Metastatic Esophageal Squamous Cell Carcinoma Research Articles

Final analysis of camrelizumab plus chemotherapy for untreated advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st trial

The interim analysis of the randomized phase 3 ESCORT-1st study demonstrated significantly longer overall survival (OS) and progression-free survival (PFS) for camrelizumab-chemotherapy than placebo-chemotherapy in untreated advanced/metastatic esophageal squamous cell carcinoma (ESCC). Here, we present the final analysis of this study and investigate potential indicators associated with OS. Patients were randomized 1:1 to receive camrelizumab (200mg) or placebo, both in combination with up to six cycles of paclitaxel (175mg/m2) and cisplatin (75mg/m2). All treatments were administered intravenously every 3weeks. The co-primary endpoints were OS and PFS assessed by the independent review committee. As of April 30, 2022, the median OS was significantly longer in the camrelizumab-chemotherapy group compared to the placebo-chemotherapy group (15.6 [95% confidence interval (CI): 14.0-18.4] vs. 12.6months [95% CI 11.2-13.8]; hazard ratio [HR]: 0.70 [95% CI 0.58-0.84]; one-sided p<0.0001), with 3-year OS rates of 25.6% and 12.8% in the two groups, respectively. The 2-year PFS rates were 20.4% in the camrelizumab-chemotherapy group and 3.4% in the placebo-chemotherapy group. Adverse events were consistent with those reported in the interim analysis. Higher PD-L1 expression correlated with extended OS, and multivariate analysis identified sex and prior history of radiotherapy as independent indicators of OS. The sustained and significant improvement in efficacy with camrelizumab-chemotherapy compared to placebo-chemotherapy, along with the absence of accumulating or delayed toxicities, supports the long-term use of camrelizumab-chemotherapy as a standard therapy in untreated advanced/metastatic ESCC. This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Identification and Characterization of Metastasis-Initiating Cells in ESCC in a Multi-Timepoint Pulmonary Metastasis Mouse Model.

Metastasis is the biggest obstacle to esophageal squamous cell carcinoma (ESCC) treatment. Single-cell RNA sequencing analyses are applied to investigate lung metastatic ESCC cells isolated from pulmonary metastasis mouse model at multiple timepoints to characterize early metastatic microenvironment. A small population of parental KYSE30 cell line (Cluster S) resembling metastasis-initiating cells (MICs) is identified because they survive and colonize at lung metastatic sites. Differential expression profile comparisons between Cluster S and other subpopulations identified a panel of 7 metastasis-initiating signature genes (MIS), including CD44 and TACSTD2, to represent MICs in ESCC. Functional studies demonstrated MICs (CD44high) exhibited significantly enhanced cell survival (resistances to oxidative stress and apoptosis), migration, invasion, stemness, and in vivo lung metastasis capabilities, while bioinformatics analyses revealed enhanced organ development, stress responses, and neuron development, potentially remodel early metastasis microenvironment. Meanwhile, early metastasizing cells demonstrate quasi-epithelial-mesenchymal phenotype to support both invasion and anchorage. Multiplex immunohistochemistry (mIHC) staining of 4 MISs (CD44, S100A14, RHOD, and TACSTD2) in ESCC clinical samples demonstrated differential MIS expression scores (dMISs) predict lymph node metastasis, overall survival, and risk of carcinothrombosis.

Final analysis of the randomized phase 3 ESCORT-1st trial: Camrelizumab plus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma.

