bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world use of anti-EGFR therapy in metastatic colorectal cancer.
Authors: Robinson Hannah Ruth , Hu Junxiao , Balmaceda Nicole Baranda , Lentz Robert William , Baiyee Toegel Emily , Leal Alexis Diane , Kim Sunnie S. , Messersmith Wells A. , Lieu Christopher Hanyoung , Davis S. Lindsey 
Published: June 2024

3552 Background: Anti-EGFR therapies including cetuximab and panitumumab are recommended in frontline or later-line treatment regimens for left-sided metastatic colorectal cancer (mCRC) lacking mutations in RAS or BRAF. Here we report patterns of anti-EGFR therapy use in patients with mCRC diagnosed between 2013 and 2023. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, which contains patient-level data originating from approximately 280 cancer clinics in the United States (~800 sites of care).Adult patients diagnosed with mCRC from January 1, 2013 to April 28, 2023 who received at least 1 line of treatment were included. The percentage of patients who received anti-EGFR agents based on biomarker indication and primary tumor sidedness (PTS) was determined. PTS was assessed by ICD codes, with left-sided disease defined as tumors originating from the splenic flexure to the rectum. Univariate and multivariable analyses were performed to evaluate for factors associated with utilization of biomarker-directed anti-EGFR therapy. Results: A total of 25,937 patients were included in this analysis. Among these, 3,425 (13.2%) had a confirmed indication for anti-EGFR therapy, based on the presence of left-sided disease and documented KRAS, NRAS,and BRAFwildtype status (Cohort 1). In contrast, 15,015 (57.9%) patients had a documented RASor BRAF mutation and/or right-sided disease (Cohort 2). Anti-EGFR therapy was included in frontline treatment for 19.7% of patients in Cohort 1 versus 3.3% of patients in Cohort 2. Anti-EGFR therapy was included in any-line treatment for 56.6% of patients in Cohort 1 versus 12.1% of patients in Cohort 2. Patients in Cohort 1 were less likely to receive anti-EGFR therapy in any treatment line if they were ≥ 75 versus < 45 years old at diagnosis (odds ratio [OR] 0.72, p = 0.027), had a primary rectal versus colon cancer (OR 0.87, p = 0.045), or were diagnosed at a later timepoint. For instance, while 72.4% of Cohort 1 patients diagnosed between 2013-2015 received anti-EGFR therapy, only 63.9% (OR 0.68, p = 0.05), 59.5% (OR 0.57, p < 0.001), and 46.7% (OR 0.34, p < 0.001) of patients diagnosed between 2016-2017, 2018-2019, and 2020-2023 received anti-EGFR therapy, respectively. Patient sex, race, ethnicity, practice setting, socioeconomic index, and performance status were not associated with anti-EGFR therapy use. Conclusions: Based on results from the Flatiron Health database, use of anti-EGFR therapy is enriched among patients with biomarker-based indications for treatment. Notably, anti-EGFR therapy was employed in only 56.6% of patients with RAS and RAF wildtype, left-sided mCRC, with decreased use observed from 2013 to 2023.
Phase Ib/II trial of hepatic arterial infusion chemotherapy in combination with fruquintinib for refractory unresectable colorectal cancer liver metastases.
