Programmed Death Ligand Research Articles

Relationship between PD-L1 expression and the number of biopsy specimens in advanced gastric cancer.

481 Background: Programmed cell death ligand 1 (PD-L1) expression shows spatial heterogeneity in gastric cancer. Compared with single biopsies, multiple biopsies may provide reliable PD-L1 expression results. However, the optimal number of biopsy specimens remains unclear. This study aimed to assess the relationship between PD-L1 expression and the number of biopsy specimens in advanced gastric cancer. Methods: We retrospectively analyzed patients with advanced gastric cancer who received first-line chemotherapy at a single institution between December 2021 and June 2024. Those in whom PD-L1 expression was evaluated using tumor-containing biopsy specimens were included. PD-L1 expression was measured using the Dako PD-L1 IHC 28-8 pharmDx assay. PD-L1 positivity was defined as a combined positive score of ≥5. The association between PD-L1 positivity and the number of biopsy specimens was tested using the chi-square or Fisher’s exact test. Results: Of the 183 patients screened, 110 were included. The patient characteristics were as follows: median age, 71 (range: 34–87) years; sex (male/female), 75/35; primary site (gastric/gastroesophageal junction), 102/8; and histological type (diffuse/intestinal/other), 59/34/17. The PD-L1 positivity prevalence was 71.8%. In 97 patients, human epidermal growth factor receptor 2 (HER2) expression was detected in the same specimens as PD-L1, with a HER2-positive rate of 14.4%. The mean numbers of biopsy and tumor-containing biopsy specimens were 5.14 (range: 2–10) and 4.25 (range: 1–10), respectively. The PD-L1 positivity prevalence was significantly higher when the number of biopsy specimens was ≥5 compared with ≤4 (77.5% vs 56.7%, P =0.03; Table). The same trend was observed according to the histological type (diffuse type, 75.0% vs. 46.7%, P =0.04; intestinal type, 79.2% vs. 60.0%, P =0.39). In HER2-negative cases, PD-L1 positivity was significantly more prevalent when the number of biopsy specimens was ≥5 compared with ≤4 (83.6% vs 54.5%, P =0.006; Table). However, there was no such difference in HER2-positive cases (54.4% vs 66.7%, P =1). Conclusions: The data suggest that collecting at least five biopsy specimens increases the likelihood of identifying PD-L1 positivity in advanced gastric cancer, particularly in HER2-negative cases. This approach may improve PD-L1 evaluation accuracy and lead to better treatment decisions. Relationship between the number of biopsy specimens and PD-L1 positivity. Number of biopsy specimens PD-L1 positivity (%) PD-L1 negativity (%) P value Overall 0.03 ≥5 77.5 22.5 ≤4 56.7 43.3 HER2-negative 0.006 ≥5 83.6 16.4 ≤4 54.5 45.5

Does chemotherapy regimen matter for first-line immunochemotherapy in low programmed cell death ligand 1 (PD-L1)-expressing esophageal squamous cell carcinoma (ESCC)? A systemic review and meta-analysis.

395 Background: Anti-programmed death 1 (PD-1) therapy plus chemotherapy has become standard first-line therapy for patients with high PD-L1-expressing advanced ESCC. The benefit for patients with low PD-L1-expressing ESCC remains debatable. Methods: Eligible studies were phase III trials investigating anti-PD-1/PD-L1 therapy plus chemotherapy (immunochemotherapy) vs chemotherapy as first-line therapy of advanced ESCC. Study-level pooled analyses of hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) with corresponding 95% confidence intervals (CI), were used to compare the different groups in random-effects model. PD-L1 expression levels with tumor proportion score (TPS) ≥ 1% vs < 1%, tumor area positivity (TAP) ≥ 10% vs < 10%, and combined positive score (CPS) ≥ 10 vs < 10 were collectively categorized as high vs low PD-L1 expression. The impact of two different chemotherapy regimens, TP (paclitaxel plus platinum) and PF (platinum pus fluoropyrimidine), stratified by PD-L1 expression levels, on the survival benefit of immunochemotherapy vs chemotherapy was investigated. Results: Eight randomized controlled trials including 4733 subjects were enrolled. Immunochemotherapy vs chemotherapy was associated with significantly improved PFS and OS irrespective of PD-L1 expression levels or chemotherapy regimens (Table). The PFS and OS benefits were more pronounced in high PD-L1 group than low PD-L1 group. In patients with high PD-L1 expression, the PFS and OS benefits were not significantly different between two chemotherapy regimen subgroups. However, in patients with low PD-L1 expression, the PFS benefit was more significant in TP subgroup than PF subgroup, and OS benefit trended to be in favor of TP subgroup. Conclusions: The addition of anti-PD-1/PD-L1 therapy to TP chemotherapy may associate with more significant survival benefit than to PF chemotherapy in advanced ESCC with low PD-L1 expression. Population PFS (immunochemotherapy vs chemotherapy) OS (immunochemotherapy vs chemotherapy) HR(95% CI) P value(subgroup differences) HR(95% CI) P value(subgroup differences) All patients 0.63 (0.57-0.69) 0.69 (0.64-0.74) High PD-L1 group 0.54 (0.49-0.60) P < 0.01 0.60 (0.53-0.67) P < 0.01 Low PD-L1 group 0.71 (0.62-0.81) 0.78 (0.70-0.87) TP group 0.56 (0.50-0.62) P < 0.01 0.66 (0.59-0.74) P = 0.32 PF group 0.68 (0.62-0.75) 0.72 (0.65-0.79) Among high PD-L1 patients TP subgroup 0.56 (0.45-0.69) P = 0.75 0.60 (0.46-0.78) P = 0.90 PF subgroup 0.53 (0.45-0.62) 0.59 (0.50-0.69) Among low PD-L1 patients TP subgroup 0.59 (0.48-0.74) P = 0.01 0.72 (0.55-0.93) P = 0.32 PF subgroup 0.82 (0.72-0.94) 0.84 (0.72-0.97)

In silico Prediction of Pranlukast as a Stabilizer of PD-L1 Homodimers.

Tumors can be targeted by modulating the immune response of the patient. Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are critical immune checkpoints in cancer biology. The efficacy of certain cancer immunotherapies has been achieved by targeting these molecules using monoclonal antibodies. Small-molecule drugs have also been developed as inhibitors of the PD-1/PD-L1 axis, with a mechanism of action that is distinct from that of antibodies: they induce the formation of PD-L1 homodimers, causing their stabilization, internalization, and subsequent degradation. Drug repurposing is a strategy in which new uses are sought after for approved drugs, expediting their clinical translation based on updated findings. In this study, we generated a pharmacophore model that was based on reported small molecules that targeted PD-L1 and used it to identify potential PD-L1 inhibitors among FDA-approved drugs. We identified 12 pharmacophore-matching compounds, but only 4 reproduced the binding mode of the reference inhibitors in docking experiments. Further characterization by molecular dynamics showed that pranlukast, an antagonist of leukotriene receptors that is used to treat asthma, generated stable and energyfavorable interactions with PD-L1 homodimers and induced homodimerization of recombinant PD-L1. Our results suggest that pranlukast inhibits the PD-1/PD-L1 axis, meriting its repurposing as an antitumor drug.