4055 Background: The ESCORT-1st trial (NCT03691090) was a randomized, double-blind, placebo-controlled, phase 3 trial that aimed to evaluate the efficacy and safety of camrelizumab plus chemotherapy compared to placebo plus chemotherapy in previously untreated patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). Interim analysis of this trial showed significantly longer overall survival (OS) and progression-free survival (PFS) with camrelizumab plus chemotherapy compared to placebo plus chemotherapy (Luo et al., JAMA, 2021). In this report, we present the final analysis of the efficacy and safety outcomes from the ESCORT-1st study, with an additional 1.5-year follow-up. Methods: A total of 596 eligible patients with previously untreated advanced or metastatic ESCC were randomly assigned in a 1:1 ratio to receive either camrelizumab 200 mg or placebo for up to 2 years, in combination with up to 6 cycles of paclitaxel and cisplatin. All treatments were administered intravenously every 3 weeks. Randomization was stratified based on the presence of liver metastases and previous definitive chemoradiotherapy. The primary endpoints of the study were OS and PFS as assessed by an independent review committee. The data cutoff for this final analysis was April 30, 2022. Results: At the data cutoff, the minimum follow-up period was 24 months, and no patients remained on the study treatment. Among the patients, 214 (71.8%) in the camrelizumab plus chemotherapy group and 250 (83.9%) in the placebo plus chemotherapy group had died. The camrelizumab plus chemotherapy group demonstrated a longer median OS compared to the placebo plus chemotherapy group (15.6 months [95% CI 14.0–18.4] vs 12.6 months [95% CI 11.2–13.8], HR 0.70 [95% CI 0.58–0.84]; one-sided P&lt;0.0001). The 1-year, 2-year, and 3-year OS rates were 62.4% vs 51.7%, 35.9% vs 23.8%, and 25.6% vs 12.8% in the camrelizumab plus chemotherapy group and the placebo plus chemotherapy group, respectively. The median investigator-assessed PFS was also longer with camrelizumab plus chemotherapy compared to placebo plus chemotherapy (7.6 months [95% CI 6.9–8.3] vs 5.8 months [95% CI 5.6–6.6]; HR 0.54 [95% CI 0.45–0.65]; one-sided P&lt;0.0001). No new safety signals were identified during the extended follow-up period. Conclusions: The extended follow-up of the ESCORT-1st trial reaffirms that camrelizumab plus chemotherapy provides significant and clinically meaningful improvements in OS and PFS compared to placebo plus chemotherapy, with a manageable safety profile for patients with untreated advanced or metastatic ESCC. These findings further support the use of first-line camrelizumab plus chemotherapy as the standard of care for these patients. Clinical trial information: NCT03691090 .

Polymeric micellar paclitaxel plus cisplatin combined with tislelizumab as the first-line treatment of advanced unresectable esophageal squamous cell carcinoma: A phase II study.

e16022 Background: Immunotherapy combined with chemotherapy has become the standard first-line treatment for advanced and metastatic esophageal squamous cell carcinoma (ESCC). However, the prophylactic use of hormones, a routine preconditioning regimen of paclitaxel, may weaken the immune response. Polymeric micellar paclitaxel is a new formulation of paclitaxel without polyoxyethylene castor oil solvent, which do not need for pretreatment with anti-allergy drugs before administration. We aimed to evaluate the efficacy and safety of polymeric micellar paclitaxel (pm-Pac) plus cisplatin combined with tislelizumab for unresectable advanced ESCC. Methods: This is a single-center, single-arm, prospective phase II clinical trial. Stage IV ESCC patients diagnosed histologically or cytologically without systemic treatment are eligible for this study. Polymeric micellar paclitaxel plus cisplatin combined with tislelizumab was treated for 2 cycles. After imaging evaluation, if there was no disease progression, an additional two cycles of treatment were completed, followed by maintenance treatment with tislelizumab for one year. At day 1 of each therapy cycle, patients were given pm-Pac 230 mg/m2 followed by cisplatin 70 mg/m2 combined with tislelizumab 200 mg via intravenous infusion, every three weeks. This trial planned to include 30 patients. The primary endpoint was objective response rate (ORR) determined by the independent review committee. And the secondary endpoints included overall survival, progression-free survival evaluated based on the Response Evaluation Criteria in Solid Tumors (version 1.1), as well as the incidence and severity of adverse events. Results: From September 2022 to January 2024, 31 patients were included in the trial. Median age was 65 years, 29 (93.5%) patients were male. Median follow-up was 13.1 months, 2 patient achieved complete response (CR), 19 of them showed partial response (PR), 8 stable disease (SD), illustrating an ORR of 67.7% and a DCR of 93.5%. Median PFS was 7.3 months. The most common AEs were neutropenia (90.3%), nausea(83.8%) and thrombocytopenia (25.8%). No grade 3 or higher immune-related AE was observed, and there were no treatment-related deaths. Conclusions: The pm-Pac plus cisplatin combined with tislelizumab as first-line treatment of unresectable advanced ESCC showed effective without new safety signal. This combination therapy may have great efficacy, but multi-center randomized trials with larger sample size are warranted in further.

