Metastatic Esophageal Squamous Cell Carcinoma Research Articles

Cost-effectiveness analysis of tislelizumab vs. camrelizumab for the treatment of second-line locally advanced or metastatic esophageal squamous cell carcinoma

BackgroundEsophageal carcinoma is a type of cancer that occurs in the esophagus. For patients with locally advanced or metastatic esophageal squamous cell carcinoma who have either experienced disease progression following first-line standard chemotherapy or are intolerant to it, the prognosis is typically poor. Additionally, these patients often bear a substantial economic burden during the course of their treatment. Tislelizumab is a selective PD-1 inhibitor with efficacy proven in locally advanced or metastatic esophageal squamous cell carcinoma. The study aims to evaluate the cost-effectiveness of tislelizumab versus camrelizumab as the second-line treatment in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) patients in China.MethodsFrom the perspective of China’s healthcare system, the partitioned survival model with three health states was established in a 3-week cycle and a lifetime horizon. Anchored matching adjusted indirect comparison was used for survival analyses based on individual patient data from RATIONALE 302 trial and the published ESCORT study due to the lack of head-to-head clinical trials. Only direct medical costs were included. Costs and utility values were derived from local charges, the published literature, and related databases. Sensitivity analyses and a scenario analysis were also performed to verify the robustness of the model results.ResultsCompared with camrelizumab monotherapy, tislelizumab monotherapy incurred a lower lifetime cost ($8,346 vs. $8,851) and yielded higher quality-adjusted life-years (QALYs) (0.87 vs. 0.63), which resulted in an incremental cost-effectiveness ratio (ICER) of -$2,051/QALY. Tislelizumab monotherapy is a dominant option over camrelizumab monotherapy in China. The three primary parameters upon which this result was most sensitive were the unit cost of camrelizumab, the unit cost of tislelizumab, and the duration of reactive cutaneous capillary endothelial proliferation (RCCEP). According to the probabilistic sensitivity analysis (PSA), tislelizumab monotherapy was 100% cost-effective when the WTP was 1–3 times GDP per capita in China($11,207/QALY∼$33,621/QALY). Scenario analysis showed that the result was consistent.ConclusionTislelizumab monotherapy is a dominant option compared with camrelizumab monotherapy as the second-line treatment for locally advanced or metastatic ESCC in China.

Cost-effectiveness analysis of tislelizumab plus chemotherapy as the first-line treatment for advanced or metastatic esophageal squamous cell carcinoma in China

IntroductionFirst-line treatment with tislelizumab plus chemotherapy has shown clinical benefits for patients with advanced or metastatic esophageal squamous cell carcinoma (OSCC) in China, while its economic burden is unknown. This study aimed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy from the perspective of the Chinese healthcare system.MethodsWe constructed a partitioned survival model to compare the cost-effectiveness of tislelizumab plus chemotherapy with chemotherapy in patients with advanced OSCC. Patient characteristics and clinical outcomes were extracted from RATIONALE-306. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were selected as the study outcomes. Sensitivity analysis and subgroup analysis were conducted to test the stability of the results.ResultsTislelizumab plus chemotherapy provided additional 0.48 QALYs with the incremental cost of $16,587.2 than chemotherapy, of which ICER was $34,699.72 per QALY. When the willingness-to-pay threshold was set as $37,260, the novel therapy had a probability of 77% to be cost-effective. Our base-case analysis results were sensitive to utilities of progression-free survival and progression of disease. Our subgroup analysis showed that the novel therapy was associated with cost-effectiveness in patients with a high expression of PD-L1.ConclusionTislelizumab plus chemotherapy was likely to be more cost-effective compared with chemotherapy in the first-line therapy of advanced OSCC from the perspective of the Chinese healthcare system. Our findings can provide clinicians and decision-makers with evidence of the cost-effectiveness of tislelizumab.

Cost-effectiveness analysis of tislelizumab plus chemotherapy as the first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma in China.

We aimed to investigate the cost-effectiveness of tislelizumab plus chemotherapy compared to chemotherapy alone as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (OSCC). A partitioned survival model was developed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy versus chemotherapy alone in patients with advanced or metastatic OSCC over a 10-year lifetime horizon from the perspective of the Chinese healthcare system. Costs and utilities were derived from the drug procurement platform and published literature. The model outcomes comprised of costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were conducted to address uncertainty and ensure the robustness of the model. Tislelizumab plus chemotherapy yielded an additional 0.337 QALYs and incremental costs of $7,117.007 compared with placebo plus chemotherapy, generating an ICER of $21,116.75 per QALY, which was between 1 time ($12,674.89/QALY) and 3 times GDP ($38,024.67/QALY) per capita. In one-way sensitivity analysis, the ICER is most affected by the cost of oxaliplatin, paclitaxel and tislelizumab. In the probabilistic sensitivity analysis, when the willingness-to-pay threshold was set as 1 or 3 times GDP per capita, the probability of tislelizumab plus chemotherapy being cost-effective was 1% and 100%, respectively. Tislelizumab plus chemotherapy was probably cost-effective compared with chemotherapy alone as the first-line treatment for advanced or metastatic OSCC in China.

