Abstract
Background
Controversy continues regarding whether immunosuppressive agents can be used across treatment lines after disease progression on first-line immunotherapy for advanced esophageal cancer. The aim of this study is to evaluate the efficacy and safety of immune checkpoint inhibitor (ICI) retreatment through real-world data.
Methods
The clinical data of patients with esophageal cancer treated at The First Affiliated Hospital of Henan University of Science and Technology were retrospectively collected. All patients received first-line combination therapy with programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors for more than 3 months, and following disease progression, received second-line therapy with PD-1/PD-L1 inhibitors for at least two cycles. Treatment efficacy and safety were evaluated.
Results
In the overall population, the median overall survival (mOS) was 10.0 months [95% confidence interval (CI): 9.5–10.5] and the median progression-free survival (mPFS) was 4.4 months (95% CI: 4.1–4.5). The objective response rate (ORR) was 33.2%, and the disease control rate (DCR) was 65.9%. The Cox regression model analysis identified first-line PFS >6 months as an independent prognostic factor for both second-line PFS and OS. Safety was manageable, and no treatment-related deaths occurred.
Conclusions
The results of this study suggest that ICI retreatment showed measurable activity in a selected real-world cohort and deserves further evaluation in comparative studies.
Keywords: Esophageal cancer, immunotherapy, cross-line treatment, second-line treatment, real-world study
Highlight box.
Key findings
• Following disease progression or the development of resistance to first-line therapy, patients with advanced esophageal cancer may still derive a survival benefit from second-line immunotherapy. A first-line progression-free survival (PFS) >6 months was identified as an independent prognostic factor for both second-line PFS and overall survival (OS).
What is known, and what is new?
• To date, most studies evaluating immune checkpoint inhibitor (ICI) retreatment in the second-line setting have been phase II trials with small sample sizes, single-arm designs, and limited high-quality evidence.
• This large, real-world study suggests that ICI retreatment in the second-line treatment of patients with esophageal cancer is associated with a clinical benefit and a manageable safety profile. Cox analysis identified first-line PFS >6 months as an independent prognostic factor for both second-line PFS and OS.
What is the implication, and what should change now?
• ICI retreatment in the second-line treatment of esophageal cancer is associated with a clinical benefit and a manageable safety profile.
Introduction
Esophageal cancer is the eighth most common cancer worldwide, with China accounting for approximately 50% of global cases annually in terms of both incidence and mortality (1). In China, the distribution of esophageal cancer exhibits marked regional variation, with Henan Province representing a high-incidence area, especially in the northern Taihang Mountain region, including Linzhou, Anyang, and Huixian. The incidence and mortality rates of esophageal cancer in these regions are among the highest in China and worldwide, placing a heavy medical burden on families and society (2,3).
In recent years, the development and advancement of immunotherapy have revolutionized the treatment landscape of esophageal cancer. Immunotherapy combined with chemotherapy (I+C) has become the standard first-line treatment for advanced esophageal cancer and has been unanimously recommended by official guidelines across the world (4-6). After progression on first-line immune checkpoint blockade, it remains uncertain whether continued or renewed programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibition can provide additional benefit. On the one hand, acquired resistance [e.g., neoantigen loss, T-cell depletion, interferon-γ (IFN-γ) signaling pathway deficiency] may impair subsequent immune efficacy; on the other hand, tumor heterogeneity, delayed immune effects, or changes in combination treatment may provide a rationale for continued immune modulation. Therefore, effective cross-line treatment regimens urgently need to be established for clinical practice.
PD-1 inhibitors or chemotherapy remains the standard for second-line or subsequent treatment of esophageal cancer in domestic and foreign guidelines. Although the safety is controllable, the efficacy is limited (7-11). Single-agent immunotherapy yielded an objective response rate (ORR) of 12.6–20.2%, median progression-free survival (mPFS) of 1.6–3.4 months, and median overall survival (mOS) of 7.2–10.9 months. Single-agent chemotherapy was associated with worse outcomes, with ORR between 6.4% and 19.7%, mPFS between 2.6 and 3.6 months, and mOS between 6.2 and 8.5 months. Combination therapy has been prioritized in the post-line treatment of advanced esophageal cancer to overcome resistance and achieve synergistic effects. For patients with advanced esophageal cancer who experience disease progression following first-line immunotherapy, current treatment strategies mainly include changing chemotherapy regimens, introducing new immunotherapeutic drugs, or combining immunotherapy with radiotherapy, anti-angiogenic therapy, and other therapies.