Impact of tislelizumab + chemotherapy versus placebo + chemotherapy on patient-reported symptoms and disease progression by programmed death-ligand 1 expression in gastroesophageal adenocarcinoma: A post hoc analysis of the RATIONALE-305 trial.

365 Background: The relationship between patient-reported outcome (PRO)-based symptom scores, recurrent PRO-based symptomatic deterioration events (RDEs), and terminal events such as progression-free survival (PFS) are rarely examined in the oncology therapeutic domain. Thus, we applied a 3-component joint model (JM) framework aiming to illuminate more clinically interpretable associations between PRO-based treatment effects, RDEs, and PFS among subgroups of patients with programmed death-ligand 1 (PD-L1) expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 378 patients in the tislelizumab + chemotherapy arm (T+C) vs 401 in the placebo + chemotherapy arm (P+C) for the PD-L1 ≥1% subgroup, 238 in the T+C arm vs 237 in the P+C for the PD-L1 ≥5% subgroup, and 118 in the T+C arm vs 125 in the P+C arm for the PD-L1 ≥10% subgroup. Symptom domain scores from the EORTC QLQ-C30 and QLQ-STO22 symptom were modeled. Change from baseline (CFBL) in each domain was analyzed every cycle up to cycle 6, then every other cycle thereafter (up to cycle 25). The joint model was applied to all PD-L1 subgroups and comprised three components: 1) linear mixed model (LMM) predicting CFBL symptom scores, 2) Cox proportional hazard (CPH) model for disease progression (PFS as terminal event), and 3) frailty (random effects for RDEs) CPH model for time to PRO-based RDEs. Osoba’s 10-point threshold was used to define RDEs. Results: In the LMM, significant treatment efficacy for the T+C arm compared with the P+C arm was observed for the GHS/QoL ( P =0.0080) and dietary restriction scores ( P =0.0475) in the PD-L1 ≥5% subgroup. In the PD-L1 ≥1% subgroup, compared with the P+C arm, the T+C arm was associated with less worsening in pain/discomfort ( P =0.0376), upper gastrointestinal symptoms ( P =0.0088), and dietary restrictions ( P =0.0352). In the CPH model, the average hazard ratio indicated that compared with the P+C arm, the T+C arm was associated with a reduction in risk of disease progression across all PRO domains and PD-L1 subgroups. Lastly, the PRO-based RDE frailty predictions were strongly associated with PFS risk in the PD-L1 ≥1% and ≥5% subgroups for GHS/QoL, and in the PD-L1 ≥1% subgroup for physical functioning, fatigue, dysphagia-odynophagia, pain/discomfort, and dietary restrictions, as well as for pain/discomfort and dietary restrictions in the PD-L1 ≥5% subgroup. Conclusions: Through the 3-component JM, PRO-based effects were detected and demonstrated strong associations between PRO-based RDEs, and investigator-assessed PFS among varying PD-L1 expression levels. This framework may be a promising alternative for analyzing and interpreting PRO data in the context of PFS.

Impact of tislelizumab + chemotherapy versus placebo + chemotherapy on patient-reported symptoms and overall survival (OS) by programmed death-ligand 1 (PD-L1) expression in advanced or metastatic esophageal squamous cell carcinoma (ESCC): A post hoc analysis of the RATIONALE-306 trial.

366 Background: While improved survival has been previously demonstrated, the impact of immunotherapy on HRQoL in ESCC has not been well examined. Traditional PRO-based analyses in oncology trials, such as time to deterioration (TTD) and mixed models for repeated measures (MMRMs), are limited by discounting recurrent PRO events. Thus, we applied a 3-component joint model (JM) framework to define more clinically interpretable associations between patient-reported symptoms, treatment effects, and OS among subgroups of patients with ESCC from RATIONALE-306, which met its primary endpoint, with PD-L1 expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 226 patients in the tislelizumab + chemotherapy arm (T+C), 242 in the placebo + chemotherapy arm (P+C) for PD-L1 ≥1%, 113 in the T+C arm and 103 in the P+C arm for PD-L1 ≥5%, and 168 in the T+C arm and 178 in the P+C arm for PD-L1 ≥10%.From EORTC QLQ-C30 and OES18, 7 keysymptom domains were modeled (GHS, physical functioning, fatigue, dysphagia, pain, reflux, dietary restrictions). PRO data were collected at baseline and at every treatment cycle (up to 6 cycles), then every other cycle, and at safety follow-up, and change from baseline (CFBL) was analyzed. The joint model comprised three components: 1) linear mixed model predicting CFBL symptom scores; 2) Cox proportional hazard model (CPH) for time to OS; and 3) frailty (random effects for recurrent deterioration events [RDEs]) CPH model for time to PRO-based RDEs. Osoba (1998) 10-point threshold was used to define RDEs. Results: Adjusted completion rates were >90% in the ITT population for both arms. Significant T+C treatment effects wereobserved for physical functioning in PD-L1 ≥5% ( P =0.0476), and pain in PD-L1 ≥1% ( P =0.0028) and PD-L1 ≥5% ( P =0.0149) subgroups, but not in PD-L1 ≥10%. For other 5 symptoms (ie, GHS, fatigue, reflux, dysphagia, dietary restrictions), there were no statistically significant differences between treatment arms. However, T+C was associated with significant reductions in the risk of death across all 7 key symptoms and PD-L1 subgroups. As one example, with respect to interaction between pain and OS, T+C was associated with a 22% (HR, 0.78 [95% CI, 0.652-0.931]), 33% (HR, 0.67 [95% CI, 0.515-0.860]), and 47% (HR, 0.50 [95% CI, 0.344-0.720]) reduction in the risk of death in PD-L1 ≥1%, ≥5%, and ≥10%, respectively compared with P+C. Conclusions: In this analysis, the addition of tislelizumab to chemotherapy was associated with significantly less deterioration in multiple PRO symptoms including physical functioning and pain, alongside a lower risk of death, after adjusting for recurring deterioration events using a frailty model across multiple PD-L1 expression subgroups.

A novel immune-based score and its immune contexture exploration in colorectal cancer.