LEAP-014: first-line lenvatinib+ pembrolizumab+chemotherapy in advanced/metastatic esophageal squamous cell carcinoma.

Treatment options for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) are improving. Current guidelines recommend first-line pembrolizumab plus chemotherapy for patients with unresectable or metastatic ESCC, which has led to improvements in survival outcomes. Antiangiogenic therapy combined with immune checkpoint inhibitors can act synergistically to convert the immunosuppressive tumor microenvironment to an immune supportive microenvironment, thus enhancing antitumor immune responses. In preclinical models, the antiangiogenic agent lenvatinib combined with an anti-PD-1 agent showed synergistic antitumor activity. We describe the design and rationale for the randomized, open-label, phase III LEAP-014 study of lenvatinib in combination with pembrolizumab plus chemotherapy in patients with advanced or metastatic ESCC. Overall survival and progression-free survival are the dual primary end points. Clinical Trial Registration: NCT04949256 (ClinicalTrials.gov).

Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial.

First-line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab-containing regimens in many countries. We report longer-term follow-up data. This open-label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression-free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD-L1) expression of ≥1% and then in the overall population. A total of 970 patients were randomly assigned. After 29 months of minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46-0.76]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65-0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48-0.80]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65-0.92]). In patients with tumor cell PD-L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51-0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79-1.36]). Among all treated patients (n = 936), Grade 3-4 treatment-related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients. Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow-up, further supporting use as first-line standard treatment options for patients with advanced ESCC.

Clinical features and treatment outcomes of PD-1 inhibitor therapy in elderly patients (≥ 65years) with advanced esophageal squamous cell carcinoma: a real-world study.

This study aims to determine the clinical features and outcomes of PD-1 inhibitor therapy as the initial treatment in patients aged 65years or older with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). The retrospective study conducted a comprehensive analysis of elder patients diagnosed with locally advanced or metastatic ESCC who underwent combined immunochemotherapy in the first affiliated hospital of Nanchang University from January 2019 to January 2023. The main efficacy measures were the objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR) and overall survival (OS). The evaluation of safety was based on the assessment of adverse events (AEs). A total of 88 patients were enrolled in the study. All patients received PD-1 inhibitors combined with chemotherapy including taxane and platinum as the first-line treatment. The median PFS was 6.2months (95% CI: 5.1-7.3), and the median OS was 15.3months (95% CI: 12.9-17.7). The ORR and DCR were 42.0% and 72.7%, correspondingly. 68 (77.3%) patients experienced treatment-related adverse events (TRAEs) of various degrees, with neutrophil count decreased (21, 23.9%) being the most frequent. TRAEs of grade 3 or 4 occurred in 13 (14.8%) patients. The study demonstrated that individuals older than 65years with locally advanced or metastatic ESCC have a survival benefit from the first-line treatment of PD-1 inhibitors combined therapy, with a manageable safety profile.

Abstract CT274: BGB-A317-LBL-007-202: A phase 2, randomized, active-controlled, open-label study to evaluate the efficacy and safety of LBL-007 (anti-LAG-3) in combination with tislelizumab (TIS; anti-PD-1) plus chemotherapy (chemo) as first-line (1L) treatment in patients with unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC)

Abstract Background: ESCC is the predominant histological subtype of esophageal cancer, accounting for 85% of cases. Patients (pts) with locally advanced/metastatic ESCC have poor clinical outcomes, with a 5-year survival rate of 6.1% for pts with distant metastases. 1L treatment with programmed cell death protein-1 (PD-1) inhibitors + platinum-based chemo has become the new standard of care for metastatic ESCC, however, there is an unmet need for enhanced treatment efficacy and a prolonged life span. LBL-007 is a monoclonal antibody (mAb) against lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor that negatively regulates T-cell activity. TIS is an anti-PD-1 mAb that blocks the PD-1/programmed death-ligand 1 (PD-L1) immune checkpoint, resulting in T-cell activation. This study (NCT06010303) aims to evaluate the efficacy and safety of LBL-007 + TIS + chemo as a 1L treatment in pts with unresectable, locally advanced/metastatic ESCC. Methods: This phase 2 study will enroll approximately 116 pts with a pathologically confirmed diagnosis of unresectable, locally advanced/metastatic ESCC and no prior systemic therapy. Pts will be randomized 2:1 to either Arm A (LBL-007 600 mg intravenously [IV] every 3 weeks [Q3W] + TIS 200 mg IV Q3W + chemo doublet) or Arm B (TIS 200 mg IV Q3W + chemo doublet), stratified by PD-L1 expression (tumor area positivity score ≥10% or <10%). The chemo doublet will consist of either cisplatin (60-80 mg/m2 IV Q3W) + 5-fluorouracil (750-800 mg/m2 IV daily on Days 1-5 Q3W), or cisplatin + paclitaxel (175 mg/m2 IV Q3W), determined by the investigator before randomization. Treatments will be administered until disease progression, intolerable toxicity, or withdrawal for other reasons. The primary endpoint is the overall response rate, as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints include progression-free survival, duration of response, and disease control rate (all by investigator per RECIST v1.1), and the incidence and severity of adverse events per National Cancer Institute-Common Terminology Criteria for Adverse Events v5.0. A safety monitoring committee is monitoring the safety of LBL-007 + TIS + chemo vs TIS + chemo. Exploratory endpoints include comparison of overall survival, assessment of predictive, prognostic, and pharmacodynamic biomarkers, pharmacokinetic evaluation of LBL-007 and TIS, and immunogenicity. The study is currently recruiting at approximately 46 sites across Asia, including Taiwan, mainland China, South Korea, and Thailand. Citation Format: Sook Ryun Park, Ming-Huang Chen, Arunee Dechaphunkul, Ningning Ding, Xiao Lin, Jinghui Zhang, Vivian Li, Qiao Li, Yi Ba. BGB-A317-LBL-007-202: A phase 2, randomized, active-controlled, open-label study to evaluate the efficacy and safety of LBL-007 (anti-LAG-3) in combination with tislelizumab (TIS; anti-PD-1) plus chemotherapy (chemo) as first-line (1L) treatment in patients with unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT274.

