n = 62), and BRAFi/aPD‐1 (n = 17) cohorts. The D/T group demonstrated a significantly longer median RFS compared to the interferon and aPD‐1group (22.7 vs. 11.9 months, p = 0.005; vs. 12.5 months, p < 0.001). Similar results were obtained by restricted‐mean‐survival‐time model. Patients who continued D/T beyond 1 year exhibited significantly improved RFS and DMFS compared to those who discontinued at 1 year duration (NR vs. 22.0 months, p = 0.048; NR vs. 22.5 months, p = 0.026). NOTCH4 and IL7R mutations may serve as prognostic and predictive biomarkers for long‐term survival and targeted‐immunotherapy efficacy, respectively. Adjuvant therapy with D/T may represent the most effective treatment strategy for Chinese patients with stage III melanoma harboring BRAF V600 mutations. A combination of BRAF‐targeted therapy and aPD‐1 immunotherapy provided comparable efficacy and may be an alternative for a specific patient.

9554 Background: Anti–PD-1 monotherapy yields limited response rates in Chinese patients with melanoma, highlighting the need for effective combination strategies. Elderly patients frequently present with multiple comorbidities and immunosenescence which may compromise both the efficacy and safety of immunotherapy. Thymosin α1 (Tα-1) promotes T-cell activation and survival, potentially enhancing responsiveness to immunotherapy, while exerting immunomodulatory effects during excessive inflammation that may reduce the risk of immune-related adverse events (irAEs). This study aimed to evaluate whether combining Tα-1 with toripalimab could improve efficacy while mitigating irAEs in elderly patients with advanced melanoma. Methods: This was a single-arm, open-label, Simon two-stage phase II study. Patients aged ≥60 years with pathologically confirmed unresectable stage III or IV melanoma and no prior immune checkpoint inhibitor exposure were enrolled. Treatment consisted of Tα-1 (1.6 mg daily during week 1, then three times weekly during weeks 2–3) plus toripalimab 240 mg intravenously every 3 weeks for up to four cycles, followed by toripalimab maintenance until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Stage I required ≥3 responses among 19 evaluable patients to proceed to Stage II. Results: Between July 2023 and September 2025, 19 patients were enrolled (median age 72 years, range 60–81). Acral melanoma accounted for 78.9% (n=15). All patients had chronic comorbidities; 63.2% had ECOG ≥2 and 47.4% had metastases in ≥3 organs. At a median follow-up of 10.5 months, ORR was 47.3% (95% CI, 22.6–72.1). Median PFS was 8.0 months (95% CI, 4.4–11.6), and median OS was not reached. Median PFS was 8.1 vs. 4.5 months in acral versus non-acral cutaneous melanoma (P=0.4). Elevated LDH showed a trend toward shorter PFS (2.8 vs. 8.1 months, P = 0.076). Six grade 1 irAEs were observed (vitiligo n=2, transaminase elevation n=2, thyroiditis n=2). Patients without progressive disease had lower neutrophil-to-lymphocyte ratios and higher lymphocyte percentages than those with PD. Conclusions: Tα-1 combined with toripalimab demonstrated promising efficacy and excellent tolerability in elderly patients with advanced melanoma. The prespecified criteria for Stage II expansion were met, and enrollment of an additional 36 patients is ongoing. Patient demographics. Characteristics No. of Patients (N=19) Age (median, range 72 (60-81) Male (%) 8 (42.1%) Melanoma subtype Acral 15 (78.9%) Cutaneous 4 (21.1%) NRAS status Wild type 14 (73.7%) Mutation 4 (21.1%) unknown 1 (5.3%) No. of organs with metastasis ≥3 9 (47.4%) Liver metastasis Yes 4 (21.1%) No 15 (78.9%) Brain metastasis Yes 2 (10.5%) No 17 (89.5%) ECOG PS 1 7 (36.8%) ≥2 12 (63.2%)