395MO Tislelizumab (TIS) + chemotherapy (CT) vs placebo (PBO) + CT in advanced or metastatic esophageal squamous cell carcinoma (ESCC): PD-L1 biomarker analysis from RATIONALE-306

395MO Tislelizumab (TIS) + chemotherapy (CT) vs placebo (PBO) + CT in advanced or metastatic esophageal squamous cell carcinoma (ESCC): PD-L1 biomarker analysis from RATIONALE-306

Efficacy, safety and DNA methylation analysis of cadonilimab combined with taxane and cisplatin as the first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC): An open-label, multicenter phase II trial– Updated results from AK104-IIT-014.

e16064 Background: Immune checkpoint inhibitors combined with chemotherapy has become the current first-line standard treatment for advanced ESCC, while still having a lot of room for improvements in objective responses and survival. Cadonilimab, a bispecific antibody simultaneously targeting PD-1 and CTLA-4, may further boost anti-tumour activity with a satisfied safety profile. Here, we present the updated data for the safety and efficacy of Cadonilimab combination therapy as the first-line treatment in advanced ESCC. Methods: Treatment-naïve patients (pts) with unresectable locally advanced or metastatic ESCC were eligible for inclusion. Cadonilimab (10mg/kg, iv, d1, q3w) combined with paclitaxel or nab-paclitaxel (175 mg/m2, iv, d1, q3w) and cisplatin (65 to 75 mg/m2, iv, d1, q3w) were administrated for up to 6 cycles, then Cadonilimab (10mg/kg, iv, d1, q3w) monotherapy continued as maintenance until progressive disease or unacceptable toxicity, with a maximum of 24 months. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Plasma cell-free DNA samples were collected before and after treatment and prepared for DNA methylation level sequencing. Results: At updated analysis (cut-off: February 5, 2024), 35 pts were enrolled with a median age of 61 years (range 44-75), 82.9% were male, 57.1% had PD-L1 CPS&lt;10 and 88.6% had distant metastases. In the efficacy-evaluable population (n = 29), 5 pts reached complete response (CR), 21 pts had partial response (PR) and 3 pts had stable disease (SD). The ORR was 89.7% (95%Cl: 71.5%-97.3%) and the DCR was 100.0% (95%Cl: 85.4%-100.0%). Among evaluable pts with PD-L1 CPS≥10 and PD-L1 CPS&lt;10, the ORR were 100.0% (12/12) and 81.3% (13/16), respectively. SEPT9 methylation was significantly higher in patients with CR or PR compared to patients with SD (33.28% vs 3.87%, p &lt; 0.001). The median PFS and OS was still not reached. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 9 (25.7%) pts. The most common TRAEs were neutropenia (17.1%), leukopenia (5.7%) and hyponatremia (5.7%). Immune-related adverse events were observed in 9 pts (25.7%). Three pts (8.6%) suffered from serious adverse events, and no grade 5 TRAEs or death were observed. Conclusions: The updated results suggested that bispecific antibody AK104 combined with taxane and cisplatin as first-line treatment showed promising anti-tumor activity and manageable safety in patients with advanced ESCC. DNA methylation level might be a potential biomarker for guiding patient outcomes. Follow-up is ongoing for survival analysis. Clinical trial information: NCT05522894 .

Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 45-month (mo) follow-up from CheckMate 648.

4034 Background: NIVO + chemo and NIVO + IPI are approved for the treatment of advanced ESCC in the US, EU, Japan, and many other countries based on the results from CheckMate 648 (NCT03143153). Here, we report 45-mo follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. The primary endpoints were overall survival (OS) and progression-free survival (PFS) per blinded independent central review (BICR) in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Results: In total, 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 45-mo minimum follow-up, NIVO + chemo and NIVO + IPI demonstrated continued OS benefit and higher 45-mo OS rates vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Duration of response (DOR) was longer (Table) and the proportion of responders with DOR ≥ 45 mo was greater with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (7% and 23% vs 0%, respectively) and all randomized pts (14% and 18% vs 6%). Any-grade treatment-related adverse events (TRAEs) occurred in 96% of pts with NIVO + chemo, 80% with NIVO + IPI, and 90% with chemo; grade 3/4 TRAEs occurred in 49%, 33%, and 37% of pts, respectively. No additional TRAEs leading to discontinuation and no new treatment-related deaths were reported with longer follow-up. Conclusions: After 45 mo of follow-up, NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit and more durable responses vs chemo, with no new safety signals. These results further support NIVO + chemo and NIVO + IPI as 1L treatment options for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]

First-line TQB2450 plus anlotinib combined with paclitaxel and cisplatin for advanced esophageal squamous cell carcinoma (ESCC): Update results of a multicenter phase II trial.