Abstract 6118: Sex-related disparity in immune checkpoint inhibitor benefit for patients with esophageal squamous cell carcinoma: A systematic review and meta-analysis

Abstract Sex-related dimorphism in cancer incidence and immune response is widely recognized, yet the impact of an individual's sex on the effectiveness of Immune Checkpoint Inhibitors (ICIs) for patients with advanced esophageal squamous cell carcinoma (ESCC) remains poorly understood. In this study, we conducted a comprehensive meta-analysis to evaluate the heterogeneity of ICIs in patients with advanced ESCC. We collected studies from PubMed, MEDLINE, Embase, and Scopus, spanning from the inception of the databases to September 30, 2023. These studies focused on phase III randomized trials comparing first-line ICIs (PD-1/PD-L1) plus chemotherapy with chemotherapy alone for advanced or metastatic ESCC. Additionally, we reviewed abstracts and presentations from AACR, ASCO, ESMO, and WCLC. Inclusion criteria mandated the reporting of overall survival (OS) data stratified by sex and nonselective baseline PD-L1 expression. The study adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The analysis included 6 randomized clinical trials comprising 3603 ESCC patients, of whom 3090 (85.8%) were male and 513 (14.2%) were female. A significant OS benefit was observed for ICIs plus chemotherapy in all patients (HR, 0.68; 95% CI, 0.62-0.74; P < 0.001). Similarly, ICIs plus chemotherapy correlated with a significantly prolonged OS in males (HR, 0.67; 95% CI, 0.61-0.74, P < 0.001). However, there was no significant OS benefit observed in females with ICIs plus chemotherapy (HR, 0.79; 95% CI, 0.58-1.09; P = 0.148). Females had a tendency toward less benefit than males (pooled HR, 1.18; 95% CI, 0.89-1.57; P = 0.245). Our findings suggest that there is no statistically significant association between patient sex and the efficacy of ICIs for ESCC patients. Importantly, we report, for the first time, a lack of survival benefit with the ICI plus chemotherapy regimen in the first-line setting compared to chemotherapy alone in female ESCC patients. Citation Format: Chaoqi Zhang, Peng Wu, Jingjing Liu, Dongyu Li, Nan Sun, Jie He. Sex-related disparity in immune checkpoint inhibitor benefit for patients with esophageal squamous cell carcinoma: A systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6118.

Molecular characteristics and multivariate survival analysis of 43 patients with locally advanced or metastatic esophageal squamous cell carcinoma.

Esophageal cancer (EC) is an aggressive malignant tumor with poor prognosis and high incidence. It is the sixth leading cause of cancer-related death in the world, and the 5-year overall survival (OS) rate is only 12-20%. The rapid development of next-generation sequencing (NGS) has provided powerful help for the treatment and management of EC patients. Tumor tissue and blood samples of 43 Chinese patients with nonsurgical esophageal squamous cell carcinoma (ESCC) were sequenced using a 425 gene-panel. Genomic profiling was explored and and the Cox proportional hazards model was used to analyze the correlations between gene or signaling pathway alterations and prognosis. In this study, the most common mutated genes were TP53 (90.5%), CCND1 (45.2%), FGF19 (38.1%), NOTCH1 (26.2%), PI3KCA (21.4%) and CDKN2A (19%). Among these mutations, PI3KCA and NOTCH1 showed mutual exclusion to some extent. In the univariate model, mutations in NOTCH1, CBLB and TSC2 genes and tumor mutation burden (TMB) ≥7 were independent biomarkers of OS. NOTCH1 (P=0.007, HR =2.87), CBLB (P=0.011, HR =4.68) and TSC2 (P=0.024, HR =3.7) were significantly associated with poorer OS, and patients with TMB ≥7 had longer OS (P=0.151, HR =0.31). In addition, patients who carried alteration in NOTCH signaling pathway had reduced OS (P=0.014, HR =2.54). NOTCH1, CBLB and TSC2 alterations were found to be potential indicators of poor prognosis in patients with ESCC. TMB was also positively correlated with the OS of ESCC patients, providing valuable insights for their treatment strategies.