Authors: Feng Aiwei , Gao Song , Guo Jianhai , Kou Fuxin , Liu Shaoxing , Zhang Xin , Liu Baojiang , Wang Xiaodong , Chen Hui , Xu Haifeng , Liu Peng , Cao Guang , Gao Qinzong , Zhu Xu 
Published: June 2024

3561 Background: Hepatic arterial infusion chemotherapy (HAIC), a highly efficient local therapy for patients with colorectal liver metastases (CRLM), is supposed to have a synergetic effect when it is in combination with a systemic therapy. The aim of this study was to determine the recommended phase 2 dose (PR2D) of fruquintinib combine with HAIC and evaluate efficacy and safety in expansion cohort of patients with CRLM. Methods: This open-label, single-arm, phase Ib/II study (NCT05406206) enrolled patients with CRLM who had received at least two prior lines of treatment. In the dose-finding phase, based on a standard 3+3 design, patients were treated with HAIC involving oxaliplatin (85 mg/m2) and 5-FU (2000 mg/m2) on day 1 and 2 every 4 weeks, alongside fruquintinib (3mg, 4mg, 5mg, d3-23, q4w, respectively) until unacceptable toxicities, progressive disease, or death occurred. In the dose-expansion phase, patients received HAIC and RP2D of fruquintinib determined in the dose-escalation phase. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included RP2D, objective response rate (ORR; RECIST 1.1), disease control rate (DCR), overall survival (OS) and safety. Results: As of data cutoff date on January 30, 2024, a total of 30 patients were enrolled. 9 (30.0%) patients were female, and the mean age was 56 years, 22 (73.3%) patients were RAS/BRAF mutant. During the dose-escalation phase, 15 patients were enrolled, with 3, 6, and 6 patients receiving doses of 3 mg, 4 mg, and 5 mg, respectively. Only one dose-limiting toxicity occurred in a patient of 4 mg level (G3 hypertension failed to control with antihypertensive treatment within 7 days). RP2D of fruquintinib was established as 5 mg. Fifteen patients were evaluable for efficacy, with best response of pathological complete response in 1 patient, partial response in 5 patients and stable disease in 6 patients, yielding an ORR of 40.0% and DCR of 80.0%. Median hepatic-PFS and median PFS was 6.8 months (95% CI, 5.890-7.710) and 5.9 months (95% CI, 3.576-8.224), respectively. The median OS reached 15.0 months (95% CI, 8.671-21.329). 7 (23.3%) patients experienced G3/4 treatment-related adverse events (TRAEs). The most common TRAEs of all grades were voice alteration, hypertension, abdominal pain and hand-foot syndrome. Conclusions: The combination of HAIC and fruquintinib showed a manageable safety profile and survival benefit of heavily treated CRLM patient. Clinical trial information: NCT05406206 .
Effect of p16 immunohistochemical expression (exp) on irinotecan in metastatic colorectal cancer (mCRC): A translational analysis of the TRIBE and TRIBE2 studies.
Authors: Germani Marco Maria , Moretto Roberto , Conca Veronica , Signorini Francesca , Proietti Agnese , Giordano Mirella , Rossini Daniele , Studiale Vittorio , Murgioni Sabina , Di Paolo Giacomo , Pietrantonio Filippo , Russo Alessandra , Taravella Ada , Passardi Alessandro , Zaniboni Alberto , Latiano Tiziana Pia , Cappetta Alessandro , Ugolini Clara , Cremolini Chiara 
Published: June 2024

3562 Background: CDKN2A encodes the inhibitor of the cyclin-dependent kinases p16 and is frequently methylated in colorectal cancer, thus reducing the exp levels of p16 protein. In pre-clinical models of colorectal cancer cells, the demethylation of CDKN2A gene induces topoisomerase I upregulation increasing the sensitivity to irinotecan. In metastatic colorectal cancer (mCRC) pts, the role of p16 expression has been poorly investigated. Methods: Tumour samples of pts randomized in the phase III TRIBE2 study comparing upfront FOLFOXIRI/bevacizumab (bev) versus (vs) FOLFOX/bev were assessed for p16 immunohistochemical exp. A validation analysis in patients treated with FOLFIRI/bev in the TRIBE study was conducted. Results: Out of 679 patients enrolled in the TRIBE2 study, 231 tumours were assessed for p16 exp. Overall, 152 (66%), and 79 (34%) were classified as positive (pos) (IHC 2+ and 3+) and negative (neg) (IHC 0 and 1+), respectively. In the p16 pos group, 69 (45%) and 83 (55%) pts received FOLFOXIRI/bev and FOLFOX/bev, respectively, while in the p16 neg cohort, FOLFOXIRI/bev was administered in 37 (47%) and FOLFOX/bev in 42 (53%) cases. Pts with p16 neg tumours had more frequently an ECOG-PS of 1-2 (16% vs 6%, p=0.0098) and