e16011 Background: PD-1 inhibitor combined with chemotherapy are the standard first-line treatment for advanced ESCC. Anlotinib, a multitargeted tyrosine kinase inhibitor (TKI), has been demonstrated favorable efficacy and manageable toxicity as both first-line treatment when combined with TP and second-line monotherapy in advanced ESCC. TQB2450 is a novel humanized anti-PD-L1 monoclonal antibody. We conducted a phase II trial to evaluate the efficacy and safety of alotinib combined with TQB2450, cisplatin, and paclitaxel as first-line treatment for advanced ESCC. Here is the update results. Methods: Eligible patients (pts) with previously untreated unresectable locally advanced or metastatic ESCC received TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) combined with paclitaxel (135mg/m2, iv, d1, q3w) and cisplatin (60~75mg/m2, iv, d1~3, q3w) for 4 - 6 cycles as initial therapy. Patients without progressive disease (PD) continued to receive same dose of anlotinib plus TQB2450 as maintenance therapy until PD or unacceptable toxicity. The primary endpoint was PFS (RECIST version 1.1). Secondary endpoints included iPFS (iRECIST), ORR (RECIST version 1.1), DCR, DOR and safety. Results: At the data cutoff date of November 14, 2023, 50 pts were enrolled with a median age of 64 years (range 41-74), male (39/50, 78%) and ECOG PS 1 (38/50, 76%). Among 43 tumor response evaluable pts , 4 achieved complete response, 32 had partial response and 8 had stable disease. The ORR was 72.00% (95% CI: 57.51, 83.77) and the DCR was 84.0% (95% CI: 70.89, 92.83). The 12-month PFS rate was 66.84% (95% CI: 48.73, 79.79) and the 12-month OS rate was 74.22% (95% CI: 59.06, 84.46), but the median PFS and OS was not reached. The incidence of ≥G3 treatment emergent adverse events was 78%, mainly included neutropenia (44%, 22/50), leukopenia (24%, 12/50) and hypertension (20%, 10/50). 20 pts (48%, 24/50) occurred serious AEs. Conclusions: The combination of TQB2450 plus anlotinib, paclitaxel and cisplatin, demonstrated encouraging efficacy and manageable toxicity in patients with advanced ESCC when used as first-line treatment. Clinical trial information: NCT05013697 .

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.

Immune checkpoint inhibitors as the second-line treatment for advanced esophageal squamous cell carcinoma: a cost-effectiveness analysis based on network meta-analysis

BackgroundImmune checkpoint inhibitors (ICIs) have demonstrated superior clinical efficacy in prolonging overall survival (OS) as the second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC), and were recommended by the guidelines. However, it remains uncertain which ICI is the most cost-effective. This study assessed the cost-effectiveness of ICIs as the second-line treatment for ESCC based on the perspective of the Chinese healthcare system.MethodsA network meta-analysis (NMA) was performed to obtain the Hazard ratios (HRs) for indirect comparisons. A three-state Markov model with a 10-year time horizon was conducted to assess the cost-effectiveness. The state transition probabilities were calculated with Kaplan-Meier (KM) curves data from clinical trial and HRs from the NMA. Utilities and costs were derived from local charges or previously published studies. Univariate and probabilistic sensitivity analyses (PSA) were performed to examine model robustness. The results were assessed based on the total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs).ResultsFive clinical trials (ATTRACTION-3, ESCORT, KEYNOTE-181, ORIENT-2, RATIONALE-302) with a total of 1797 patients were included in the NMA. The NMA showed that both camrelizumab and tislelizumab received relatively high rankings for progression-free survival (PFS) and OS. Compared with sintilimab, treatment with tislelizumab and camrelizumab gained 0.018 and 0.034 additional QALYs, resulting in incremental ICERs of $75,472.65/QALY and $175,681.9/QALY, respectively. Nivolumab and pembrolizumab produced lower QALYs and greater costs, suggesting that both were dominated in comparison to sintilimab. HRs and health state utilities were the most influential parameters in most univariate sensitivity analyses of paired comparisons. PSA results suggested that sintilimab had an 84.4% chance of being the most cost-effective treatment regimen at the WTP threshold of $38,223.34/QALY. In the scenario analysis, sintilimab would no longer be cost-effective, if the price of camrelizumab was assumed to decrease by 64.6% or the price of tislelizumab was assumed to decrease by 16.9%.Conclusions and relevanceAmong the five potential competing ICIs, sintilimab was likely to be the most cost-effective regimen 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.

First-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. We 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. Tislelizumab 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. Tislelizumab 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 &amp;lt;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 &amp;lt; 0.001). Similarly, ICIs plus chemotherapy correlated with a significantly prolonged OS in males (HR, 0.67; 95% CI, 0.61-0.74, P &amp;lt; 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)].