Cost-effectiveness analysis of PD-1 inhibitors as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma in China: an economic evaluation based on network meta-analysis.

Several economic studies have assessed the cost-effectiveness of programmed cell death protein-1 (PD-1) inhibitors compared to second-line chemotherapy in treating esophageal squamous cell carcinoma (ESCC). However, there is a lack of economic comparisons among the different PD-1 inhibitors. This study aimed to assess the cost-effectiveness of PD-1 inhibitors (nivolumab, pembrolizumab, camrelizumab, and tislelizumab) in second-line treatment for advanced or metastatic ESCC within the Chinese healthcare system. The clinical trials were systematically retrieved from PubMed, Embase, Web of Science, and the Cochrane Library. We established a fractional polynomials model to conduct a network meta-analysis, enabling the calculation of hazard ratios and expected survival rates. Economic outcomes were estimated using a partitioned survival model. The costs and utilities were gathered from published sources. The threshold for willingness-to-pay (WTP) for a quality-adjusted life year (QALY) was set at three times China's per capita gross domestic product in 2022. Sensitivity analyses(SA) were performed to address uncertainties in the model. Four phase III randomized controlled trials were included, evaluating the cost-effectiveness of four PD-1 inhibitors, camrelizumab, nivolumab, tislelizumab, and pembrolizumab, compared to chemotherapy for the second-line treatment of advanced or metastatic ESCC. For camrelizumab, nivolumab, tislelizumab, and pembrolizumab, the corresponding incremental cost-effectiveness ratios were $27,375.43/QALY, $205,312.19/QALY, $9,266.73/QALY, and $220,368.10/QALY, respectively. The SA results indicated the robustness of the base analysis findings. From the Chinese healthcare system, under the WTP of $38,253.48/QALY, tislelizumab is a cost-effective treatment option for the second-line treatment of advanced or metastatic ESCC.

Circulating tumor DNA serial monitoring of relapse and responses to tislelizumab immunotherapy as second‑line monotherapy for metastatic esophageal squamous cell carcinoma: A prospective study.

Anti-programmed cell death 1 immuno-monotherapy has become the second-line standard treatment for advanced esophageal squamous cell carcinoma (ESCC) after the failure of first-line chemotherapy. However, new biomarkers are still needed to identify patients at risk of tumor progression and to select patients with advanced ESCC who are likely to benefit from immunotherapy. A total of 12 patients with advanced ESCC treated with tislelizumab were prospectively enrolled and endoscopic biopsy samples were collected. Plasma was obtained prior to and after every 2-3 treatment cycles with tislelizumab and when disease progression occurred. Targeted sequencing of 425 genes from plasma cell-free DNA, DNA from leukocytes and fixed esophageal tumor biopsies was performed. The patients underwent imaging analyses every 6-8 weeks until disease progression. The association between status of circulating tumor DNA (ctDNA) or changes in ctDNA following tislelizumab immunotherapy and response, tumor progression and survival was determined. All patients had evaluable next-generation sequencing results at the time of analysis. The results showed that patients with ESCC with liver metastasis had a significantly shorter median progression-free survival (mPFS: 1.4 vs. 11.7 months; P=0.037). TSC complex subunit 2 [11.7 months vs. not reached (NR); P=0.004] and zinc finger protein 217 (11.7 months vs. NR; P=0.022) gene mutations were the independent and negative prognostic factors for median overall survival (OS), respectively. Of note, ctDNA dynamic changes expressed as ∆ mutant molecules per milliliter of plasma (∆MMPM; MMPM detected at the first monitoring time-point after the first infusion of tislelizumab as baseline MMPM) predicted progression-free survival (PFS) and OS more accurately compared to the ctDNA change of an individual gene. ∆MMPM <20% was an independent predictor of PFS (2.8 vs. 14.6 months; P=0.029), although there was no significant difference for OS (16.7 vs. 17.6 months; P=0.830). In conclusion, changes in ctDNA levels were associated with anti-tumor effects, progression and disease-specific survival. ctDNA sequencing is promising for predicting response and progression after tislelizumab immunotherapy as second-line monotherapy for advanced ESCC [the present study was part of the RATIONALE-302 study (ClinicalTrials.gov identifier no. NCT03430843; 29.01.2018)].

