Effectiveness of Immune Checkpoint Inhibitors in Patients With Advanced Esophageal Squamous Cell Carcinoma

Abstract

ImportanceImmune checkpoint inhibitors (ICIs) have improved survival outcomes of patients with advanced esophageal squamous cell carcinoma in both first- and second-line settings. However, the benefit of ICIs in patients with low programmed death ligand 1 (PD-L1) expression remains unclear.ObjectiveTo derive survival data for patient subgroups with low PD-L1 expression from clinical trials comparing ICIs with chemotherapy in esophageal squamous cell carcinoma and to perform a pooled analysis.Data SourcesKaplan-Meier curves from the randomized clinical trials were extracted after a systematic search of Scopus, Embase, PubMed, and Web of Science from inception until October 1, 2021.Study SelectionRandomized clinical trials that investigated the effectiveness of anti–PD-1–based regimens for advanced esophageal squamous cell carcinoma and that reported overall survival (OS), progression-free survival, or duration of response were included in this meta-analysis.Data Extraction and SynthesisKaplan-Meier curves of all-comer populations, subgroups with high PD-L1, and those with low PD-L1 (when available) were extracted from published articles. A graphic reconstructive algorithm was used to calculate time-to-event outcomes from these curves. In studies with unreported curves for subgroups with low PD-L1 expression, KMSubtraction was used to impute survival data. KMSubtraction is a workflow to derive unreported subgroup survival data with from subgroups. An individual patient data pooled analysis including previously reported and newly imputed subgroups was conducted for trials with the same treatment line and PD-L1 scoring system. Data analysis was conducted from January 1, 2022, to June 30, 2022.Main Outcomes and MeasuresPrimary outcomes included Kaplan-Meier curves and hazard ratios (HRs) for OS for subgroups with low PD-L1 expression. Secondary outcomes included progression-free survival and duration of response.ResultsThe randomized clinical trials CheckMate-648, ESCORT-1st, KEYNOTE-590, ORIENT-15, KEYNOTE-181, ESCORT, RATIONALE-302, ATTRACTION-3, and ORIENT-2 were included, totaling 4752 patients. In the pooled analysis of first-line trials that evaluated a tumor proportion score (CheckMate-648 and ESCORT-1st), no significant benefit in OS was observed with immunochemotherapy compared with chemotherapy in the subgroup of patients who had a tumor proportion score lower than 1% (HR, 0.91; 95% CI, 0.74-1.12; P = .38) compared with chemotherapy. In the pooled analysis of first-line trials that evaluated combined positive score (KEYNOTE-590 and ORIENT-15), there was a significant but modest OS benefit for immunochemotherapy compared with chemotherapy in the subgroup with a combined positive score lower than 10 (HR, 0.77; 95% CI, 0.62-0.94; P = .01).Conclusions and RelevanceFindings suggest a lack of survival benefit of ICI-based regimens in the first-line setting compared with chemotherapy alone in the subgroup with a tumor proportion score lower than 1%.

Progression-Free and Overall Survival of First-Line Treatments for Advanced Renal Cell Carcinoma: Indirect Comparison of Six Combination Regimens

“…In recent years, the Shiny method has increasingly been used not only in oncology but also in other areas of of therapeutics, such as medical devices [ 20 ], surgery [ 21 , 22 ] and also in patients with COVID-19 [ 23 ]. However, oncology and oncohematology remain the two main areas of application, where the Shiny method represents a quite simple alternative to network meta-analysis [ 8 , 9 , 24 , 25 ].…”

Immune Checkpoint Inhibitor, Nivolumab, Combined with Chemotherapy Improved the Survival of Unresectable Advanced and Metastatic Esophageal Squamous Cell Carcinoma: A Real-World Experience

“…Additionally, PFS with nivolumab plus chemotherapy was significantly better than that with chemotherapy alone in patients with PD-L1 ≥ 1% [ 27 ]. A meta-analysis that enrolled 4752 advanced esophageal SCC patients from several randomized clinical trials reports that no significant benefit in OS was observed with immunochemotherapy compared with chemotherapy in the subgroup of patients who had a tumor proportion score lower than 1% compared with chemotherapy [ 28 ]. Because the PD-L1 detection is not reimbursement by insurance, we only chose six patients who received either first-line immunechemotherapy, second-line immunechemotherapy, or dual immune checkpoint inhibitor treatment to arrange PD-L1 immunostaining.…”

Real-world clinical outcomes of nivolumab and taxane as a second- or later-line therapy for recurrent or unresectable advanced esophageal squamous cell carcinoma

“…Factors associated with immune checkpoint inhibitor efficacy include PD-1 and PD-L1 expression, mutation burden, CD8 lymphocyte count, interferon-γ level, and interleukin 12; nevertheless, it remains challenging to accurately predict clinical efficacy ( 19 – 22 ). Recent meta-analysis reports on the association between PD-L1 and immune checkpoint inhibitor treatment efficacy have shown no survival benefit of immune checkpoint inhibitor-based regimens compared to chemotherapy alone in subgroups with tumor proportion scores of less than 1% ( 23 ). Further studies are required to identify predictors of treatment efficacy in this context.…”