Currently, several studies have explored immune re-treatment in esophageal cancer (12-16) and have reported mPFS between 4.6 and 6.9 months, mOS between 7.5 and 12.8 months, an ORR between 21.9% and 40.8%, and a disease control rate (DCR) between 67.7% and 89.5%, suggesting favorable efficacy. These findings suggest that immune re-treatment strategies have considerable potential in the treatment of esophageal squamous cell carcinoma (ESCC). However, most current evidence is derived from phase II trials with small sample sizes and single-regimen designs. Thus, large-sample, multi-regimen studies are needed to provide more robust evidence and to guide the application of Immune re-treatment in clinical practice. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-2110/rc).
Methods
Study population
This was a single-center, retrospective, observational, real-world study. The general and clinical data of esophageal cancer patients treated at The First Affiliated Hospital of Henan University of Science and Technology between February 1, 2020 and February 29, 2024 were retrospectively collected.
The inclusion criteria were as follows: pathological diagnosis of esophageal cancer; receipt of first-line therapy with PD-1 or PD-L1 inhibitors for more than 3 months; receipt of second-line therapy with PD-1 or PD-L1 inhibitors for at least two cycles following disease progression; and availability of imaging-based response evaluations during and after treatment. The major exclusion criteria were as follows: a history of other malignancies within the past 5 years; lack of survival or clinical efficacy data; and/or receipt of a combined radiotherapy regimen in the second-line treatment.
Data from patients hospitalized in our hospital for second-line treatment of esophageal cancer were first screened based on medical records, and patients who did not receive immunotherapy in both the first- and second-line settings were excluded. Baseline demographic and clinical characteristics, including age and sex, were extracted from the medical records. Missing key data, such as PFS and OS, were obtained by telephone by the attending physician. The follow-up deadline was April 10, 2024. Immune re-treatment was classified according to whether patients continued the same checkpoint target or switched between PD-1 and PD-L1 inhibitors between first- and second-line treatment.
The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of Henan University of Science and Technology (approval No. 2024-03-K0118), which waived the requirement for additional consent for the use of medical records due to the retrospective study design and the use of anonymized data. All patients signed the informed consent form for treatment.
Assessment
This study primarily evaluated the efficacy and safety of PD-1 or PD-L1 inhibitor-based therapy as a second-line treatment for patients with advanced esophageal cancer. According to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the efficacy of immunotherapy included complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Patients were assessed every 6 weeks. The ORR was defined as the percentage of patients who achieved a CR or PR, while the DCR was defined as the percentage of patients who achieved a CR, PR, or SD. OS was defined as the time from the start of second-line treatment to death from any cause, and PFS was defined as the time from the start of second-line treatment to the first occurrence of PD or death. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. The cut-off date was April 10, 2024.
Statistical analysis
Baseline characteristics are presented as proportions for categorical variables and medians for continuous variables. Categorical variables were compared using Pearson’s Chi-squared test or Fisher’s exact test, as appropriate. The Kaplan-Meier method was used to analyze the survival data. Cox proportional hazards regression models were used to examine the associations between clinical features and OS and PFS. First, univariate Cox regression analysis was performed, and all variables with P<0.10 among them were included in multivariate Cox regression analysis. Subsequent analyses were terminated if only 1 or 2 variables reached statistical significance in the multivariate analysis. The statistical analyses were conducted using SPSS 25.0 (SPSS Inc., Chicago, IL, USA). A P value <0.05 was considered statistically significant.
Results
Patients and tumor characteristics
We selected 820 patients with advanced esophageal cancer who received second-line treatment from February 1, 2020 to February 29, 2024. After further screening, 214 patients with complete data on PFS and OS were finally included (Figure 1). The median age of these patients was 69.0 (range, 47–87) years; 66.8% were male. Among them, 201 (93.9%) patients had ESCC and 11 (5.1%) patients had esophageal adenocarcinoma. Metastases in more than one organ were observed in 67 (31.3%) patients.