Camrelizumab combined with apatinib for unresectable, metastatic esophageal squamous cell carcinoma: a single-center, single-arm, prospective study.

The prognosis for esophageal cancer (EC), a common malignant tumor, is poor. The new oral small-molecule tyrosine kinase inhibitor apatinib has shown an excellent therapeutic effect on treating EC. Camrelizumab is a humanized programmed death 1 (PD-1) inhibitor with high affinity. Immune checkpoint inhibitors combined with chemotherapy have become the standard first-line treatment for advanced EC. The new combination strategy of anti-angiogenic therapy combined with immunotherapy has great application prospects in the treatment of tumors. We aimed to assess camrelizumab in combination with apatinib as a new combination regimen for advanced or metastatic esophageal squamous cell carcinoma (ESCC). In this study, we recruited patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, with pathologically confirmed unresectable, locally advanced, locally recurrent, or metastatic ESCC. Each patient received an intravenous infusion of camrelizumab 200 mg and oral administration of apatinib 250 mg once a day, every 21 days, as a cycle until disease progression, intolerance, or death. The primary endpoint was the objective response rate (ORR), while the Kaplan-Meier method and LIFETEST procedure were used to estimate survival functions for overall survival (OS) and progression-free survival (PFS). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used to evaluate adverse events. Between December 1, 2019 and July 31, 2022, 35 patients were enrolled, with 29 patients in the efficacy and safety analysis. The ORR was 34.5%, and the disease control rate (DCR) reached 82.8%. Median OS was 13.8 months (95% CI: 11.2-16.2), and the estimated 6-, 9-, and 12-month OS rates were 85.5% (95% CI: 65.7-94.3%), 80.9% (95% CI: 60.3-91.5%), and 67.0% (95% CI: 43.8-82.4%), respectively. Median PFS was 9.5 months (95% CI: 7.0-13.6). The most prominent grade ≥3 adverse events associated with treatments were alanine aminotransferase (ALT) increase (10.3%), hypertension (10.3%), and reactive cutaneous capillary endothelial proliferation (CCEP) (6.9%), and no deaths occurred due to adverse events. Among patients with advanced or metastatic ESCC, camrelizumab combined with apatinib showed a reasonable remission rate and survival benefit with a manageable safety profile.

Phase 2 study of pembrolizumab plus lenvatinib and belzutifan in patients with metastatic esophageal squamous cell carcinoma.

TPS425 Background: Initial signal finding studies demonstrated promising antitumor activity with the anti–PD-1 antibody pembrolizumab in combination with the anti-angiogenic multikinase inhibitor lenvatinib in patients with advanced gastric cancer or head and neck squamous cell carcinoma. Because hypoxia is common in many solid tumors and is known to induce an immunosuppressive tumor microenvironment, targeting hypoxia-inducible factor-2 alpha (HIF-2α) may enhance the activity of immune checkpoint inhibitors. The ongoing phase 2 LITESPARK-016 study (NCT04976634) is evaluating the combination of pembrolizumab plus lenvatinib and the HIF-2α inhibitor belzutifan (MK-6482) in multiple solid tumors. LITESPARK-016 includes 2 esophageal squamous cell carcinoma cohorts: one enrolling patients with immunotherapy-naive and the other enrolling patients with immunotherapy-resistant esophageal squamous cell carcinoma, cohorts F and G, respectively. We report the methodology for these cohorts. Methods: In this phase 2, open-label, multicenter study, eligible patients in the esophageal squamous cell carcinoma cohorts have histologically or cytologically confirmed metastatic disease and have tumors that are either immunotherapy-naive with disease progression on 1 prior line of standard systemic therapy (cohort F) or immunotherapy-resistant with disease progression during or after 1 prior line of treatment that contained an anti–PD-1/PD-L1 therapy (cohort G). Patients must be aged at least 18 years, have measurable disease per RECIST v1.1 (verified by BICR) with no radiographic evidence of major blood vessel encasement or intratumoral cavitation, ECOG PS of 0 to 1, and an archival/new tumor sample for biomarker analysis. Patients in cohort F receive triple therapy with pembrolizumab plus lenvatinib plus belzutifan; patients in cohort G are randomized 1:1 to receive either the same triple therapy or doublet therapy with pembrolizumab plus lenvatinib. The planned starting doses are pembrolizumab 400 mg given intravenously every 6 weeks, lenvatinib 20 mg orally once daily, and belzutifan 120 mg orally once daily. Treatment will continue for up to 2 years (for pembrolizumab) or until PD or discontinuation criteria are met. Approximately 30 patients will be enrolled in cohort F and in each arm of cohort G (approximately 90 total patients), with potential expansion of up to 70 additional patients in cohort F and each treatment arm of cohort G after safety/efficacy review with at least 6 months follow-up. The primary endpoints in cohorts F and G are safety (AEs, treatment discontinuation due to AEs) and ORR per RECIST v1.1 by BICR. Secondary endpoints are duration of response, disease control rate, and PFS per RECIST v1.1 by BICR, and OS. Assessment of biomarkers is an exploratory objective. Enrollment for this study began in September 2022 and is ongoing across 48 global sites. Clinical trial information: NCT04976634 .