234 Background: The majority of currently available biomarkers in colorectal cancer (CRC) perform poorly with respect to prognostication and prediction of response. Immunoscore (IS) has been proposed as a signature of host immune cancer response reflecting a favorable prognosis. Next, through AtezoTRIBE, ‘Immunoscore immune checkpoint’ (IS-IC) was introduced, indicating its potential predictive value for immune checkpoint blockade (ICB) in pMMR metastatic CRC. IS-IC is computed through quantitative and spatial variables related to density and proximity of CD8 cells and programmed cell death-ligand 1 (PD-L1) cells in the tumor core (TC). There are little confirmatory studies. In this work we test the application of IS-IC through multiplex immunofluorescence (mIF) on our own cohort of patients. Next we explore immune contexture differences through subgroup analysis. Methods: 15 prospectively collected, treatment naïve, primary CRC samples (9 dMMR/MSI-H, 6 pMMR/MSS) where analyzed with mIF. Cell density, proximity between cells, cell clustering and spatial distribution of selected mIF biomarkers (CD3, CD20, CD11c, CD163, CD15, CD4, CD8, Foxp3, CD56, Granzyme B, PD-L1, programmed cell death protein 1 (PD-1), pan-cytokeratin (CK) and Ki67) were analyzed both at the invasive margin (IM) and TC using digital pathology. All slides subjected to digital image analysis met predefined quality control criteria. Results: Serial mIF showed PD-L1 was enriched in stromal cells (CK - ) within IM ( p =0.0148) and confirmed its co-localization with macrophages (CD163 + ) ( p =0.0092). Hence, both TC and IM were included to quantify the densities of CD8, PD-L1 and the proximity between them, as a suggested novel IS-IC TC+IM . During exploration of the immune context we found that both IS-IC and IS-IC TC+IM high groups exhibited significantly increased infiltration of PD-1 + cells ( p =0.0074 and p =0.0058, respectively) and CD8 + PD-1 + cells ( p =0.0101 and p =0.0062, respectively), compared to the corresponding low groups. Whereas only the IS-IC TC+IM high group showed increased natural killer (NK) cells (CD56 + ) ( p =0.0192), found mainly at IM ( p =0.0167) in contrast to TC ( p =0.0824). The novel IS-IC TC+IM scoring system captures the immunosuppressive and immune responsive interaction among PD-1 + cells, PD-L1 + cells, NK cells and CD8 + cells in TC and IM from the cell numbers and cell-cell proximity. A validation cohort is underway. Conclusions: In this study we confirm the ease of replicating IS-IC and the presence of ICB sensitive stroma in the high score group. This study further explored the immune context in both TC and IM, emphasizing the importance of regional differences. Additionally it was found that NK cells were only increased at IM. Altogether we suggests adding dual quantification in TC and IM as a novel IS-IC TC+IM , which may be a more sufficient reflection of the tumor micro environment.

Correlation between PD-L1 CPS and clinical outcomes in patients treated with first-line nivolumab plus chemotherapy for advanced gastric or gastroesophageal junction cancer: A multi-center retrospective study in Japan.

364 Background: The CheckMate 649 trial showed the superiority of first-line nivolumab plus chemotherapy (Nivo-CT) compared with chemotherapy alone for advanced gastric and gastroesophageal junction (GEJ) cancer with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) >5, while survival benefit was poor in PD-L1 CPS <1 and <5. However, there were few studies on correlation between PD-L1 CPS and efficacy of first-line Nivo-CT for advanced gastric or GEJ cancer in real world data. Methods: This multi-center retrospective study included patients with histologically confirmed advanced gastric or GEJ cancer who were started on first-line Nivo-CT between December 2021 and December 2023. PD-L1 CPS was assessed before the start of Nivo-CT by classified into three groups at each center: <1, 1~5 and >5, using the Dako PD-L1 immunohistochemistry 28-8 pharmDx assay. The efficacy was evaluated by overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: A total of 271 patients were included (median age, 70 [range 18–85] years; male/female, 64/36%; performance status (PS) 0/1/2, 47/49/4%; primary tumor site gastric/GEJ, 90/10%; status unresectable/recurrent, 81/19%; histology intestinal/diffuse, 30/70%). PD-L1 CPS status were evaluated 234 (86%) patients and PD-L1 CPS <1, 1~5 and >5 was found in 35 (15%), 76 (33%) and 123 (53%) patients, respectively. Median follow-up time was 11.3 (range 1-30) months. The median PFS was 9.7 (95%CI, 5.9-16.3), 8.8 (95%CI, 7.2-13.0) and 6.3 (95%CI, 5.3-9.0) months in the patient with PD-L1 CPS <1, 1~5 and >5, respectively. The median OS was 18.7 (95%CI, 17.4-NA), 23.4 (95%CI, 17.7-NA) and 18.3 (95%CI, 13.3-22.5) months, and the ORR were 30.8, 66.7 and 61.3% (p = 0.075) in the patient with PD-L1 CPS <1, 1~5 and >5, respectively. Liver metastases were found in 43 (35.0%) of the patients with PD-L1 CPS >5, significantly more than in the patients with PD-L1 CPS <5 (p < 0.001). Multivariate analysis indicated that PD-L1 CPS status was not associated with prognosis (PD-L1 CPS ≥5 vs. <1, HR 1.18 [95%CI, 0.75-1.86], p = 0.48). In the overall population, grade ≥3 adverse events were observed in 102 (37.6%) patients and grade ≥3 immune-related adverse events were observed in 26 (9.6%) patients. Conclusions: There were no significant differences in prognosis and response between PD-L1 CPS in first-line Nivo-CT for advanced gastric or GEJ cancer in real world data.

Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 5-year (y) follow-up results from CheckMate 649.