Figure 1.
Patient data screening flowchart. OS, overall survival; PFS, progression-free survival.
In first-line treatment, 183 (85.5%) patients received I+C, and 31 (14.5%) patients received immunotherapy combined with chemoradiotherapy (I+R+C). In second-line treatment, 162 (75.7%) patients received I+C, 37 (17.3%) patients received immunotherapy combined with anti-angiogenic drugs (I+A), and 15 patients (7.0%) received I+C and anti-angiogenic drugs (I+C+A). The immune checkpoint inhibitors (ICIs) used in second-line therapy included tislelizumab (n=85, 39.7%), camrelizumab (n=60, 28.0%), sintilimab (n=45, 21.0%), toripalimab (n=19, 8.9%), pembrolizumab (n=3, 1.4%), and nivolumab (n=2, 0.9%). Other specific baseline conditions are shown in Table 1.
Table 1. Baseline characteristics of study patients.
| Characteristics | ITT (n=214), n (%) |
|---|---|
| Age (years) | |
| ≤60 | 46 (21.5) |
| >60 | 168 (78.5) |
| Gender | |
| Male | 143 (66.8) |
| Female | 71 (33.2) |
| ECOG PS | |
| 0 | 72 (33.6) |
| 1 | 124 (57.9) |
| 2 | 18 (8.4) |
| Smoking history | |
| Yes | 74 (34.6) |
| No | 140 (65.4) |
| Drinking history | |
| Yes | 53 (24.8) |
| No | 161 (75.2) |
| Prior surgery | |
| Yes | 69 (32.2) |
| No | 145 (67.8) |
| Histological type | |
| Squamous cell carcinoma | 201 (93.9) |
| Adenocarcinoma | 11 (5.1) |
| Other | 2 (0.9) |
| Tumor location | |
| Upper | 38 (17.8) |
| Middle | 92 (43.0) |
| Lower | 84 (39.2) |
| Number of metastatic organs | |
| ≤1 | 147 (68.7) |
| >1 | 67 (31.3) |
| T stage | |
| T1 | 3 (1.4) |
| T2 | 41 (19.2) |
| T3 | 92 (43.0) |
| T4 | 67 (31.3) |
| N stage | |
| N0 | 51 (23.8) |
| N1 | 72 (33.6) |
| N2 | 68 (31.8) |
| N3 | 12 (5.6) |
| First-line immunotherapy | |
| I+C | 183 (85.5) |
| I+R+C | 31 (14.5) |
| First-line PFS | |
| ≤6 months | 90 (42.1) |
| >6 months | 124 (57.9) |
| Second-line immunotherapy | |
| I+C | 162 (75.7) |
| I+A | 37 (17.3) |
| I+C+A | 15 (7.0) |
| ICI retreatment model | |
| PD-1 or PD-L1 inhibitors† | 189 (88.3) |
| PD-1 and PD-L1 inhibitors‡ | 25 (11.7) |
Data cut-off was April 10, 2024. †, PD-1 or PD-L1 inhibitors: only one of the PD-1 or PD-L1 inhibitors were used across first- and second-line treatment regimens. ‡, PD-1 and PD-L1 inhibitors: PD-1 and PD-L1 inhibitors were used in a cross-over manner between the first- and second-line treatment regimens. ECOG, Eastern Cooperative Oncology Group; I+A, immunotherapy combined with anti-angiogenic drugs; I+C, immunotherapy combined with chemotherapy; I+C+A, immunotherapy combined with chemotherapy and anti-angiogenic drugs; I+R+C, immunotherapy combined with chemoradiotherapy; ICI, immune checkpoint inhibitor; ITT, intention-to-treat analysis; N, node; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PS, performance status; T, tumor.