a BRAF mut tumour (26% vs 7%, p=0.0002). No PFS difference was observed between p16 neg and pos patients, while a trend for a longer OS was shown in favour of p16 pos pts (25.5 vs 21.3 months; HR: 0.74, 95%CI: 0.53-1.02, p=0.068) that was not confirmed at the multivariate analysis (p=0.61). Among patients with p16 pos tumours, those treated with FOLFOXIRI/bev reported longer PFS (12.8 vs 9.4 months, HR: 0.55, 95%CI: 0.39-0.78, p=0.0008) and OS (30.0 vs 21.4 months, HR: 0.66, 95%CI: 0.46-0.95, p=0.026) than those receiving FOLFOX/bev. On the other hand, no significant difference was observed among p16 neg patients in terms of both PFS (9.0 vs 9.4 months, HR: 0.91, 95%CI: 0.57-1.46, p=0.69) and OS (21.3 vs 19.5 months, HR: 0.95, 95%CI: 0.58-1.57, p=0.85), thus suggesting a differential treatment effect according to p16 exp (pinteraction for PFS =0.12; pinteraction for OS =0.19). Among patients treated with FOLFIRI/bev in the TRIBE study (N=58) patients with p16 pos tumours reported longer PFS and OS than those with p16 neg. (HR for PFS: 0.45, 95%CI: 0.22-0.92, p=0.026; HR for OS: 0.41, 95%CI: 0.20-0.85, p=0.013). Conclusions: In mCRC, p16 pos exp seems associated with higher benefit from irinotecan. Prospective confirmation in independent randomized series is warranted.
International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).
Authors: El-Khoueiry Anthony B. , Kim Tae-You , Blanc Jean-Frédéric , Rosmorduc Olivier , Decaens Thomas , Mathurin Philippe , Merle Philippe , Dayyani Farshid , Masi Gianluca , Pressiani Tiziana , Galle Peter Robert , Hatogai Ken , Ishii Yuko , Seidel Henrik , Mueller Udo , Kalambakas Stacey Anastasia , Bouattour Mohamed 
Published: June 2024

4007 Background: The optimal second-line treatment for HCC after ICI is not established. Regorafenib is approved for treatment of advanced HCC after sorafenib. The primary aim of this study was to evaluate the activity of regorafenib plus pembrolizumab in patients with advanced HCC who progressed on only one prior ICI regimen. Methods: Patients aged ≥18 years, CP Class A, BCLC stage B or C, and ECOG PS of 0 or 1 received oral regorafenib 90 mg once daily 3 weeks (wk) on/1 wk off plus i.v. pembrolizumab 400 mg every 6 wk. The daily regorafenib dose could be escalated to 120 mg after the first 4-wk cycle of regorafenib if tolerated. Pembrolizumab dose reductions were not allowed. Cohorts were defined by prior treatment: Cohort 1 = atezolizumab + bevacizumab; Cohort 2 = any other ICI regimen (alone or combination). Primary endpoint was overall response rate (ORR) by independent central review (RECIST 1.1). Results: 95 patients were treated in 8 countries; Cohort 2 appeared to have more favorable disease characteristics (Table). Most common prior ICIs in Cohort 2 were durvalumab (30%), nivolumab (30%), ipilimumab (22%), and pembrolizumab (19%). Overall, median follow up was 7.1 months (mo). Median duration of regorafenib/pembrolizumab treatment (including interruptions, delays) was shorter in Cohort 1 vs Cohort 2 (11.0/9.4 wk vs 21.4/24.1 wk). ORR was 5.9% in Cohort 1 and 11.1% in Cohort 2; stable disease rates were 48.5% and 63.0%, respectively. Median PFS was 2.8 mo in Cohort 1 and 4.2 mo in Cohort 2. Overall, treatment-emergent adverse events (TEAE) were grade 3 in 56% of patients and grade 4 in 5%; drug-related grade 3 and 4 TEAE occurred in 37% and 3%, respectively. One patient (Cohort 1) had a grade 5 drug-related TEAE (cardiac arrest). Most common drug-related TEAE were palmar-plantar erythrodysesthesia syndrome (39%), asthenia (33%), decreased appetite (32%), diarrhea (28%), and hypertension (20%). Biomarkers assessed in paired biopsies (baseline and wk 6/day 1) showed on-treatment reductions in macrophages and angiogenesis RNA signatures. Conclusions: To our knowledge, this is the first prospective evaluation of a kinase inhibitor plus an ICI following first-line ICI therapy for HCC. Regorafenib plus pembrolizumab had modest activity in second line after first-line ICI regimens. The safety profile of the combination was consistent with those of either drug. Optimal treatment for patients with advanced HCC who progress after an ICI regimen remains an unmet need. Biomarker findings will be detailed in presentation. Clinical trial information: NCT04696055 . [Table: see text]
Safety and efficacy of IBI389, an anti-CLDN18.2/CD3 bispecific antibody, in patients with advanced pancreatic ductal adenocarcinoma: Preliminary results from a phase 1 study.