398 Background: At 4-y follow-up, 1L NIVO + chemo continued to demonstrate clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit vs chemo with acceptable safety in patients (pts) with advanced non-HER2+ GC/GEJC/EAC from CheckMate 649. We report efficacy and safety results of NIVO + chemo vs chemo at 5-y follow-up. Methods: Adults with previously untreated, unresectable, advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. Pts were randomized to NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: Pts were randomized to NIVO + chemo (n = 789) or chemo (n = 792). NIVO + chemo continued to show OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts at 60-month (mo) minimum follow-up (Table). OS rates at 60-mo were higher with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts (Table), and OS benefit with NIVO + chemo continued to be observed in most prespecified subgroups. Objective response rates (ORRs) were higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts (Table). No new safety signals were identified. Conclusions: These results represent the first report of 5-y follow-up for anti–PD-1 + chemo combination therapy in GC/GEJC/EAC to our knowledge. NIVO + chemo continued to provide sustained long-term survival vs chemo with an acceptable safety profile after 5 y of follow-up. These data continue to support the use of NIVO + chemo as a standard 1L treatment for advanced GC/GEJC/EAC. Clinical trial information: NCT02872116 . Efficacy PD-L1 CPS ≥ 5 PD-L1 CPS ≥ 1 All randomized NIVO + chemo(n = 473) Chemo (n = 482) NIVO + chemo (n = 641) Chemo (n = 656) NIVO + chemo (n = 789) Chemo (n = 792) mOS (95% CI), mo 14.4 (13.1–16.2) 11.1 (10.1–12.1) 13.8 (12.4–14.8) 11.4 (10.7–12.3) 13.7 (12.4–14.5) 11.6 (10.9–12.5) HR (95% CI) 0.71 (0.61–0.81) 0.76 (0.67–0.85) 0.79 (0.71–0.88) 60-mo OS rate (95% CI), % 16 (12–19) 6 (4–9) 13 (11–16) 5 (4–7) 12 (10–14) 6 (4–8) mPFS a (95% CI), mo 8.3 (7.0–9.4) 6.1 (5.6–6.9) 7.5 (7.0–8.5) 6.9 (6.2–7.1) 7.8 (7.1–8.6) 6.9 (6.7–7.2) HR (95% CI) 0.71 (0.61–0.82) 0.77 (0.68–0.87) 0.79 (0.71–0.89) ORR a,b (95% CI), % 60 (55–65) 45 (40–50) 60 (55–64) 46 (42–51) 58 (54–62) 46 (42–50) mDOR a,c (95% CI), mo 9.6 (8.3–12.4) 7.0 (5.7–8.0) 8.6 (7.9–10.5) 6.9 (5.8–7.6) 8.5 (7.7–9.9) 6.9 (5.9–7.6) a Per BICR. b In pts with measurable target lesions at baseline. c In all measurable responders. DOR, duration of response; m, median.

First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) vs chemo in patients (pts) with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC): 5-year (y) follow-up of Chinese pts from CheckMate 649.

392 Background: NIVO + chemo demonstrated clinically meaningful survival benefit and an acceptable safety profile vs chemo in previously untreated Chinese pts with advanced GC/GEJC/EAC from CheckMate 649, consistent with the overall study population. 1L NIVO + chemo is currently approved for pts with advanced non-HER2+ GC/GEJC/EAC in China and other countries. We report 5-y results of NIVO + chemo vs chemo in Chinese pts from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled regardless of programmed death ligand 1 (PD-L1) expression. Randomized pts received NIVO + chemo, NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 208 Chinese pts were randomized to NIVO + chemo or chemo. At 61-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). 5-y OS rate was 24% with NIVO + chemo vs 8% with chemo in pts with PD-L1 CPS ≥ 5 and 20% vs 7% in all randomized pts. Objective response rate (ORR) was higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). No new safety signals were identified with longer follow-up. Conclusions: NIVO + chemo continued to demonstrate clinically meaningful long-term survival benefit, more durable responses, and acceptable safety vs chemo in Chinese pts after 5 y of follow-up, consistent with earlier reports and with the overall study population of pts with advanced non-HER2+ GC/GEJC/EAC. These results further support NIVO + chemo as a standard 1L treatment option for Chinese pts. Clinical trial information: NCT02872116 . Efficacy PD-L1 CPS ≥ 5 All randomized NIVO + chemo(n = 75) Chemo (n = 81) NIVO + chemo (n = 99) Chemo (n = 109) mOS (95% CI), mo 15.5(11.9–21.1) 9.6(8.0–12.1) 14.3(11.5–16.5) 10.3(8.1–12.1) HR (95% CI) 0.57 (0.40–0.82) 0.63 (0.46–0.85) mPFS a (95% CI), mo 8.5(6.0–14.0) 4.3(4.1–6.5) 8.3(6.2–12.4) 5.6(4.2–6.8) HR (95% CI) 0.51 (0.34–0.76) 0.57 (0.41–0.80) ORR a,b (95% CI), % 68 (56–79) 48 (36–60) 66 (55–76) 45 (35–56) mDOR a,c (95% CI), mo 12.5 (7.2–23.4) 6.9 (3.9–8.5) 12.5 (7.2–17.7) 5.6 (4.4–8.3) a Per BICR. b In pts with measurable target lesions at baseline. c In responders. DOR, duration of response; m, median.

Perioperative adebrelimab combined with chemotherapy for locally advanced resectable esophageal squamous cell carcinoma: A single-arm, open-label, multicenter study.

421 Background: Neoadjuvant programmed cell death 1 (PD-1) inhibitors combined with chemotherapy have shown promising results in treating locally advanced esophageal squamous cell carcinoma (LA-ESCC). However, relatively little attention has been focused on programmed cell death ligand 1 (PD-L1) blockades. This study aims to evaluate the efficacy and safety of neoadjuvant adebrelimab (anti-PD-L1 antibody) plus chemotherapy followed by adjuvant adebrelimab for resectable LA-ESCC. Methods: In this single-arm, multicenter study, patients (pts) with newly diagnosed, locally advanced resectable thoracic ESCC (cT1b-2, N+ or cT3-4a, N0/+) received 2 cycles of neoadjuvant chemoimmunotherapy with adebrelimab (1200 mg), paclitaxel (175 mg/m 2 ) and cisplatin (75 mg/m 2 ) every 3 weeks, followed by esophagectomy and 16 doses of adebrelimab. The primary endpoints were safety and pathological complete response (pCR) rate. Secondary endpoints included surgery completion rate, R0 resection rate, major pathological response (MPR) rate, event-free survival (EFS) and disease-free survival (DFS). The trial was registered at Chinese Clinical Trial Registry, identifier: ChiCTR2300069179. Results: Between May 2023 and January 2024, 36 pts met inclusion criteria, with a median age of 65 years (range: 42-73). Of these, 66.7% (24/36) were classified as stage III-IVa. As of August 1, 2024, the median number of treatment cycles for all pts was 7 (interquartile range, 2-12). The neoadjuvant therapy completion rate was 91.7% (33/36). Thirty-two pts underwent minimally invasive esophagectomy, resulting in an overall surgical resection rate of 88.9% and an R0 resection rate of 90.6%. The pCR rate was 15.6% (5/32) and the MPR rate was 31.2% (10/32). The EFS and DFS outcomes were not mature. During the preoperative treatment period, 35 pts (97.2%) experienced any grade of treatment-related adverse events (TRAEs). Grade 3 or 4 TRAEs occurred in 7 pts (19.4%), and there were no grade 5 TRAEs. The most common grade 3/4 adverse events included neutropenia (11.1%), leukopenia (5.6%), diarrhea (5.6%) and hyponatremia (5.6%). Surgical complications of grade 3/4 were reported in 7 pts (21.9%), with anastomotic fistula (6.3%) being the most common. No perioperative deaths occurred. Conclusions: Neoadjuvant adebrelimab combined with chemotherapy and adjuvant adebrelimab demonstrated encouraging clinical efficacy and manageable safety in pts with LA-ESCC. Further study is warranted. Clinical trial information: ChiCTR2300069179.