Updated pooled analyses of first-line anti-PD1/PD-L1 inhibitors plus chemotherapy in advanced esophageal squamous cell carcinoma.

366 Background: Advanced and metastatic esophageal squamous cell carcinoma (ESCC) patients have limited treatment options and poor prognosis. Recently, several studies demonstrated the clinical benefit of combining immune checkpoint inhibitors (ICI) and chemotherapy (CT), leading to its approval in the first-line setting. Since then, efforts have been made to identify the patients who may benefit the most or not from the combination of ICI plus CT. Methods: We searched PubMed, Scopus, and the Cochrane Library for randomized clinical trials investigating first-line ICI plus chemotherapy (CT) for advanced or metastatic ESCC patients. Outcomes of interest included: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and OS according to gender, PD-L1 expression (&lt;1% / ≥1%), and PD-L1 CPS (&lt;10 / ≥10). We used I2 statistics to assess heterogeneity, and the fixed-effect model was used to pool studies. Results: Eight studies were included with 4,702 patients. Of them, most had an ECOG 0 or 1, and were younger than 65 years (62%), male (77%), and Asian (78%). Metastatic disease was diagnosed in 75% of patients. ICI plus CT was administered to 58%, and 43% received CT +/- placebo. Median follow-up ranged from 7.1 to 22.6 months. ICI plus CT significantly improved all efficacy outcomes compared to CT alone: decreasing the risk of death by 32% (HR for OS: 0.68; 95%CI 0.63-0.74; p&lt;0.00001); reducing the risk of progression or death by 38% (HR for PFS: 0.62; 95%CI 0.58-0.67; p&lt;0.00001); and increasing the objective response rate (risk difference: 0.17; 95%CI 0.14-0.20; p&lt;0.00001). A survival benefit was seen across all subgroup analyses, but it was significantly higher in patients with PD-L1 ≥1% compared to those with PD-L1 &lt;1% (reduction in the risk of death of 38% versus 23% respectively, p=0.03). OS was not significantly different between males versus females, or PD-L1 CPS≥10 versus CPS&lt;10. Conclusions: Our large systematic review and meta-analysis support the efficacy and survival benefit of ICI plus CT as first-line therapy for all ESCC patients, regardless of gender or PD-L1 expression.

Camrelizumab plus apatinib after progression on immune checkpoint inhibitors in patients with advanced esophageal squamous cell carcinoma (CAP 02 Re-challenge): A single-arm multicenter, phase II trial.

364 Background: The optimal therapies for patients with advanced esophageal squamous cell carcinoma (ESCC) who have progressed after immune checkpoint inhibitors (ICIs) are unclear. This phase II single-arm study aimed to assess the efficacy and safety of re-challenge with camrelizumab plus apatinib in this population. Methods: This study enrolled patients with unresectable locally advanced, locally recurrent, or metastatic ESCC who had experienced prior progression on ICI treatment. Enrolled patients received camrelizumab 200 mg intravenously every two weeks along with daily oral apatinib 250 mg. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal of consent. The primary endpoint was the confirmed objective response rate (ORR). Secondary endpoints included disease control rate (DCR), duration of response (DOR), time to response (TOR), progression-free survival (PFS), overall survival (OS), 3- and 6-month PFS rates, 6-, 9- and 12-month OS rates, and safety. Results: From September 1, 2021, to March 29, 2023, 49 eligible patients were enrolled and given treatment. Among 38 treated patients who had at least one post-baseline efficacy measurement, the ORR and confirmed ORR were 36.8% (95% CI 21.8–54.0) and 13.2% (95% CI 4.4–28.1); the DCR was 89.5% (95% CI 75.2–97.1); the median DOR was 3.0 months; and the median TOR was 2.2 months. Among the 49 treated patients, the median PFS was 4.6 months (95% CI 3.8–6.5) and OS was 7.5 months (95% CI 5.5–13.6). Patients who were both PD-L1 positive and had responded to previous ICI therapy had the longest median PFS (5.7 months, 95% CI 3.9–not reached) and OS (9.6 months, 95% CI 7.5–not reached). Grade ≥ 3 treatment-related adverse events occurred in 34.7% of patients (17/49). Conclusions: This study showed promising efficacy and an acceptable safety profile of camrelizumab plus apatinib for patients with advanced ESCC who had progressed after ICI therapy. The subset of patients who were both PD-L1 positive and had a prior ICI response seemed to benefit most. Clinical trial information: NCT03736863 .

SKYSCRAPER-08: A phase III, randomized, double-blind, placebo-controlled study of first-line (1L) tiragolumab (tira) + atezolizumab (atezo) and chemotherapy (CT) in patients (pts) with esophageal squamous cell carcinoma (ESCC).