Importance The currently recommended postoperative adjuvant treatment for sinonasal mucosal melanoma (SNMM) (chemotherapy, optionally accompanied by local radiotherapy) has limited efficacy. Objective We aimed to provide a potentially optimal adjuvant therapeutic strategy for patients with SNMM. Design Retrospective cohort study. Setting Our hospital’s cancer center. Participants Seventy-nine patients with stage III/IV SNMM who underwent complete resection and received adjuvant radiotherapy between April 2012 and October 2022 were included in the study. Interventions Patients were categorized into 2 groups based on different adjuvant medical regimens: a temozolomide/dacarbazine-based chemotherapy group (n = 44) and a temozolomide/dacarbazine chemotherapy plus PD-1 inhibitor group (n = 35). Main outcome measures These included recurrence-free survival (RFS), distant metastasis-free survival (DMFS), failure patterns, and overall survival (OS). Results The median follow-up duration was 56.8 (8.85-104.75) months in the chemotherapy group and 27.7 (14.53-40.87) months in the chemotherapy plus PD-1 inhibitor group, respectively. Relative to adjuvant chemoradiotherapy, the combination of additional PD-1 inhibitor significantly prolonged RFS (mRFS: 10.0 months vs 18.9 months; HR, 0.43; 95% CI, 0.25-0.75; P = .002), DMFS (mDMFS: 11.2 months vs 18.9 months; HR, 0.48; 95% CI, 0.27-0.84; P = .009), and OS (29.1 months vs NA; HR, 0.36; 95% CI, 0.17-0.77; P = .006) in patients with SNMM. Within a 2-year timeframe, patients in the chemotherapy plus PD-1 inhibitor group exhibited a lower regional recurrence rate than those in the chemotherapy group (0.0% vs 18.8%, P < .001). The 2-year OS rates in the adjuvant chemotherapy group and the chemotherapy combined with PD-1 inhibitor group were 54.5% versus 75.7%, respectively, while the corresponding 4-year OS rates were 20.9% and 62.4%. Conclusions and relevance Surgery followed by adjuvant chemoradiotherapy and prompt initiation of PD-1 inhibitor therapy may improve local disease control in patients with SNMM.

4080 Background: The use of Disitamab vedotin (RC48) and programmed death-1 (PD-1) inhibitor is effective in patients with HER2-expressing advanced gastric or gastroesophageal junction (G/GEJ) cancer. However, their use has not been investigated in patients with localized disease. This trial evaluated the safety and anti-tumor activity of perioperative chemotherapy combined with RC48 and toripalimab in the treatment of locally advanced HER2-overexpressed (defined as IHC 2+ or 3+) G/GEJ cancer. Methods: This study was an investigator-initiated, open-label, single-arm, phase 2 trial was conducted at Sun Yat-sen University Cancer Center. Eligible patients with HER2-overexpressed locally advanced G/GEJ cancer received 3-4 cycles of neoadjuvant XELOX plus RC48 and toripalimab, followed by surgery. The primary endpoint was TRG 0/1 after neoadjuvant treatment. This study is registered at Chinese Clinical Trial Registry (ChiCTR2400081677). Results: Between July 11, 2024, and July 11, 2025, of 26 patients screened for eligibility, 25 patients were enrolled, all patients had no distant metastasis confirmed by laparoscopic exploration and ascitic fluid cytology, 20 (80%) patients had clinical stage III disease and 5(20%) with stage II. Of these 25 patients, the median age was 58 (IQR, 37-74) years. Tumors were located in the stomach in 21(84%) patients and in the gastroesophageal junction in 4 (16%) patients. The patients with HER2 IHC expression of 2+ and 3+ was 21 (84%) and 4 (16%) respectively. 15 (60%) patients had the PD-L1 CPS of 1 or more, 24 (96%) patients were pMMR. The primary endpoint of TRG 0/1 was met in 16 (64%) patients, 9 (36%) patients achieved pCR (ypT0N0), and 24 (96%) were ypN0. 10 (40%) patients experienced grade 3 treatment-related adverse events, the most common treatment-related adverse events were increased ALT or AST (5 [20%] patients) and neutropenia (3 [12%] patients), no grade 4 treatment-related adverse events. Surgical morbidity (Clavien-Dindo II/III) occurred in 2 of 25 (8%) patients, with no 30-day surgical mortality. Conclusions: Our findings suggested that perioperative chemotherapy plus RC48 and toripalimab had controllable safety and showed encouraging efficacy in patients with HER2-overexpressed G/GEJ cancer. Clinical trial information: ChiCTR2400081677.