Comparison of efficacy and safety of PD-1 and PD-L1 antibodies in combination with hepatic arterial infusion chemotherapy and target therapy for unresectable intrahepatic cholangiocarcinoma: A multicenter retrospective study.

553 Background: Immune checkpoint inhibitors (ICIs) in combination with hepatic arterial infusion chemotherapy (HAIC) and target therapy have shown promising antitumor activity in unresectable intrahepatic cholangiocarcinoma (iCCA). The present study aimed to compare the efficacy and safety of programmed cell death protein 1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors in this setting. Methods: In this multicenter retrospective study, we included patients with iCCA who received ICIs + HAIC + target therapy from June 2018 to June 2023. Propensity score matching (PSM) was performed to reduce confounding factors. Patients were divided into two groups: those treated with PD-L1 antibody + HAIC + target therapy (Group A) and those treated with PD-1 antibody + HAIC + target therapy (Group B). Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were compared between the two groups. Adverse events were assessed according to CTCAE v5.0. Results: A total of 336 patients met the inclusion criteria and were enrolled for analysis. There were no significant differences in OS, PFS, or ORR between the two groups (median OS: 17.7 vs. 25.3 months, P=0.139; median PFS: 8.3 vs. 10.0 months, P=0.534; ORR: 48.4% vs. 31.1%, P=0.051). Following PSM (ratio = 3, caliper = 0.2), 30 patients in Group A and 83 patients in Group B were included. The ORR, according to the modified RECIST criteria, was significantly higher in Group A compared to Group B (50% vs. 28.9%, P=0.037). However, no significant difference in PFS (median 10.0 vs. 9.0 months, P=0.29) or OS (median 17.6 vs. 22.8 months, P=0.293) was observed between the two groups. Adverse events (AEs) occurred in all 113 patients (100%), wherein grade 3–4 AEs were reported for 12 (10.6%) patients in group A and 45 (39.8%) in group B. There was a tendency for Group A to have a lower incidence of grade 3–4 AEs compared to Group B (40.0% vs. 54.2%, P=0.182),although this difference was not statistically significant. Conclusions: This study found that in the treatment combining ICIs with HAIC and target therapy for unresectable iCCA, Group A demonstrated a superior tumor response and a more favorable safety profile.

Investigation of synergistic effects in trials of combination therapies with immune-checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer.

405 Background: Combinations of immune checkpoint inhibitors (ICI) and chemotherapy (CT) have been approved for gastric cancer. However, there is a hypothesis that this combination may blunt antitumor immune responses because most chemotherapeutic agents also target lymphocytes. The primary objective was to investigate that the ICI and CT does not interfere each other’s therapeutic effects in advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) patients. Methods: The reconstructed individual patient data was electronically extracted from the Kaplan-Meier curve of phase III randomized controlled trials (RCTs). The observed PFS curve of each constituent monotherapies was used to estimate simulated PFS curves expected under a model of independent drug action. If the observed curve demonstrated significantly better PFS than simulated curve, the combination of ICI and CT may have a synergistic effect, implying a superior outcome compared to simply adding the component monotherapy. Results: The study included 2,538 unresectable advanced, recurrent, or metastatic GC or GEJC patients from three RCTs comparing pembrolizumab (KEYNOTE-061, KEYNOTE-062 and KEYNOTE-859). In patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater, the 1-year and median PFS of the observed and simulated curves were 28.0% vs. 27.9%, and 6.89 months vs. 6.88 months, respectively. One sample log-rank test showed no significant differences between the observed and simulated curves (p = 0.107). In the subgroups with PD-L1 CPS ≥10 or <1, the 1-year PFS of the observed and simulated curves was 34.7% vs 32.8%, and 28.5% vs 26.8%. Conclusions: The observed PFS of ICT involving pembrolizumab was comparable to the simulated PFS estimated from the data for each monotherapy regardless of the magnitude of PD-L1 CPS. Although it was not clear whether potential synergies existed for ICT, these findings at least suggest that the benefits of ICI and CT are not interfering each other, thereby providing theoretical support for the efficacy of ICT in patients with advanced GC or GEJC.

Targeting intracellular cancer proteins with tumor-microenvironment-responsive bispecific nanobody-PROTACs for enhanced therapeutic efficacy.

Proteolysis targeting chimeras (PROTACs) are pivotal in cancer therapy for their ability to degrade specific proteins. However, their non-specificity can lead to systemic toxicity due to protein degradation in normal cells. To address this, we have integrated a nanobody into the PROTACs framework and leveraged the tumor microenvironment to enhance drug specificity. In this study, we engineered BumPeD, a novel bispecific nanobody-targeted PROTACs-like platform, by fusing two nanobodies with a Furin protease cleavage site (RVRR) and a degron sequence (ALAPYIP or KIGLGRQKPPKATK), enabling the tumor microenvironment to direct the degradation of intracellular proteins. We utilized KN035 and Nb4A to target PD-L1(programmed death ligand 1) on the cell surface and intracellular Survivin, respectively. In vitro experiments showed that BumPeD triggers Survivin degradation via the ubiquitin-proteasome pathway, inducing tumor apoptosis and suppressing bladder tumor cell proliferation and migration. In vivo experiments further confirmed BumPeD's robust anti-tumor efficacy, underscoring its potential as a precise protein degradation strategy for cancer therapy. Our platform provides a systematic approach to developing effective and practical protein degraders, offering a targeted theoretical basis and experimental support for the development of novel degradative drugs, as well as new directions for cancer therapy.

Efficacy of pembrolizumab in advanced esophageal carcinoma: A systematic review and meta-analysis.