245 Background: Inhibition of TIGIT, a novel checkpoint inhibitor, may further amplify immune responses by complementing the PD-L1/PD-1 pathway. Anti-tumor activity has been demonstrated with cancer immunotherapy in ESCC. SKYSCRAPER-08 (NCT04540211) is evaluating the efficacy and safety of tira (anti-TIGIT) + atezo (anti-PD-L1) in combination with CT compared with placebo + CT as 1L treatment (tx) in an Asian population with unresectable locally advanced (LA), unresectable recurrent, or metastatic (R/M) ESCC. Methods: Eligible pts (confirmed LA or R/M ESCC; ECOG PS 0–1; no prior systemic tx) were randomized 1:1 to receive tira 600mg + atezo 1200mg + CT (paclitaxel 175mg/m2 + cisplatin 60–80mg/m2, local standard of care) or placebo + CT on Day 1 of each 21-day cycle (cycles 1–6); followed by tira + atezo or placebo maintenance until loss of clinical benefit/unacceptable toxicity. Primary endpoints: independent review facility (IRF)-assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints: investigator (INV)-assessed PFS, objective response rate (ORR), duration of response (DoR), and safety. Results: Overall, 461 pts were randomized (tira + atezo + CT, n= 229; placebo + CT, n=232). Pt characteristics were generally balanced between arms. As of 15 June 2022 (minimum survival follow-up 6.5 months [mo]; PFS primary analysis), median IRF-assessed PFS was 6.2 mo for tira + atezo + CT vs 5.4 mo for placebo + CT (HR 0.56; 95% CI: 0.45, 0.70; P&lt;0.0001). As of 13 Feb 2023 (minimum survival follow-up 14.5 mo; OS final analysis), median OS was 15.7 mo for tira + atezo + CT vs 11.1 mo for placebo + CT (HR: 0.70; 95% CI: 0.55, 0.88; P= 0.0024). INV-assessed PFS, IRF-assessed ORR and DoR are presented in Table. Treatment-related adverse events (TRAEs) occurred in 98.2% of pts (both arms); Grade 3/4 TRAEs in 59.6% (tira + atezo + CT) and 56.4% (placebo + CT) of pts; Grade 5 TRAEs in 2.6% (tira + atezo + CT) and 0.9% (placebo + CT) of pts. Conclusions: The study met both primary endpoints of IRF-assessed PFS and OS, demonstrating statistically significant and clinically meaningful improvements in PFS and OS for tira + atezo + CT over placebo + CT. Generally consistent benefit was observed across subgroups, including PD-L1 status. The safety profile was consistent with the known risks of the individual tx. Clinical trial information: NCT04540211 . [Table: see text]

Second-line tislelizumab versus chemotherapy in Japanese patients with advanced or metastatic esophageal squamous cell carcinoma: subgroup analysis from RATIONALE-302.

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, with limited second-line systemic therapy options, and represents an increasing disease burden in Japan. In the phase 3 RATIONALE-302 study, the anti-programmed cell death protein 1 antibody, tislelizumab, significantly improved overall survival (OS) versus chemotherapy as second-line treatment for advanced/metastatic ESCC. Here, we report the Japanese patient subgroup results. Patients with advanced/metastatic ESCC, with disease progression during/after first-line systemic therapy were randomized 1:1 to open-label tislelizumab 200mg every 3weeks or investigator's choice of chemotherapy (paclitaxel/docetaxel). Efficacy and safety were assessed in all randomized Japanese patients. The Japanese subgroup comprised 50 patients (n = 25 per arm). Tislelizumab improved OS versus chemotherapy (median: 9.8 vs. 7.6months; HR 0.59; 95% CI 0.31, 1.12). Among patients with programmed death-ligand 1 score ≥ 10%, median OS was 12.5months with tislelizumab (n = 10) versus 2.9months with chemotherapy (n = 6) (HR 0.31; 95% CI 0.09, 1.03). Tislelizumab improved progression-free survival versus chemotherapy (median: 3.6 vs. 1.7months, respectively; HR 0.50; 95% CI 0.27, 0.95). Objective response rate was greater with tislelizumab (32.0%) versus chemotherapy (20.0%), and responses were more durable (median duration of response: 8.8 vs. 2.6months, respectively). Fewer patients experienced ≥ grade 3 treatment-related adverse events with tislelizumab (24.0%) versus chemotherapy (47.8%). Tislelizumab demonstrated an improvement in health-related quality of life versus chemotherapy. As second-line therapy for advanced/metastatic ESCC, tislelizumab improved OS versus chemotherapy, with a favorable safety profile, in the Japanese patient subgroup, consistent with the overall population. ClinicalTrials.gov: NCT03430843.

Immune checkpoint inhibitors versus chemotherapy as second-line therapy for advanced oesophageal squamous cell carcinoma: a systematic review and economic evaluation.