Objective:This study aims to elucidate the molecular regulatory mechanisms of Chitinase-3-like protein 1 (CHI3L1) in rheumatoid arthritis (RA) and its association with disease activity, focusing on its translational potential in RA diagnosis, dynamic monitoring, and precision therapy. Methods:Transcriptomic datasets (GSE77298, GSE89408) and single-cell RNA-seq data (GSE200815) were obtained from Gene Expression Omnibus (GEO). CHI3L1 expression was analyzed by Wilcoxon test, and diagnostic accuracy by Receiver Operating Characteristic (ROC) curve. Single-cell analysis defined cell type-specific expression of CHI3L1. Differential analysis combined with weighted gene co-expression network analysis (WGCNA) identified CHI3L1-related genes, followed by protein-protein interaction (PPI) and enrichment analyses. Immune infiltration was estimated with CIBERSORT, and competing endogenous RNA (ceRNA)/transcription factor networks were constructed to explore upstream regulation. Drug databases and molecular docking were integrated to predict therapeutic candidates. Clinically, serum CHI3L1 was measured by chemiluminescence immunoassay (CLIA) in RA patients (n=102) and controls (n=79), stratified by 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR), and correlated with C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (CCP), and ESR. Results:CHI3L1 expression was significantly higher in RA across datasets (P<0.01) with strong diagnostic performance (AUC>0.8). Single-cell analysis revealed predominant fibroblast expression. Integrated analysis identified 51 candidate genes, enriched in chemokine signaling and mineral absorption pathways. PPI analysis highlighted TIMP1 and AQP9 as key genes, both strongly correlated with CHI3L1 (r>0, P<0.001). Immune infiltration showed increased M0 macrophages and plasma cells, reduced regulatory T cells, and significant correlations with CHI3L1. The ceRNA network indicated involvement of multiple miRNAs and lncRNAs. Drug prediction identified glibenclamide with the lowest binding energy (-9.386 kcal/mol). Clinically, serum CHI3L1 was markedly elevated in RA (P<0.001) with excellent diagnostic accuracy (AUC = 0.907). Higher CHI3L1 levels were observed in high-activity patients (P<0.01). CHI3L1 correlated with CRP (r=0.40, P<0.001), ESR (r=0.35, P<0.001), and moderately with CCP (r=0.21, P<0.05). Conclusion:This exploratory study suggests that CHI3L1 is a fibroblast-enriched molecule closely associated with immune dysregulation and RA activity, showing promise as a diagnostic and monitoring biomarker and a potential therapeutic target, though further validation through functional experiments and prospective studies is warranted.

e16108 Background: Treatment options for Borrmann Type 4 gastric cancer (Linitis Plastica) have long been a topic of debate. This patient group is characterized by diffuse cancer infiltration throughout the stomach, early metastasis, and a poor prognosis. In this study, we aim to evaluate the efficacy and safety of combining immunotherapy with chemotherapy for patients with Borrmann Type 4 (B-IV) or large Type 3 (B-III) gastric cancer. Methods: Patients (pts) diagnosed with gastric adenocarcinoma (B-IV or B-III) without distant metastasis were eligible for the study. Participants received a prolonged neoadjuvant treatment regimen consisting of the anti-PD-1 inhibitor (ICI) Tislelizumab and platinum-based chemotherapy (oxaliplatin combined with either capecitabine or S-1) administered in 3-week cycles. After completing six cycles, patients underwent radical surgery. The primary endpoint was the pathological response rate, assessed using the tumor regression grade (TRG) system. Results: As of January 2025, 42 pts were enrolled in this trial (intention-to-treat group), of whom 27 completed the neoadjuvant treatment and underwent radical gastrectomy. Among the 27 pts, 17 completed all the 6 cycles of neoadjuvant treatment, while 5 pts completed either 3-4 cycles or 5 cycles. All 42 pts were included in the safety and demographics analysis, while 27 were included in the efficacy analysis. The median age was 59 (range: 31–73), with 57% male. All pts had an ECOG performance status of 0 or 1, and 79% (33 pts) were B-IV. Lauren’s histological classification included intestinal (12 pts), diffuse (18 pts), and mixed (9 pts) types. 38 pts showed proficient mismatch repair proteins(pMMR, the other 4 not evaluated). Following surgery, all 27 pts had R0 resection. 11 of 27 pts (41%) demonstrated a pathological response of TRG 0/1 (95% CI: 24%–59%), exceeding the prespecified endpoint. Pts with a PD-L1 CPS score ≥5 or < 5 showed a comparable percentage of those with TRG 0/1. Notably, 7 pts (26%) achieved ypTNM stage 0 (pCR), and 18 pts (67%) were ypN0. A significantly higher pathological response rate (TRG 0/1) was observed in pts with Lauren’s intestinal or mixed types (9/16, 59%; 95% CI: 36%–78%) compared to those with diffuse type (2/11, 18%; 95% CI: 3%–48%; p < 0.05). Treatment-related adverse events were reported in 35 of 42 pts (83%), with common events including thrombocytopenia, nausea, and liver injury. 7 pts (17%) experienced grade 3/4 adverse events. 5 pts (18%) underwent surgical morbidity including bleeding, anastomotic leak and infection. Conclusions: Prolonged neoadjuvant treatment with ICI Tislelizumab combined with platinum-based chemotherapy demonstrated promising clinical efficacy and a manageable safety profile in pts with B-IV or large B-III gastric cancer. The study is ongoing and up to 53 pts will be enrolled into this cohort. Clinical trial information: NCT06451211 .