Authors: Hao Jihui , Zheng Li , Ruihong Dai , Jieer Ying , Xu Qi , Wang Li-Wei , Jin Yongdong , Zhao Ying , Pan Yueyin , Liu Lulu , Zhang Jun , Sun Yuping , Niu Zuoxing , Yao Jun , Hua Dong , Zhang Mingjun , Guanghai Dai , Zhang Yulong , Zhou Hui , Bi Feng 
Published: June 2024

4011 Background: CLDN18.2 expression has been observed in various solid tumors. In pancreatic ductal adenocarcinoma (PDAC), positive CLDN18.2 expression was reported in nearly 60% patients (pts), indicating its potential as a novel target for anti-tumor therapy. IBI389 is an anti-CLDN18.2/CD3 bispecific antibody that induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the membrane of tumor cells. Herein, we report preliminary result from a phase I study to evaluate safety and efficacy of IBI389 in pts with PDAC. Methods: EligibleCLDN18.2-positivepts with locally advanced, refractory or metastaticPDAC who failed or were intolerant to standard treatments were enrolled. IBI389 monotherapy was intravenously administered at 6 dose levels (5-600 µg/kg, Q3W or Q2W) during the 2-stage dose escalation and the dose expansion. In dose levels ≥ 30 µg/kg, the step-up dosing strategy with priming dose of 3 to 10 µg/kg was applied. The primary objective was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 9, 2024, a total of 64 CLDN18.2-positive PDAC pts were enrolled (males: 64.1%, females:35.9%, median age: 60.0 years, stage IV: 84.4%). All patients received prior therapy with a median of 2 lines (range: 1 to 5). Treatment-related adverse events (TRAEs) occurred in 62 (96.9%) pts including 35 (54.7%) pts had grade ≥3 TRAEs. The most common grade ≥3 TRAEs (≥5%) were gamma-glutamyl transferase increased (20.3%), lymphocyte count decreased (9.4%) and nausea (7.8%). Cytokine release syndrome (CRS) related adverse events occurred in 33 (51.6%) pts with no grade ≥3 CRS occurred. TEAEs leading to dose interruption and treatment discontinuation occurred in 24 (37.5%) and 3 (4.7%) pts. Preliminary efficacy of IBI389 was observed in pts with CLDN18.2 expression ≥10% (immunohistochemistry 2+/3+) at 600 µg/kg. As of January 31, 2024, there were 23 evaluable pts including 7 pts with PR and 9 pts with SD. The ORR was 30.4% (95%CI: 13.2-52.9) and DCR was 69.6% (95%CI: 47.1-86.8). The median duration of response (DoR) and progression-free survival (PFS) was not reached. More updated data on safety and efficacy will be presented at the meeting. Conclusions: IBI389 showed manageable safety profiles in pts with advanced PDAC. Preliminary efficacy was observed, including in pts with relatively low expression of CLDN18.2. Clinical trial information: NCT05164458 .
Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): Minimum 3-year survival follow-up.