Efficacy
In the overall cohort, the 214 patients had a mOS of 10.0 months [95% confidence interval (CI): 9.5–10.5] (Figure 2A) and a mPFS of 4.4 months (95% CI: 4.1–4.5) (Figure 2B). In the treatment subgroups, the mOS for the I+C, I+A, and I+C+A groups was 9.8 months (95% CI: 9.4–10.2), 10.0 months (95% CI: 9.1–10.9), and 11.5 months (95% CI: 10.9–12.1), respectively (Figure 2C); the corresponding mPFS values were 4.3 months (95% CI: 4.0–4.6), 4.3 months (95% CI: 4.0–4.6), and 5.3 months (95% CI: 4.2–6.4), respectively (Figure 2D). No statistically significant differences in mPFS or mOS were observed among the treatment groups. When stratified by first-line PFS (>6 vs. ≤6 months), statistically significant differences in second-line PFS and OS were observed between the two groups (P<0.01) (Figure 2E,2F, Table 2). Higher efficacy was observed in patients with ESCC compared with those with esophageal adenocarcinoma; however, this difference was not statistically significant (Table 2).
Figure 2.
K-M curves of OS (A,C,E) and PFS (B,D,F). (A,B) For all patients; (C,D) for second-line treatment subgroups; (E,F) stratified by first-line PFS >6 and ≤6 months. CI, confidence interval; I+A, immunotherapy combined with anti-angiogenic drugs; I+C, immunotherapy combined with chemotherapy; I+C+A, immunotherapy combined with chemotherapy and anti-angiogenic drugs; K-M, Kaplan-Meier; m, months; OS, overall survival; PFS, progression-free survival.
Table 2. Efficacy in different clinical groups.
| Variables | Number | mOS (95% CI) (months) | mPFS (95% CI) (months) | ORR (95% CI) (%) | DCR (95% CI) (%) |
|---|---|---|---|---|---|
| All patients | 214 | 10.0 (9.5, 10.5) | 4.4 (4.1, 4.5) | 33.2 (26.9, 39.9) | 65.9 (59.1, 72.2) |
| Second-line treatment | |||||
| I+C | 162 | 9.8 (9.4, 10.2) | 4.3 (4.0, 4.6) | 31.5 (24.4, 39.2) | 63.6 (55.7, 71.0) |
| I+A | 37 | 10.0 (9.1, 10.9) | 4.3 (4.0, 4.6) | 35.7 (20.2, 52.5) | 70.2 (53.0, 84.1) |
| I+C+A | 15 | 11.5 (10.9, 12.1) | 5.3 (4.2, 6.4) | 46.7 (21.3, 73.4) | 80.0 (51.9, 95.7) |
| Pathological classification | |||||
| Squamous carcinoma | 201 | 10.0 (9.6, 10.4) | 4.3 (4.1, 4.5) | 33.3 (26.9, 40.3) | 65.7 (58.7, 72.2) |
| Adenocarcinoma | 11 | 9.0 (5.6, 12.4) | 4.0 (2.7, 5.3) | 27.3 (6.0, 61.0) | 63.6 (30.8, 89.1) |
| Other | 2 | 11.0 (NA) | 5.0 (NA) | 50.0 (NA) | 100.0 (NA) |
| First-line PFS | |||||
| >6 months | 124 | 11.0 (10.4, 11.6) | 5.0 (4.8, 5.2) | 43.5 (34.7, 52.7) | 81.5 (73.5, 87.9) |
| ≤6 months | 90 | 8.6 (8.2, 9.0) | 3.5 (3.2, 3.8) | 18.9 (11.4, 28.5) | 44.4 (34.0, 55.3) |
| ICI retreatment model | |||||
| PD-1 or PD-L1 | 189 | 10.0 (9.7, 10.3) | 4.3 (4.1, 4.5) | 33.3 (26.7, 40.5) | 66.1 (58.9, 72.8) |
| PD-1 and PD-L1 | 25 | 10.6 (9.1, 12.1) | 4.6 (3.7, 5.5) | 32.0 (15.0, 53.5) | 64.0 (42.5, 82.0) |
CI, confidence interval; DCR, disease control rate; I+A, immunotherapy combined with anti-angiogenic drugs; I+C, immunotherapy combined with chemotherapy; I+C+A, immunotherapy combined with chemotherapy and anti-angiogenic drugs; ICI, immune checkpoint inhibitor; mOS, median overall survival; mPFS, median progression-free survival; NA, not applicable; ORR, objective response rate; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PFS, progression-free survival.
Regarding treatment response, the ORR was 33.2% (n=71), and the DCR was 65.9% (n=141). The treatment responses among different clinical subgroups are shown in Table 3.