[Objective] To determine the relationship between specific timing pattern of immune checkpoint inhibitor infusion and the prognosis of Chinese melanoma patients. [Methods] Clinical data were collected from 126 melanoma patients who received immune checkpoint inhibitors in Sun Yat-sen University Cancer Center between April 2015 and March 2024. Patients who received ≥20% of PD-1 antibody infusions after 16:30 were assigned to the afternoon group, while those who received <20% of infusions after 16:30 were assigned to the morning group. Survival outcomes between the two groups were compared using the log-rank test to determine statistical significance. [Results] Among 61 patients who received adjuvant PD-1 antibody therapy, the median recurrence-free survival (RFS) was 9.10 months in the morning group and 19.57 months in the afternoon group, with no significant difference (P=0.546). The median overall survival (OS) in the afternoon group was not inferior to that in the morning group (NR vs. 47.77 months, P=0.950, HR=0.98). Among 65 patients who received palliative PD-1 antibody therapy, the median progression-free survival (PFS) was 3.57 months in the morning group and 5.60 months in the afternoon group, with no statistically significant difference (P=0.260). Compared to the morning group, the afternoon group showed a significantly longer median overall survival (OS) (22.70 vs. 14.40 months, P=0.047, HR=0.53). However, the analysis of prognostic factors revealed that receiving ≥20% of PD-1 antibody infusions in the afternoon was not an independent risk factor for survival in this cohort. [Conclusions] The daily infusion timing of immune checkpoint inhibitors may not significantly influence survival in Chinese melanoma patients. However, multicenter prospective studies are still needed to further validate the potential chronotherapeutic effects in immunotherapy.

This prospective, nonrandomized, open-label phase 2 trial (Chinese Clinical Trial Registry, ChiCTR2200061906) aimed to evaluate the effectiveness of adding the PD-1 antibody tislelizumab to perioperative chemotherapy in patients with locally advanced gastroesophageal junction adenocarcinoma (GEJA). This study enrolled patients with GEJA clinically staged as cT3-4aNanyM0 or cT1-2N+M0 from October 2022 to June 2023. Eligible patients were administered three preoperative and five postoperative 3-week cycles of treatment with PD-1 antibody tislelizumab plus SOX (S-1 and oxaliplatin) regimen. The primary endpoint was major pathological response (MPR) rate. Thirty-two patients were enrolled. The median age was 60 years (range: 28-74 years), and 53.1% (17/32) patients were Siewert III type. All patients received at least one cycle of assigned preoperative treatment, and 93.8% (30/32) patients completed three cycles of assigned preoperative tislelizumab and SOX. The R0 resection rate was 96.9% (31/32). MPR, pathological complete response (pCR) of primary tumors and ypT0N0 rates were 50.0% (16/32, 95% CI: 31.9-68.1%), 28.1% (9/32, 95% CI: 13.7-46.7%) and 25.0% (8/32, 95% CI: 11.5-43.4%), respectively. The surgical morbidity rate was 15.6% (5/32), and no 30-day mortality was observed. In the preoperative and postoperative treatment periods, the rate of treatment-related grade 3-4 adverse events was 31.2% (10/32). At the date of 7th Jan 2025, 8 (25.0%) patients occurred recurrence. Therefore, perioperative tislelizumab plus chemotherapy demonstrated significantly improved pathological regression and might be a promising option for patients with locally advanced resectable GEJA.