438 Background: Pembrolizumab, a monoclonal immunoglobulin G4 antibody is a programmed cell death protein 1 inhibitor, approved for treatment of advanced (metastatic or recurrent) esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). We performed a pooled analysis to assess the efficacy of pembrolizumab in esophageal carcinoma (EC) and to compare it with chemotherapy alone. Methods: We conducted a systemic literature search, using PubMed, EMBASE, and ClinicalTrials.gov, till July 30, 2024. Initial search yielded 412 articles. We excluded duplicates and irrelevant studies and included 4 clinical trials (CT) that reported pembrolizumab’s efficacy in EC. We estimated pooled objective response rate (ORR), partial response (PR), and hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS), along with 95% confidence interval (CI) and p-value in RevMan v.5.4. Subgroup analysis, based on combined positive score (CPS) for programmed cell death ligand-1 (PDL-1) expression and tumor histology type was also performed. Results: We included four CTs in our study; their characteristics are shown in the table. The estimated pooled ORR and PR of pembrolizumab in all patients was 21% (CI: 0.10-0.41) (p < 0.001) and 19% (CI: 0.08-0.37) (p < 0.001), respectively. Pooled median PFS was 3.05 mo (CI: 0.92-5.17) (p = 0.004), and pooled median OS was 8.05 mo (CI: 5.21-10.88) (p < 0.001). Pembrolizumab use in EC showed a reduced risk of disease progression vs chemotherapy alone [HR: 0.85 (CI: 0.75-0.96) (p < 0.05)] and a 21% reduction in mortality [HR: 0.79 (CI: 0.71-0.88) (p < 0.001)]. Safety analysis revealed less grade ≥3 adverse events [OR: 0.56 (CI: 0.35-0.90), p < 0.05)] with pembrolizumab compared with chemotherapy alone. On subgroup analysis between ESSC and EAC, pembrolizumab exhibited statistically nonsignificant responses with ORR (OR: 1.29, CI: 0.89-1.88, p = 0.18), OS (pooled HR: 0.94, CI: 0.76-1.15, p = 0.53). Pembrolizumab in patients with CPS ≥10 vs CPS <10 also showed statistically non-significant responses with ORR [OR: 1.70, CI: 0.99-2.91, p = 0.06), OS (pooled HR: 0.63 vs 1.00) (p = 0.05) and PFS (pooled HR: 0.62 vs 0.83, p = 0.08). Conclusions: Pembrolizumab alone or combined with chemotherapy compared with chemotherapy alone exhibited favorable responses in terms of ORR, OS and PFS with a manageable toxicity profile, setting a benchmark for future studies. Characteristics of included studies. Trial ID, phase Histology Line Number of patients Regimen Median follow-up (mo) ORR (%) Median PFS (mo) Median OS (mo) KEYNOTE-590, III ESCC, EAC 1 st 749 Pembro + chemo vs chemo 58.8 45 vs 29.3 6.3 vs 5.8 12.3 vs 9.8 KEYNOTE-181, III ESCC, EAC 2 nd 628 Pembro vs chemo 7.1 13.1 vs 6.7 2.1 vs 3.4 9.3 vs 6.9 KEYNOTE-180, II ESCC, EAC 3 rd or later 121 Pembro 5.8 9.9 2.0 5.8 KEYNOTE-028, 1b ESCC, EAC 3 rd or later 21 Pembro 7 30 1.8 7 Pembro: pembrolizumab, mo: month.

Efficacy of PD-1 inhibitor plus chemotherapy versus chemotherapy in advanced esophageal carcinoma: A meta-analysis of phase III clinical trials.

397 Background: Programmed death cell death protein-1 (PD-1) inhibitors combined with chemotherapy have demonstrated survival benefits in patients with advanced esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). Our pooled analysis aims to analyze the efficacy of PD-1 inhibitor plus chemotherapy in advanced esophageal carcinoma (EC) in phase III randomized clinical trials (RCTs). Methods: We collected data from eligible phase III RCTs searched through PubMed, EMBASE, ClinicalTrials.gov, and meeting abstracts till July 5, 2024. Initial screening revealed 792 articles. We excluded duplicates, review articles and irrelevant studies, and we included eight RCTs that reported objective response rate (ORR), treatment-related adverse events (TRAEs), overall survival (OS) and progression-free survival (PFS). Odds ratio (OR) for ORR and TRAEs, and hazard ratio (HR) for OS and PFS were computed along with a 95% confidence interval (CI) and p-value for pooled analysis, using a random effect model in RevMan v.5.4. We performed a subgroup analysis based on a combined positive score (CPS) for programmed cell death ligand-1 (PDL-1) expression and tumor histology. Results: We included eight phase III RCTs (Jupiter-06, Checkmate 648, Keynote 590, ESCORT-1st, Orient-15, Checkmate 649, ESCORT-NEO, and ASTRUM-007), including 4131 patients with 2137 in group A (PD-1 inhibitor + chemotherapy) and 1994 in group B (placebo + chemotherapy, or chemotherapy). PD-1 inhibitors against EC included nivolumab, pembrolizumab, camrelizumab, sintilimab, toripalimab, and serplulimab. A total of 9.9% of patients were diagnosed with EAC, and 90.1% were ESCC. A pooled analysis showed significant achievement in ORR in group A compared to group B with an OR of 2.19 (CI: 1.77-2.69, p < 0.05, I² = 60%). In terms of OS benefit, group A led to a 29% reduction in death risk compared to group B (HR: 0.71, CI: 0.66-0.76, p < 0.05, I² = 0). Group A also showed a significantly reduced risk of disease progression compared to group B (HR: 0.62, CI: 0.54-0.70, p < 0.05, I² = 60%). Safety analysis revealed more TRAEs (OR: 1.93, CI: 1.43-2.60, p < 0.01, I² = 11%) and grade ≥3 AEs (OR: 1.34, CI: 1.08-1.67, p < 0.05, I² = 54%) in group A compared with group B. Sub-group analysis based on CPS revealed that patients with CPS ≥10 showed more OS (pooled HR: 0.59 vs 0.75) (p = 0.04) and PFS (pooled HR: (0.59 vs 0.64) (p = 0.18) benefits as compared to patients with CPS <10. Survival analysis between ESCC and EAC also exhibited statistically non-significant OS benefits (p = 0.28). Conclusions: PD-1 inhibitor plus chemotherapy as a first-line therapy in advanced EC, mainly in patients with CPS ≥10, showed improved antitumor efficacy in terms of superior ORR, OS, and PFS, with a manageable toxicity profile providing a benchmark for future studies.

A mechanistic, functional, and clinical perspective on targeting CD70 in cancer.

The oncoimmunology research has witnessed notable advancements in recent years. Reshaping the tumor microenvironment (TME) approach is an effective method to improve antitumor immune response. The T cell-mediated antitumor response is crucial for favorable therapeutic outcomes in several cancers. The United States Food and Drug Administration (FDA) has approved immune checkpoint inhibitors (ICIs) for targeting the immune checkpoint proteins (ICPs) expressed in various hematological and solid malignancies. The ICPs are T cell co-inhibitory molecules that block T cell activation and, thus, antitumor response. Currently, most of the FDA-approved ICIs are antagonistic antibodies of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). In contrast to ICPs, the T cell costimulatory molecules are required for T cell activation, expansion, and effector function. However, the abrupt expression of these costimulatory molecules in tumors presents a concern for T cell-mediated antitumor response. One of the T cell costimulatory molecules, the cluster of differentiation 70 (CD70), has emerged as a druggable target in various hematological and solid malignancies due to its role in T cell effector function and immune evasion. The present review describes the expression of CD70, factors affecting the CD70 expression, the physiological and clinical relevance of CD70, and the current approaches to target CD70 in hematological and solid malignancies.