Table 3. Univariate analysis of clinical variables for the prediction of OS.
| Variables | Univariate analysis | |
|---|---|---|
| HR (95% CI) | P value | |
| Gender (female vs. male) | 0.87 (0.63, 1.19) | 0.38 |
| Age (≤60 vs. >60 years) | 1.06 (0.75, 1.48) | 0.75 |
| ECOG PS (0–1 vs. 2) | 1.03 (0.81, 1.30) | 0.83 |
| Smoking history (yes vs. no) | 0.91 (0.66, 1.25) | 0.55 |
| Drinking history (yes vs. no) | 0.95 (0.67, 1.34) | 0.77 |
| Prior surgery (yes vs. no) | 0.82 (0.60, 1.13) | 0.23 |
| Histological type (EAC vs. ESCC) | 1.10 (0.62, 1.95) | 0.75 |
| T stage (T1–2 vs. T3–4) | 0.84 (0.58, 1.23) | 0.38 |
| N stage (N0–1 vs. N2–3) | 0.97 (0.71, 1.33) | 0.86 |
| Number of metastatic organs (>1 vs. ≤1) | 1.33 (0.97, 1.83) | 0.08 |
| First-line immunotherapy (I+R+C vs. I+C) | 0.79 (0.51, 1.23) | 0.29 |
| First-line PFS (≤6 vs. >6 months) | 2.93 (2.11, 4.07) | <0.001 |
| Second-line immunotherapy (I+C vs. I+A) | 1.10 (0.83, 1.46) | 0.52 |
| ICI retreatment model (PD-1 and PD-L1 vs. PD-1 or PD-L1) | 0.84 (0.54, 1.30) | 0.43 |
CI, confidence interval; EAC, esophageal adenocarcinoma; ECOG, Eastern Cooperative Oncology Group; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio; I+A, immunotherapy combined with anti-angiogenic drugs; I+C, immunotherapy combined with chemotherapy; I+R+C, immunotherapy combined with chemoradiotherapy; ICI, immune checkpoint inhibitor; N, node; OS, overall survival; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PS, performance status; T, tumor.
Univariate Cox analyses showed that first-line PFS >6 months was an independent prognostic factor for both second-line PFS and OS (Tables 3,4).
Table 4. Univariate analysis of clinical variables for the prediction of PFS.
| Variables | Univariate analysis | |
|---|---|---|
| HR (95% CI) | P value | |
| Gender (female vs. male) | 0.97 (0.72, 1.29) | 0.81 |
| Age (≤60 vs. >60 years) | 1.19 (0.87, 1.63) | 0.28 |
| ECOG PS (0–1 vs. 2) | 0.94 (0.75, 1.18) | 0.59 |
| Smoking history (yes vs. no) | 0.93 (0.70, 1.25) | 0.65 |
| Drinking history (yes vs. no) | 0.99 (0.72, 1.36) | 0.96 |
| Prior surgery (yes vs. no) | 0.82 (0.61, 1.10) | 0.18 |
| Histological type (EAC vs. ESCC) | 1.34 (0.77, 2.32) | 0.30 |
| T stage (T1–2 vs. T3–4) | 0.88 (0.63, 1.23) | 0.45 |
| N stage (N0–1 vs. N2–3) | 0.91 (0.69, 1.21) | 0.53 |
| Number of metastatic organs (>1 vs. ≤1) | 1.18 (0.88, 1.58) | 0.26 |
| First-line immunotherapy (I+R+C vs. I+C) | 0.81 (0.55, 1.20) | 0.29 |
| First-line PFS (≤6 vs. >6 months) | 2.88 (2.15, 3.86) | <0.001 |
| Second-line immunotherapy (I+C vs. I+A) | 1.15 (0.89, 1.49) | 0.27 |
| ICI retreatment model (PD-1 and PD-L1 vs. PD-1 or PD-L1) | 0.85 (0.56, 1.29) | 0.44 |
CI, confidence interval; EAC, esophageal adenocarcinoma; ECOG, Eastern Cooperative Oncology Group; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio; I+A, immunotherapy combined with anti-angiogenic drugs; I+C, immunotherapy combined with chemotherapy; I+R+C, immunotherapy combined with chemoradiotherapy; ICI, immune checkpoint inhibitor; N, node; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PS, performance status; T, tumor.