Authors: Yoon Harry H. , Kato Ken , Raymond Eric , Hubner Richard , Shu Yongqian , Pan Yueyin , Jiang Yi , Zhang Jingdong , Park Sook Ryun , Kojima Takashi , Lin Chen-Yuan , Wyrwicz Lucjan S. , Tougeron David , Ishihara Ryu , Li Liyun , Wu Hongqian , Peng Yanyan , Yan Shican , Xu Jianming 
Published: June 2024

4032 Background: RATIONALE-306 (NCT03783442) is the first global study to investigate anti-programmed cell death protein 1 therapy in combination with different chemotherapy (chemo) options in the first-line (1L) treatment of advanced/metastatic esophageal squamous cell carcinoma (ESCC). At interim analysis (IA), tislelizumab (TIS) plus chemo demonstrated a statistically significant, clinically meaningful improvement in overall survival (OS) versus placebo (PBO) plus chemo, with a manageable safety profile. Here, we report updated efficacy and safety data with minimum 3 years’ follow-up after study unblinding at IA. Methods: Adults with unresectable locally advanced recurrent/metastatic ESCC and no prior systemic treatment for advanced disease were enrolled and randomized (1:1; stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg (Arm A) or PBO (Arm B) IV every 3 weeks plus chemo (platinum plus fluoropyrimidine or platinum plus paclitaxel), until disease progression or intolerable toxicity. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR), all per INV, and safety. Results: In total, 649 patients (pts) were randomized (Arm A, n=326; Arm B, n=323). At a minimum study follow-up of 36.0 months, improvements in OS, PFS, and DoR in Arm A versus B (Table) were maintained relative to the IA. The hazard ratio (HR) for OS with TIS plus chemo versus PBO plus chemo was 0.70 (95% confidence interval: 0.59, 0.83). Similar to the IA, incidences of any-grade (96.6% vs 96.3%) or grade ≥3 (67.0% vs 64.5%) treatment-related adverse events (TRAEs) were comparable between Arms A and B, respectively; treatment-emergent adverse events leading to treatment discontinuation were higher in Arm A (32.1%) versus B (22.1%). In Arm A versus B, respectively, serious TRAEs occurred in 29.9% vs 19.6% of pts; TRAEs leading to death occurred in 1.9% and 1.2%. Conclusions: After minimum 3 years’ follow-up, 1L TIS plus chemo continued to demonstrate clinically meaningful improvements in OS and PFS and durable antitumor response benefit versus PBO plus chemo in pts with advanced/metastatic ESCC, with no new safety signals. Clinical trial information: NCT03783442 . [Table: see text]
Updated results and biomarker analyses from the phase 2 trial of nab-paclitaxel plus sintilimab as second-line therapy for advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (G/GEJA).
Authors: Jiang Zhichao , Zhang Wen , Yang Lin , SUN Yongkun , Zhao Yun-Bo , Deng Wei , Cui Liang , Zhou Aiping 
Published: June 2024

4037 Background: Sintilimab plus Nab-paclitaxel (nab-PTX) has exhibited promising efficacy and safety in the second line (2L) treatment of PD-1/PD-L1 inhibitor naïve advanced G/GEJA (ZC Jiang et al 2022 ASCO GI). This update presents the latest findings on efficacy, survival outcomes and exploration of biological markers. Methods: We collected blood samples from the advanced G/GEJA patients (pts) who were enrolled in our Phase 2 clinical trial and treated with sintilimab plus nab-PTX. Target-capture deep sequencing of 1,021 genes was conducted to identify somatic variants in circulating tumor DNA (ctDNA) from the baseline plasma samples (N=55) and disease progression samples of the pts with PFS >4 months (N=17). And T cell repertoire sequencing was performed on pretreatment samples (N=55) as well as on paired blood samples obtained during the first tumor evaluation (N=45). Results: From Nov 2019 to Sep 2022, 58 pts were enrolled, with a median follow-up of 20.9 months (95% CI 17.04-24.76) until July 10, 2023. The objective response rate (ORR) and disease control rate (DCR) were 44.8% and 79.3%, respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.8 months (95%CI 3.06-6.54) and 11.8 months (95%CI 10.43-13.17). Analysis of baseline ctDNA revealed a notably higher prevalence of EPHB1 mutation in non-responders (PD+increased SD) compared to responders (CR+PR+decreased SD) (21.43% vs. 0%, P=0.022). Pts with EPHB1 mutation showed a significantly increased risk of disease progression (HR 3.86, 95% CI 0.43-34.41, p=0.013) and death (HR 4.49, 95% CI 0.43-46.93, p=0.005) compared to wild-type EPHB1 pts. In contrast to high ctDNA level (mean tumor molecules [MTM] per mL of plasma, cutoff value=2999.7), low ctDNA level demonstrated a significantly reduced risk of disease progression (HR 1.88, 95% CI 1.05-3.37, p=0.034). Dynamic T cell receptor (TCR) diversity analysis during baseline and the initial tumor assessment showed a significant post-treatment increase in the Shannon index within the responder group (P=0.045, median Shannon index change: responder 0.43 vs. non-responder -0.49). An increased Shannon index was correlated with significantly prolonged mPFS (HR 0.44, 95% CI 0.22-0.91, P=0.009), while no significant difference was observed in mOS (HR 0.74, 95% CI 0.36-1.54, P=0.399). A negative correlation between the Shannon index and MTM was observed (R=-0.37, P=0.009). Conclusions: 2L-treatment with sintilimab plus nab-PTX maintains favorable efficacy in advanced G/GEJA pts without prior PD-1/PD-L1 inhibitor treatment. EPHB1 mutation and dynamic change of TCR could serve as potential predictive factors. Further investigation is warranted. Clinical trial information: NCT04140318 .