e21524 Background: Anti-PD-1 antibodies show limited response rates in Chinese melanoma patients, necessitating combination therapies to enhance efficacy. Elderly patients often have multiple comorbidities, complicating the balance between therapeutic benefits and toxicities. Additionally, age-related declines in naïve T-cell numbers and immunosenescence may impact the effectiveness and safety of immunotherapy. Thymosin α1 (Tα-1) promotes T-cell generation, proliferation, activation, and survival, increasing lymphocyte counts. It also helps maintain immune homeostasis in cases of excessive inflammation, potentially reducing immune-related side effects.This study aims to evaluate the efficacy and safety of Tα-1 in combination with toripalimab in elderly patients with advanced melanoma. Methods: A prospective cohort of nine stage IV melanoma patients was enrolled between July 5, 2023, and May 7, 2024. Each patient received up to four cycles of combination therapy with Tα-1 (1.6 mg daily during the first week, then three times weekly for the next two weeks) and toripalimab. After four cycles, patients continued on toripalimab until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Results: The median age was 74 years (range 60–81), with five males and four females. Eight patients had acral melanoma, and one had an unknown primary origin. All patients had at least one chronic underlying condition, and seven had an ECOG performance status of ≥2. The median follow-up was 9.9 months (8.3–16.0 months). The ORR was 22.2%, and the disease control rate (DCR) was 77.8%. Median PFS was 8.2 months, while median OS was not reached. Adverse events occurred in three patients, all grade 1 per CTCAE 4.0: two cases of vitiligo and one case of elevated transaminases. Non-progressive disease (non-PD) patients had lower neutrophil-to-lymphocyte ratios and higher lymphocyte percentages during treatment compared to PD patients. Conclusions: The combination of Tα-1 and toripalimab demonstrated significant efficacy with a favorable safety profile in elderly patients with advanced melanoma. These findings suggest a promising therapeutic strategy for this population. Larger clinical trials are needed to validate these results and elucidate the underlying mechanisms.

Background/Objectives: Natural killer (NK) cells play a crucial role in immune surveillance against melanoma, yet they frequently exhibit dysfunction in the tumor microenvironment. This study aims to establish an NK cell activation-related prognostic signature and identify potential druggable targets to overcome NK cell dysfunction. Methods: A prognostic signature was developed using the TCGA-SKCM cohort and validated across independent datasets. NK cell activation and cytotoxicity were evaluated in melanoma-NK-92MI co-culture systems via flow cytometry. Mechanistic studies employed Western blotting, co-immunoprecipitation, ELISA, and qRT-PCR. Single-cell RNA-seq data were used to analyze cell–cell communication. Results: A four-gene NK cell activation signature was identified and validated for prognostic significance across five independent melanoma datasets. Among the identified genes, cyclin B1 (CCNB1) emerged as a novel therapeutic target for overcoming NK cell resistance. In vivo, pharmacological inhibition of the CCNB1/Cyclin-dependent kinase 1 (CDK1) complex with RO-3306 significantly suppressed melanoma growth by enhancing NK cell infiltration and IFN-γ production. In vitro, CCNB1 knockdown in melanoma cells augmented NK-92MI activation, as evidenced by increased expression of CD69, CD107a, IFN-γ, and NKG2D, thereby improving NK cell-mediated cytotoxicity. Mechanistically, in melanoma cells, the CCNB1/CDK1 complex phosphorylates STAT3, activating the IL-6/STAT3 positive feedback loop, which upregulates PD-L1 and enables resistance to NK cell-mediated cytotoxicity. Beyond its role in immune evasion, CCNB1 also promoted melanoma invasiveness by inducing epithelial–mesenchymal transition (EMT) through the TGF-β-SMAD2/3 signaling. Conclusions: This study establishes CCNB1/CDK1 as a novel immunotherapeutic target and uncovers a new role for CDK1 inhibitors in enhancing NK cell function and suppressing melanoma progression.