Updated results of ALTER-H006: A phase II study of benmelstobart (PD-L1 inhibitor) plus anlotinib as adjuvant therapy in hepatocellular carcinoma (HCC) with high risk of recurrence after radical resection.

601 Background: Although radical resection offers one of the most favorable prognosis for hepatocellular carcinoma (HCC), the rate of postoperative recurrence remains high, which is the primary cause of mortality in HCC patients. The optimal adjuvant treatment strategy for patients is still under active investigation. Herein we evaluated the efficacy and safety of the anti-angiogenic tyrosine kinase inhibitor, anlotinib, plus benmelstobart, a novel programmed death-ligand 1 (PD-L1) inhibitor as an adjuvant treatment for HCC with high risk of recurrence after radical resection. Methods: This study enrolled patients diagnosed with HCC confirmed through histological or cytological examination, whose age was 18-75, with ECOG 0-1, Child-Pugh class A, 4~8 weeks after R0 resection with any of the following high-risk factors for recurrence: a) tumor nodules ≥4; b) portal vein tumor thrombus (PVTT): vp1 or vp2; c) hepatic vein tumor thrombus (HVTT): vv1 or vv2. Enrolled patients received anlotinib (12 mg, p.o., qd, d1-14, q3w) plus benmelstobart (1200 mg, i.v., d1, q3w) until disease recurrence or unacceptable toxicity or up to 18 cycles (~1 year), whichever occurred first. Tumor assessment was performed at the end of the second cycle and every four cycles thereafter, according to RECIST v1.1. The predefined sample size was 37. The primary endpoint was 1-year recurrence-free survival (RFS) rate. Secondary endpoints included RFS, 1-year overall survival (OS) rate, and safety. Results: As the cutoff date of September 13,2024, a total of 38 patients (pts) were enrolled and 35 pts included in per-protocol set analysis. The majority of the 38 pts were male (94.7%, n = 36), and the median age was 56.5 years (range: 33-75). 18 pts (47.3%) had CNLC Stage IIb and 20 (52.6%) had CNLC Stage IIIa HCC. Among them, 35 pts received at least once tumor assessment. According to RECIST 1.1, of the 35 pts, 18 had no recurrence, 15 experienced relapse, 1 dropped out and 1 discontinued due to serious adverse events. The 1-year RFS rate was 59.97% (95%CI: 39.12-79.68) and the primary median RFS was 16.89m(95%CI: 6.82-26.96). The 1-year OS rate was 91.47% (95%CI: 69.23-97.86). 34 of 38 pts (89.5%) experienced treatment-related adverse events (TRAEs). The most common grade 3 TRAEs occurred in 17 pts (44.7%) including hypertension (32%) and neutropenia(5.3%). No grade 4 or 5 TRAEs were observed. Conclusions: The present study indicated that anlotinib plus benmelstobart as adjuvant treatment for HCC with high risk of recurrence after radical resection exhibited promising efficacy and tolerable safety profile. The conclusion should be validated in more participants included subsequently. Clinical trial information: NCT05111366 .

Real-world experience with atezolizumab plus bevacizumab (A+/-B) in Hispanic patients with advanced hepatocellular carcinoma (HCC) at a Hispanic-majority cancer center.

549 Background: Combination of atezolizumab (A), a programmed death-ligand 1 (PD-L1) inhibitor, and bevacizumab (B), a vascular endothelial growth factor (VEGF) inhibitor, has demonstrated efficacy for first-line treatment for HCC. However, real-world data on the outcomes of this combination therapy in diverse patient populations, particularly in Hispanic U.S. patients, remains limited. This study aims to evaluate the clinical outcomes of patients intended to treat with A+/-B at a Hispanic-majority U.S. cancer center. Methods: This retrospective study of patients diagnosed with advanced unresectable HCC who received treatment with A+B at a Hispanic-serving NCI-designated cancer center. Patients were included if they received at least one dose of A, either as monotherapy or in combination with B, between January 2019 and April 2022. Demographic and clinical data, including age, gender, ethnicity, liver disease etiology, Child-Pugh (CP) classification, comorbidities, and treatment details, were collected. The primary endpoints were the overall response rate (ORR) and complete response (CR) rate. Statistical analyses were conducted to evaluate the association between baseline characteristics and clinical outcomes. The median overall survival (mOS) evaluated by Kaplan-Meier Method. Results: 38 patients received at least A (84% A+B, 6 patients had B held due to bleeding risk after consent). Median age 65 years (45-90). 32 (84%) patients were male. 22 (58%) patients were Hispanic. 45% had HCV-related liver disease. 32% had CP B with no statistically significant association between CP Class and ethnicity. 53% had concurrent diabetes. 26% patients had obesity. The median time on treatment was 7.5 mo (1- 24 mo) with no statistical difference between Hispanics and non-Hispanics (9 vs 6 mo, p 0.70). CR 37% with ORR of 42%. Using Fisher’s exact test, no association was noted between obesity, ethnicity, treatment option or CP class to occurrence of complete or partial response. mOS was 19 mo. There was no statistical difference in mOS between CP A and CP B (19 vs 10 mo, p value 0.6) and no difference between Hispanics (14 mo) vs non-Hispanics (19 mo) (p 0.5), using log rank test. Conclusions: This real-world analysis of a Hispanic-majority U.S. cohort of patients with advanced HCC shows 42% ORR and 37% CR. The findings suggest that this regimen is effective across a diverse patient population, including those with comorbid conditions, such as liver dysfunction (CP B 32%), HCV (45%), diabetes (53%, and obesity (26%). Limitations are the small study population and retrospective nature of the study. Evaluation of toxicity data is ongoing. Further prospective studies are needed to identify biomarkers of outcomes in Hispanic patients with HCC, which is ongoing at our cancer center (NCT03894917).

First-line (1L) tislelizumab (TIS) plus chemotherapy (CT) vs placebo (PBO) plus CT in advanced/metastatic esophageal squamous cell carcinoma (ESCC): RATIONALE-306 Japanese subgroup analysis with longer follow-up.