Safety
Among the 214 patients, 147 (68.7%) experienced treatment-related AEs (TRAEs) (Table 5). The most common TRAEs were anemia (27.6%), neutropenia (25.7%), and leukopenia (24.8%). Grade ≥3 immune-related AEs (irAEs) were observed in 5.6% of the patients, with rash and pruritus (1.9%), hypothyroidism (1.9%), and fatigue (1.4%) being the most common. No treatment-related deaths occurred.
Table 5. TRAEs.
| Variables | Grade 1–2, n (%) | Grade 3–4, n (%) |
|---|---|---|
| Any event | 92 (43.0) | 55 (25.7) |
| TRAEs | 88 (41.1) | 52 (24.3) |
| irAEs | 62 (29.0) | 13 (6.1) |
| Treatment-related death | 0 | 0 |
| TRAEs occurring in at least 10% of patients | ||
| Anemia | 52 (24.3) | 7 (3.3) |
| Neutropenia | 49 (22.9) | 6 (2.8) |
| Decreased white blood cell count | 47 (22.0) | 6 (2.8) |
| Decreased neutrophil count | 43 (20.1) | 6 (2.8) |
| Decreased appetite | 41 (19.2) | 6 (2.8) |
| Nausea | 36 (16.8) | 4 (1.9) |
| Decreased platelet count | 30 (14.0) | 9 (4.2) |
| Diarrhea | 26 (12.1) | 4 (1.9) |
| Vomiting | 26 (12.1) | 4 (1.9) |
| irAEs occurring in at least 5% of patients | ||
| Fatigue | 21 (9.8) | 4 (1.9) |
| Rash and pruritus | 20 (9.3) | 4 (1.9) |
| Increased alanine/aspartate | 21 (9.8) | 2 (0.9) |
| Hypothyroidism | 19 (8.9) | 4 (1.9) |
TRAEs, treatment-related adverse events; irAEs, immune-related adverse events.
Discussion
Multiple phase III clinical studies, including KEYNOTE-590 (17), CheckMate-648 (18), ESCORT-1st (19), ORIENT-15 (20), JUPITOR-06 (21), and RATIONALE 306 (22), have shown that first-line treatment with PD-1 inhibitors combined with chemotherapy significantly improves the survival outcomes of patients with locally advanced, unresectable, or metastatic esophageal cancer. The 2025 European Society for Medical Oncology guidelines (4), the 2025 Chinese Society of Clinical Oncology guidelines, and the 2026 National Comprehensive Cancer Network guidelines (6) recommend I+C as the standard first-line treatment for advanced esophageal cancer. However, no standard treatment strategy currently exists for ICI resistance, posing challenges in clinical practice.
The mechanisms underlying ICI resistance include defects in antigen presentation, neoantigen depletion, interferon signaling dysfunction, tumor-induced immunosuppression, upregulation of other immune checkpoints, and dysregulation of the microbiome and diet (23). Based on these mechanisms, research has focused on strategies to overcome ICI resistance, including promoting tumor antigen release, enhancing antigen presentation, boosting T cell priming and activation, and converting the “cold” tumor microenvironment (TME) into a “hot” TME by inhibiting tumor-induced suppressive factors and promoting stimulatory immunogenic pathways (24,25). Clinically, for patients with advanced esophageal cancer who develop resistance or disease progression after first-line immunotherapy, second-line treatment strategies typically include modifying chemotherapy regimens, introducing new ICIs, or combining immunotherapy with radiotherapy, targeted therapies, and anti-angiogenic agents.