Validation of PD-L1 as a predictive biomarker of response in operable gastroesophageal adenocarcinoma: A meta-analysis and meta-regression of neoadjuvant chemoimmunotherapy trials.
Authors: Cammarota Antonella , Kamarajah Sivesh Kathir , Markar Sheraz , Smyth Elizabeth Catherine 
Published: June 2024

4065 Background: Perioperative chemotherapy (ChT) is a standard for operable gastroesophageal adenocarcinoma (GEA). The addition of immune checkpoint inhibitors (ICIs) has improved pathological complete response (pCR) with unclear survival advantages in an unselected population. In the advanced setting, PD-L1 is a validated biomarker of response to ICIs. We aimed to assess its predictive role in the early stages wherein remains unexplored. Methods: We conducted a systematic review of randomised clinical trials (RCTs) of neoadjuvant or peri-operative ChT +/- ICIs in non-metastatic GEA, published between 2006-2024. Biomarker-unselected phase 2/3 or phase 3 RCTs with an active comparator were selected. Odds ratios (ORs) for pathological response (defined as pCR, ypT0, or ypT≤1), the primary outcome of this meta-analysis, were extracted and analysed using a random-effect meta-analysis. Subgroup analysis (ICI-ChT versus ChT) was performed to estimate the pooled effect of peri-operative ICIs on pathological response. Sensitivity analyses were performed to account for between-study heterogeneity. We then extracted pCR data by PD-L1 (cutoffs 1, 5, 10) from phase 2 trials of neoadjuvant ICIs+ChT or chemoradiotherapy (CRT) published between 2006-2024. Weighted Pearson trial-level correlation and a meta-regression model were used to assess the relationship of PD-L1 with pCR. Results: Nine RCTs were eligible for the analysis, one of which had two experimental arms contributing to two comparisons. Of 5359 included patients, 1302 received ICI-ChT and 4057 systemic ChT. ICI-ChT showed a significant improvement in pathological response (pooled OR 2.90, 95% CI 1.81-4.63, p<0.001) with a larger effect compared to ChT-only trials (pooled OR 1.40, 95% CI 1.10-1.79, p=0.007). Results were consistent in sensitivity analyses of pCR-only, non-Asian, and since-FLOT studies. Fourteen studies were included in the phase 2 trials dataset (n=10 ICI+ChT and n=4 ICI+CRT) accounting for 708 patients receiving ICIs. PD-L1 showed a moderate positive correlation with pCR, stronger for higher cut-offs (weighted R for cut-offs 1, 5, and 10: 0.33, 0.51, and 0.65, respectively) and after exclusion of CRT trials (weighted R for cut-offs 5 and 10: 0.67 and 0.99, respectively). In a mixed-effect meta-regression model, PD-L1 ≥5 was a significant predictor of response (effect size [ES]: 0.71, 95% CI, 0.29-1.13, p=0.001), even after accounting for the backbone treatment (ChT versus CRT) (ES: 0.60, 95% CI, 0.20-1.00, p=0.003). Conclusions: Neoadjuvant ICI-ChT consistently improves pathological response in operable GEA, particularly in PD-L1-positive tumours. PD-L1 ≥5 appears a significant biomarker of pCR in non-metastatic GEA, supporting stratification by PD-L1 and biomarker-selected trials for evaluation at the individual patient level.