9553 Background: Results of the global, phase 3 LEAP-003 study, showed that lenvatinib (len) + pembrolizumab (pembro) significantly improved PFS compared with pembro alone in participants (pts) with predominantly cutaneous melanoma at the first interim analysis, but this benefit was not maintained with additional follow-up and there was no improvement in OS. Previous studies have shown that mucosal and acral melanomas, which are the predominant subtypes in Chinese patients, may benefit from combination therapy. Here, we present results for Chinese participants (pts) enrolled in the LEAP-003 global (NCT03820986) and China extension (NCT04889118) studies. Methods: Eligible pts were aged ≥18 y, had previously untreated unresectable stage III or IV melanoma, an ECOG PS of 0 or 1, and measurable disease per RECIST v1.1. Pts were randomly assigned 1:1 to len 20 mg or placebo (pbo) PO QD + pembro 200 mg IV Q3W for ≤2 y. Dual primary end points were PFS per RECIST v1.1 by BICR and OS. Secondary end points were ORR, DOR, and safety. Results: 131 pts from China enrolled and received treatment (len + pembro, n = 64; pbo + pembro, n = 67). Median time from first dose to data cutoff (Jan 18, 2023) was 18.1 mo (range, 12.7-29.5). In the overall China subgroup, median PFS was 6.1 mo (95% CI, 4.1-8.1) for len + pembro vs 2.0 mo (95% CI, 2.0-2.1) for pbo + pembro (HR, 0.55; 95% CI, 0.37-0.81); 18-mo PFS was 20.0% vs 12.8%. Median OS was 19.9 mo (95% CI, 11.9-26.8) for len + pembro vs 17.0 mo (95% CI, 12.7-25.7) for pbo + pembro (HR, 0.93; 95% CI, 0.58-1.48); 18-mo OS was 53.4% vs 49.6%. ORR was 26.6% (95% CI, 16.3-39.1; 4 CR, 13 PR) for len + pembro vs 16.4% (95% CI, 8.5-27.5; 4 CR, 7 PR) for pbo + pembro; median DOR was 13.7 mo (range, 3.8-21.4) vs NR (range, 4.2-21.4+). Among 30 pts with mucosal melanoma, median PFS was 8.1 mo (95% CI, 5.9-12.4) for len + pembro (n = 16) vs 2.0 mo (95% CI, 1.9-4.1) for pbo + pembro (n = 14; HR, 0.44; 95% CI, 0.20-0.97); 12-mo PFS was 33.5% vs 21.4%. Median OS was 26.8 mo (95% CI, 10.6-NR) for len + pembro vs 14.3 mo (95% CI, 9.0-NR) for pbo + pembro (HR, 0.51; 95% CI, 0.17-1.55); 18-mo OS was 68.8% vs 49.0%. ORR among pts with mucosal melanoma was 50.0% (95% CI, 24.7-75.3; 1 CR, 7 PR) for len + pembro vs 7.1% (95% CI, 0.2-33.9; 1 PR) for pbo + pembro. Treatment-related AEs occurred in 96.9% in the len + pembro arm vs 97.0% in the pbo + pembro arm (grade 3-5: 62.5% vs 16.4%). One pt (1.5%) in the pbo + pembro arm died due to treatment-related immune-mediated lung disease. Conclusions: In Chinese pts, the efficacy and safety profile observed with len plus pembro vs pembro alone was consistent with the global population. Numerical improvements in PFS and ORR in the mucosal melanoma subtype treated with len + pembro were notable, although the data should be interpreted with caution due to the limited sample size. These results support first-line pembro monotherapy as a standard-of-care for this population. Clinical trial information: NCT03820986 , NCT04889118 .