A single-arm phase II study (12) showed that in patients with oligometastatic ESCC after failure of first-line I+C, second-line immune-synergistic chemoradiotherapy resulted in a survival benefit. The mPFS was 6.9 months (95% CI: 4.6–9.3), the mOS was 12.8 months (95% CI: 10.1–15.5), the ORR was 40.8% (95% CI: 27.3–55.7%), and the DCR was 75.5% (95% CI: 60.8–86.2%). A real-world retrospective study presented at the 2023 World Congress on Gastrointestinal Cancer reported (13) that anlotinib combined with PD-1 inhibitors in advanced ESCC previously treated with ICIs resulted in a mPFS of 6.31 months (95% CI: 5.10–7.52), a mOS of 10.97 months (95% CI: 8.83–13.11), an ORR of 21.9% (95% CI: 14.1–31.5%), and a DCR of 67.7% (95% CI: 57.4–76.9%). In 2024, the American Society of Clinical Oncology Gastrointestinal Cancers Symposium reported (14) that immunotherapy combined with apatinib as a second-line treatment for patients with ESCC who experienced disease progression following immunotherapy resulted in a mPFS of 4.6 months (95% CI: 3.8–6.5), a mOS of 7.5 months (95% CI: 5.5–13.6), an ORR of 36.8% (95% CI: 21.8–54.0%), and a DCR of 89.5% (95% CI: 75.2–97.1%). Another cohort study (15) also reported that patients with advanced ESCC who had previously undergone immunotherapy and were treated with adabepilimab combined with apatinib achieved an ORR of 22%, a DCR of 78%, a mPFS of 3.8 months, and a mOS of 9.2 months, with a median follow-up of 6.8months. Another retrospective study (16) compared the efficacy of second-line ICI treatment with non-ICI treatment in patients with ESCC in whom first-line ICI therapy had failed. The results showed that the mOS in the ICI group increased by 4.6 months (10.4 vs. 5.8 months, P=0.006), while the mPFS increased by 2 months (5.0 vs. 3.0 months, P=0.20). The ORR and DCR were 30.3% vs. 13.8% and 79.8% vs. 58.6%, respectively.
The present study collected data from 214 patients with advanced esophageal cancer who received immune cross-line treatment at The First Affiliated Hospital of Henan University of Science and Technology between February 2020 and February 2024. The patients achieved a mOS of 10.0 months (95% CI: 9.5–10.5), a mPFS of 4.4 months (95% CI: 4.1–4.5), an ORR of 33.2% (95% CI: 26.9–39.9%), and a DCR of 65.9% (95% CI: 59.1–72.2%). Consistent with the above findings (12-15), these real-world findings suggest that second-line immune re-treatment for esophageal cancer is associated with a clinical benefit.
The study had several notable strengths. First, it was the first to explore different combination treatment regimens, including I+C, I+A, and I+C+A. The results suggest that all three treatment regimens provide consistent survival benefits, providing guidance for treatment selection and clinical decision-making. Although no statistically significant differences were observed among the three groups, the I+C+A group showed a trend toward improved OS and PFS, which may be attributed to the synergistic effects of anti-angiogenesis and immunotherapy (26). However, this regimen requires greater patient tolerability and carries higher costs, which may partly explain the smaller sample size of this subgroup.
This study also evaluated the efficacy of different immune cross-line modes by stratifying the patients into a PD-1 or PD-L1 inhibitor group (in which the same class of PD-1 or PD-L1 inhibitor was used across first- and second-line regimens) and a PD-1 and PD-L1 inhibitor group (in which PD-1 and PD-L1 inhibitors were used across first- and second-line regimens in a cross-over manner). Clinically, the PD-1 or PD-L1 inhibitor cross-line mode was more commonly used (n=189, 88.3%). The mOS and PFS of the PD-1 or PD-L1 inhibitor group were 10.0 months (95% CI: 9.7–10.3) and 4.3 months (95% CI: 4.1–4.5), respectively; while the mOS and PFS of the PD-1 and PD-L1 inhibitor group were 10.6 months (95% CI: 9.1–12.1) and 4.6 months (95% CI: 3.7–5.5), respectively. No statistically significant differences were observed between the two groups. These results suggest that the efficacy of Immune re-treatment is not significantly associated with the type of immunotherapy drug used.