420 Background: In the global phase 3 RATIONALE-306 study (NCT03783442), TIS + CT showed a significant overall survival (OS) benefit vs PBO + CT as 1L therapy for advanced/metastatic ESCC. After a minimum 3-year follow-up, the hazard ratio (HR) for OS was 0.70 for all randomized patients (pts) and for pts with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥10%.We report results for the Japanese subgroup. Methods: Eligible pts enrolled in Japan were randomized (1:1) to receive intravenous TIS 200 mg or PBO every 3 weeks + investigator-chosen CT (platinum + fluoropyrimidine/paclitaxel) until disease progression or intolerable toxicity. The primary endpoint was OS in the intent-to-treat (ITT) population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and OS in pts with PD-L1 TAP score ≥10%. Results: Of 649 randomized pts, 66 (10.2%) were Japanese, median age was 67 years, 89.4% were male, and 28.8% had PD-L1 TAP score ≥10%. At study entry, Eastern Cooperative Oncology Group performance status was 0 for 77.3% pts and 97.0% had metastatic disease. As of Nov 24, 2023, 78.8% vs 84.8% Japanese pts on TIS + CT vs PBO + CT received post-systemic therapy (ITT: 51.5% vs 57.9%). After a minimum follow-up of 37.9 months, TIS + CT showed improvements vs PBO + CT in median OS (24.5 vs 15.1 months [mo]; HR: 0.75) in all pts and in pts with PD-L1 TAP score ≥10% (HR: 0.79), median PFS (HR: 0.77) and ORR (63.6% vs 45.5%) (Table). Treatment-related adverse events (TRAEs) with TIS + CT vs PBO + CT in Japanese pts were 45.5% vs 36.4% for any grade (ITT: 69.8% vs 60.7%); 27.3% vs 6.1% for grade ≥3 (ITT: 32.1% vs 20.2%); 24.2% vs 3.0% for serious TRAEs (ITT: 19.8% vs 8.4%); TRAEs led to treatment discontinuation in 3.0% vs 6.1% (ITT: 13.3% vs 6.5%). No TRAEs leading to death were reported in Japanese pts (ITT: 1.5% vs 0.6%). Conclusions: After 3 years, TIS + CT continued to demonstrate robust efficacy and a tolerable safety profile in Japanese pts as 1L therapy for advanced/metastatic ESCC in the RATIONALE-306 study, consistent with the overall population. Clinical trial information: NCT03783442 . Efficacy outcomes. JapanTIS + CT(n=33) JapanPBO + CT(n=33) OverallTIS + CT(n=326) OverallPBO + CT(n=323) Median OS, mo (95% CI) 24.5 (17.6, 26.9) 15.1 (8.0, 22.5) 17.2 (15.8, 20.1) 10.6 (9.3, 12.1) HR (95% CI) 0.75 (0.43, 1.30) - 0.70 (0.59, 0.83) b - PD-L1 TAP score ≥10%, n (%) 12 (36.4) 7 (21.2) 116 (35.6) 107 (33.1) Median OS by PD-L1 TAP score ≥10%, mo (95% CI) 25.5(10.9, NE) 16.8(0.9, NE) 16.6(15.3, 23.4) 10.0(8.6, 13.3) HR (95% CI) 0.79 (0.26, 2.36) - 0.70 (0.52, 0.95) b - Median PFS a , mo (95% CI) 6.8 (4.4, 8.5) 4.5 (4.1, 6.7) 7.3 (6.9, 8.3) 5.6 (4.9, 6.0) HR (95% CI) 0.77 (0.45, 1.32) - 0.60 (0.50, 0.72) b - ORR a , n (%) 21 (63.6) 15 (45.5) 207 (63.5) 137 (42.4) a Investigator assessed. b Stratified. CI, confidence interval; NE, not estimable.

Updated results from the trastuzumab deruxtecan (T-DXd) 5.4 mg/kg triplet combination of DESTINY-Gastric03 (DG-03): First-line (1L) T-DXd with fluoropyrimidine (FP) and pembrolizumab in advanced/metastatic HER2-positive (HER2+) esophageal adenocarcinoma, gastric cancer (GC), or gastroesophageal junction adenocarcinoma (GEJA).

448 Background: T-DXd is a HER2-directed antibody-drug conjugate; T-DXd 6.4 mg/kg monotherapy is approved for patients with metastatic HER2+ GC/GEJA who have received a prior trastuzumab-based regimen. Preliminary results from DG-03 Part 2 showed feasibility and promising antitumor activity with 1L T-DXd 6.4 mg/kg (arm D) or 5.4 mg/kg (arm F) with FP and pembrolizumab in patients with esophageal adenocarcinoma/GC/GEJA. T-DXd 6.4 mg/kg and FP with pembrolizumab was associated with higher than expected toxicity; alternatively, early safety data from T-DXd 5.4 mg/kg triplet combination showed a manageable safety profile. We report updated results for arm F from DG-03 Part 2 with an approximate time-matched analysis with arm D. Methods: DG-03 (NCT04379596) is a Phase 1b/2 multicenter, open-label, dose-escalation (Part 1) and -expansion (Parts 2, 3, and 4) study. In Part 2, patients with HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization–positive by local testing) esophageal adenocarcinoma/GC/GEJA, irrespective of programmed cell death ligand 1 status, and no prior treatment for metastatic disease were enrolled. In arm D, patients received T-DXd 6.4 mg/kg intravenous (IV) infusion every 3 weeks (Q3W) and FP (5-fluorouracil [5-FU] 600 mg/m 2 continuous IV or capecitabine [cape] 1000 mg/m 2 twice daily [BID]) with pembrolizumab 200 mg IV Q3W; in arm F, patients received T-DXd 5.4 mg/kg IV Q3W and FP (5-FU 600 mg/m 2 continuous IV or cape 750 mg/m 2 BID) with pembrolizumab 200 mg IV Q3W.Primary endpoint was confirmed objective response rate by investigator assessment (INV) per RECIST 1.1. Secondary endpoints included duration of response by INV and progression-free survival by INV. Safety and tolerability were also assessed. Results: A time matched analysis was performed to compare the efficacy of arm D (n=43), data cut-off (DCO) October 27, 2022, and arm F (n=32), DCO May 6, 2024, given the limited follow up of the 5.4mg/kg. The median duration of follow up for the two cohorts was 4.1 months and 4.6 months for arm D and arm F, respectively. Objective response rate for arm D was 41.9% and 59.4% for arm F. Median PFS was 6.4 months (95% CI: 5.0, NC) for arm D and 5.8 months (95% CI: 5.6, NE) for arm F. At DCO, the median overall survival in both arms was not reached. Updated time matched safety and efficacy data will be provided at the time of presentation. Conclusion: The time matched analysis shows that lowering the dose of T-DXd to 5.4 mg/kg from 6.4 mg/kg and lowering the starting dose of capecitabine, did not result in decrease in efficacy of the combination of T-DXd + FP + pembrolizumab. Funding: This study is sponsored by AstraZeneca in collaboration with Daiichi Sankyo. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201). Editorial acknowledgment: Under guidance of the authors and in accordance with Good Publication Practice, medical writing and editorial support was provided by Carmen Grimaldos, PhD, of Helios Medical Communications, part of Helios Global Group, and was funded by AstraZeneca. Clinical trial information: NCT04379596 .