Anti-PD-1 immunotherapy and targeted therapy (TT) represent two major therapeutic modalities for BRAFV600-mutant advanced melanoma, but the efficacy of combination therapy in Asian populations remains unknown. Asian melanoma patients differ significantly from Caucasians in tissue subtypes, pathogenesis and response to treatment. We retrospectively analyzed data of BRAFV600-mutant advanced melanoma patients treated with first-line vemurafenib (V) ± anti-PD-1 or dabrafenib+trametinib (D+T) ± anti-PD-1 between 2014 and 2023 from three centers in China. 178 patients were included, with V (n = 45), D+T (n = 51), V+anti-PD-1 (n = 39) and D+T+anti-PD-1 (n = 43). The median PFS (21.9 vs. 11.1 months, p < 0.001), OS (NR vs. 32.6 months, p = 0.027), and DoR (20.0 vs. 8.4 months, p = 0.002) were significantly prolonged with D+T+anti-PD-1 versus D+T. Addition of anti-PD-1 to V also significantly prolonged PFS, OS, and DoR (p < 0.001). V+anti-PD-1 was superior to D+T in terms of PFS (15.0 vs. 11.1 months, p = 0.007) and DoR (18.0 vs. 8.4 months, p = 0.013), and was comparable to D+T+anti-PD-1. Addition of anti-PD-1 to BRAF inhibitor-based TT was associated with lower incidence of brain metastases (p = 0.032). Addition of anti-PD-1 to BRAF inhibitor-based TT appears to be a safe and effective treatment option, conferring a survival benefit and delaying the onset brain metastases in patients with BRAFV600-mutant advanced melanoma.

e21516 Background: LMD is one of the most severe complications of melanoma and has an extremely poor prognosis. Over the past decade, the incidence of LMD is increasing with improved treatment strategies and prolonged survival. This real-world study aims to evaluate the safety and efficacy of intrathecal anti-PD-1 treatment in MM patients with LMD. Methods: MM patients with LMD diagnosed by MRI and/or cerebrospinal fluid (CSF) cytology were assigned to intrathecal nivolumab infusion 20mg once every 2 weeks (n = 4) or pembrolizumab 20mg once every 3 weeks (n = 3). The patients received a median of 4 cycles of treatment (range 2–7 cycles). Efficacy and safety analyses were performed on all the treated patients. Results: Between June 2022 and December 2022, 7 patients were treated, including 3 cutaneous, 2 acral and 2 primary leptomeningeal melanoma. All patients presented linear or small nodular enhancement of leptomeningeal on MRI. Four patients had concurrent parenchymal brain metastases. The tumor cells were found in 5 patients by CSF cytology, and pathologic diagnosis was obtained by leptomeningeal biopsy in 2 patients. According to RANO-LM criteria, 4 patients responded to treatment with symptom improvement and reduction or disappearance of linear enhancement on MRI, while 3 patients developed progressive disease. The median overall survival (OS) was 39.7 months after initial diagnosis and 24 weeks after LMD. With a median follow-up of 13.3 weeks (range 9.4–20.3 weeks), the median intracranial progression-free survival (IPFS) and median OS for intrathecal anti-PD-1 were 16.1 and 20.3 weeks, respectively. All treatment-related adverse events were grade 1-2, including headache (grade 1, n = 1; grade 2, n = 2) and low back pain (grade 1, n = 1). Conclusions: In this real-world study, intrathecal anti-PD-1 treatment was found to be well tolerated and effective in metastatic melanoma patients with LMD.

4083 Background: The combination of PD-1 antibody and chemotherapy was shown to be effective in advanced gastric cancer, but has not yet been comprehensively investigated in locally advanced patients, especially in the context of adenocarcinoma of gastro-oesophageal junction (GEJ). In this study, we conducted a prospective, nonrandomized, open-label phase II trial to evaluate the effectiveness of adding PD-1 antibody to perioperative chemotherapy in patients with locally advanced resectable GEJ cancer. Methods: In this nonrandomized, open-label, phase II study, patients with resectable GEJ adenocarcinoma clinically staged as cT3-4aNanyM0 or cT1-2N+M0 were allocated three preoperative and five postoperative 3-week cycles of PD-1 antibody tislelizumab plus SOX (S-1 and oxaliplatin) regimen. The primary endpoint was major pathological response (MPR) rate. The secondary endpoints were pathological complete response (pCR), pathological complete /moderate regression rate (TRG 0/1), R0 resection rate, recurrence-free survival, event-free survival, overall survival, treatment safety and quality of life. The trial is registered at Chinese Clinical Trial Registry, identifier: ChiCTR2200058732. Results: Between Oct 2022 and June 2023, 32 patients were enrolled and assessed using intention-to-treat analysis. The median age was 60 years (range: 28-74 years), and 53.1% (17/32) patients were Siewert III type. All patients received at least one cycle of assigned preoperative treatment, and 96.9% (31/32) patients completed three cycles of assigned preoperative tislelizumab and SOX. R0 resection rate was 96.9% (31/32). The MPR rate was 37.5% (12/32, 95% CI: 21.1%-56.3%) and the pCR rate was 28.1% (9/32, 95% CI: 13.7%-46.7%). The surgical morbidity was 12.5% (4/32), and no 30-day mortality was observed. In the preoperative and postoperative treatment period, treatment-related grade 3-4 adverse events was 9.4% (3/32). At the date of 6th Feb 2024, three (9.4%) patients occurred recurrence. Conclusions: This is the first prospective study that focus on the perioperative immunotherapy in patients with resectable GEJ adenocarcinoma. Perioperative PD-1 antibody tislelizumab plus chemotherapy demonstrated a significantly improved pathological regression and might be a promising option for patients with locally advanced resectable GEJ adenocarcinoma. Clinical trial information: ChiCTR2200058732.