Second, this study examined the effect of different resistance types after first-line immunotherapy on the efficacy of second-line immunotherapy. Referring to the definition of primary resistance by the Society for Immunotherapy of Cancer (SITC) (27) (i.e., a minimum drug exposure of 6–12 weeks and disease progression within ≤6 months), this study included patients who received PD-1 or PD-L1 inhibitor–based combination therapy for more than 3 months in the first-line setting to exclude those with primary resistance and no immune response. Patients were stratified according to first-line PFS as >6 or ≤6 months. The results showed that the patients with first-line PFS >6 months had significantly better second-line mOS and mPFS than those with PFS ≤6 months (P<0.01). In the univariate Cox proportional hazards regression analyses, first-line PFS >6 months was an independent prognostic factor for second-line PFS and OS. This result suggests that patients who achieve longer remission following first-line immunotherapy may also achieve better efficacy from second-line immunotherapy. The SITC (27) definition of acquired resistance to I+C includes a drug exposure duration of at least 6 months, with the best response lasting more than 6 months. These results also suggest that patients with acquired resistance may have a better response to subsequent immunotherapy, supporting screening of advantageous populations for Immune re-treatment in esophageal cancer.
In terms of study design, this study included a relatively large sample size, enhancing the robustness and generalizability of the findings, and further supporting the results of previous prospective or retrospective studies. Safety analysis showed only 6.1% ≥ grade 3 irAEs, further confirming the safety and tolerability of immunotherapy in clinical practice. The benefits of immune re-treatment for esophageal cancer may stem from sustained immune activation, incomplete cross-resistance, and remodeling of the immune microenvironment. In immune re-treatment of esophageal cancer, retaining the PD-1 inhibitor does not rely on the exhausted old T-cell clones, but rather targets the T cell factor-1 (TCF-1)+ progenitor cell depleted T-cell (Tpex) pool that remains activated. After switching to chemotherapy or combining with anti-angiogenic drugs, the release of new antigens and the remodeling of the vasculature reshape the microenvironment, reactivate and differentiate Tpex. At this point, continuing to retain the PD-1 inhibitor can block the continuous high expression of PD-L1 on the surface of tumor cells, protect newly differentiated effector T cells from immediate depletion, and thereby transform the chronic continuous activation into an effective acute response to new antigens (28). At the microenvironment level, advanced tumors often exist in a hypoxic state and an immune exclusion state mediated by cancer-associated fibroblasts (CAFs), and introducing anti-angiogenic drugs can normalize the vasculature, reduce interstitial pressure, alleviate hypoxia, increase CD8+ T-cell infiltration, and its targets have no cross-resistance with chemotherapy/PD-1 (29-31). For example, anti-vascular endothelial growth factor (anti-VEGF) drugs promote vasculature normalization, remove the physical barrier of CAFs/transforming growth factor-β (TGF-β), and alleviate immune suppression caused by hypoxia (32). From the antigen perspective, changing to different mechanisms of chemotherapy drugs can induce a new pattern of immunogenic cell death, release different damage-related molecular patterns and generate new antigens, and some drugs can upregulate human leukocyte antigen class Ⅰ (HLA-I) expression, thereby overcoming antigen loss and presentation defects after first-line treatment (33,34).
This greater inclusiveness of real-world data is bound to be accompanied by inherent limitations such as treatment selection bias, missing key data, and confounding that are difficult to fully control, as compared to prospective randomized controlled trial populations that are underrepresented in patients with poor performance status, comorbidities, older age, or more complex prior treatment history, which is an inevitable cost at the methodological level. Given the presence of several confounding factors inherent to retrospective studies, patients who received radiotherapy in the second-line setting were excluded from the study. However, radiotherapy is an important treatment option for esophageal cancer, as it can induce tumor cell death while initiating an acquired anti-tumor immune response. When combined with immunotherapy, the acquired anti-tumor immune response may be further enhanced and sustained, exerting a synergistic anti-tumor effect (35,36). Thus, the exclusion of patients who received radiotherapy represents a limitation of this study. Further prospective, multi-cohort studies are needed to confirm the efficacy of Immune re-treatment for advanced esophageal cancer.
Conclusions
Overall, the results of this study suggest that ICI retreatment showed measurable activity in a selected real-world cohort and deserves further evaluation in comparative studies.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The First Affiliated Hospital of Henan University of Science and Technology (approval No. 2024-03-K0118), which waived the requirement for additional consent for the use of medical records due to the retrospective study design and the use of anonymized data. All patients signed the informed consent form for treatment.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-2110/rc
Funding: This work was supported by the Key Specialized Research and Development Breakthrough Program (No. 242102310301).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-2110/coif). The authors have no conflicts of interest to declare.
(English Language Editor: L. Huleatt)
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-2110/dss
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