Recently, several novel programmed cell death protein 1 (PD-1) inhibitors have been approved for second-line treating advanced or metastatic oesophageal squamous cell carcinoma (OSCC), including camrelizumab, nivolumab, pembrolizumab, sintilimab and tislelizumab. However, the optimal treatment regimen remained ambiguous. The purpose of this study was to investigate the efficacy, safety and economy of available PD-1 inhibitors to determine the optimal treatment from the Chinese healthcare system perspective. A systematic review and economic evaluation. A systematic review was undertaken utilizing PubMed, Web of Science, Cochrane Library, Embase and Scopus databases to identify eligible studies until 31 August 2023. Primary outcomes were progression-free survival (PFS), overall survival (OS) and adverse events (AEs). We also developed a partitioned survival model at 3-week intervals based on five clinical trials to predict long-term costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios for various treatment options. Direct medical costs and utility values were obtained from public drug bidding databases, clinical trials or published literature. The parameter uncertainties within the model were determined via one-way and probabilistic sensitivity analyses. Five randomized controlled trials involving 2837 patients were included in the analysis. Compared with other treatments examined, camrelizumab provided the best PFS benefits [hazard ratio (HR): 0.69, 95% confidence interval (CI): 0.56-0.86], and pembrolizumab provided the best OS benefits (HR: 0.55, 95% CI: 0.37-0.82). Nivolumab caused a relatively lower incidence of treatment-related AEs (HR: 0.10, 95% CI: 0.05-0.20) and grade 3-5 AEs (HR: 0.13, 95% CI: 0.08-0.21) than other immunotherapy regimens. In the economic evaluation, average 10-year costs ranged from $5,433.86 (chemotherapy) to $50,617.95 (nivolumab) and mean QALYs ranged from 0.55 (chemotherapy) to 0.82 (camrelizumab). Pembrolizumab was eliminated because of dominance. Of the remaining strategies, when the willingness-to-pay thresholds were 1, 2 and 3 times GDP per capita in 2022, sintilimab, tislelizumab and camrelizumab were the most cost-effective treatment options, respectively. Sintilimab might be the optimal treatment alternative for second-line therapy of advanced OSCC in China, followed by tislelizumab and camrelizumab. This study has been registered on the PROSPERO database with the registration number CRD42023495204.

USP10 promotes migration and cisplatin resistance in esophageal squamous cell carcinoma cells.

Cisplatin-based chemotherapy is the main treatment option for advanced or metastatic esophageal squamous cell carcinoma (ESCC). However, most ESCC patients develop drug resistance within 2years after receiving cisplatin chemotherapy. Ubiquitin-specific protease 10 (USP10) is abnormally expressed in a variety of cancers, but the mechanistic roles of USP10 in ESCC are still obscure. Here, the effects of USP10 on the migration and cisplatin resistance of ESCC in vivo and in vitro and the underlying mechanisms have been investigated by bioinformatics analysis, RT-PCR, western blotting, immunoprecipitation, immunohistochemistry, cell migration and MTS cell proliferation assays, deubiquitination assay, and mouse tail vein injection model. USP10 was significantly up-regulated in ESCC tissues compared with adjacent normal tissues in both public databases and clinical samples and was closely associated with overall survival. Subsequent results revealed that USP10 contributed to the migration and cisplatin resistance of ESCC cells, while knocking down USP10 in cisplatin-resistant cells exhibited opposite effects in vitro and in vivo. Further Co-IP experiments showed that integrin β1 and YAP might be targets for USP10 deubiquitination. Moreover, deficiency of USP10 significantly inhibited the migrative and chemo-resistant abilities of ESCC cells, which could be majorly reversed by integrin β1 or YAP reconstitution. Altogether,USP10 was required for migration and cisplatin resistance in ESCC through deubiquinating and stabilizing integrin β1/YAP, highlighting that inhibition of USP10 may be a potential therapeutic strategy for ESCC.

Nivolumab in unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma.

Esophageal cancer (EC) is the eighth most common cancer worldwide. In view ofbiology and anatomical restrictions, multimodality treatment strategies have been developed for EC. However, the prognosis of patients with advanced EC remains especially poor. Immunotherapy, such as PD-1/PD-L1 and CTLA-4/B7 blockade, has emerged as a potent treatment for many types of cancer and has been approved in many countries. Based on the results of the ATTRACTION-3 trial, nivolumab, an anti-PD-1 monoclonal antibody, was approved by the US FDAfor patients with platinum-resistant, unresectable, recurrentor metastatic esophageal squamous cell carcinoma. The CheckMate 648 trial demonstrated that the combination of nivolumab with platinum-based fluoropyrimidine chemotherapy and combination immunotherapy with nivolumab and ipilimumab, an anti-CTLA-4 monoclonal antibody, showed a survival benefit in patients with advanced esophageal squamous cell carcinomacompared with doublet chemotherapy. This review focuses on nivolumab-containing treatments for patients with advanced esophageal squamous cell carcinoma.