e21520 Background: Mucosal melanoma therapy remains a formidable challenge especially in Asia. Although several therapies are available for skin type of melanoma, the efficacy of mucosal melanoma is not satisfactory. YH003, a humanized agonistic anti-CD40 monoclonal antibody specifically recognizes and agonizes CD40 to enhance immune responses, has demonstrated good safety and promising antitumor activity in Phase I clinical studies in patient with ocular melanoma. Here, we report the results of the phase II study of YH003 in combination with pembrolizumab and nab-paclitaxel in the first-line treatment of patients with unresectable/metastatic mucosal melanoma. Methods: Patients with unresectable/metastatic mucosal melanoma were enrolled and received 0.3 mg/kg YH003, 200 mg pembrolizumab and 200 mg/m 2 of nab-paclitaxel iv, every 21 days. The treatment continued for 12 months if subject was deriving an ongoing clinic benefit. The primary endpoint was overall Response Rate (ORR) by investigator’s assessment per RECIST 1.1. Results: A total of 20 patients were enrolled and had at least 1 evaluable post-treatment tumor assessment, the unconfirmed ORR was observed in 7 patients (35.0%), with 7 partial responses (PR). 7 patients (35.0%) had stable disease (SD), and the Disease Control Rate (DCR) was 70.0%. The mOS was not reached, mPFS was 4.11 months. The grade 3 or above TEAE that occurred in the 20 patients were 30.0% (6/20). There is no significant safety signal from the study. Conclusions: The results of the phase II study have shown that YH003 in combination with pembrolizumab and nab-paclitaxel, as 1L treatment in patients with unresectable/metastatic mucosal melanoma have promising antitumor activity and response durability and well tolerated. Clinical trial information: NCT05420324 .

Background PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repairdeficient colorectal cancer. Methods We initiated a single -arm, open -label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18-75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1 -mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion >= 5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0-1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1-14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing. Findings Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 164 (IQR 105-235) months. 28 (54%; 95% CI 35-68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39-80) had a pathological complete response. 38 (73%; 95% CI 59-84) of 52 patients had a complete response. Grade 3-5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis. Interpretation Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach.

e15521 Background: Programmed death-1 (PD-1) inhibitor is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. Methods: LS patients with CRC who had evaluable tumors and received ≥2 cycles of PD-1 inhibitors were included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies including anti cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) treatment, radiotherapy, chemotherapy, and targeted therapy. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analyzed. Results: A total of 75 LS patients were included, with a median age of 39 years. The median duration of follow-up was 27 months (range, 3 to 71). The objective response rate (ORR) was 70.7%, including 28.0% (n = 21) complete responses (CRs) and 42.7% (n = 32) partial responses (PRs). Three cases of LS CRCs displaying pMMR/MSS or discordant MMR/MSI status were not responsive even with a high tumor mutation burden (TMB). Mucinous/signet-ring cell differentiation was associated with a lower ORR ( P= 0.013). The 3-year OS and PFS was 91.2% and 81.0%, respectively. Colorectal polyp/adenoma was detected in 26 patients during surveillance. Seven adenomas disappeared after treatment and their maximum diameters were all larger than 7mm. Conclusions: PD-1 inhibitors are highly effective for dMMR/MSI-H LS CRCs, but not for pMMR/MSS LS CRCs or those displaying discordant MMR/MSI status or mucinous/signet-ring cell CRC. Some of the large LS adenomas may also be sensitive to anti-PD-1 treatment.