Efficacy and safety of camrelizumab combined with chemotherapy as second-line treatment for locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma

Abstract

Background

This study aims to evaluate the efficacy and safety of camrelizumab in combination with chemotherapy as a second-line treatment for patients with locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC).

Methods

In this retrospective, single-center observational study, we collected medical records of patients with locally advanced, recurrent, or metastatic ESCC who received either camrelizumab combined with chemotherapy or chemotherapy alone as second-line treatment between July 1, 2019, and May 31, 2023. We evaluated short-term efficacy, including overall response rate (ORR) and disease control rate (DCR), as well as survival outcomes, including progression-free survival (PFS) and overall survival (OS). Safety was also assessed. Additionally, factors influencing OS in ESCC patients were analyzed.

Results

A total of 60 patients with locally advanced, recurrent, or metastatic ESCC were included, with 30 receiving camrelizumab combined with chemotherapy and 30 receiving chemotherapy alone as second-line treatment. There were no statistically significant differences in ORR (33.33% vs. 13.33%) and DCR (73.33% vs. 56.67%) between the combination therapy and chemotherapy-alone groups (P > 0.05). However, the median PFS was significantly longer in the combination therapy group compared to the chemotherapy group (4.7 months vs. 3.4 months, P = 0.048). Additionally, the median OS was significantly improved in the combination therapy group compared to the chemotherapy group (11.7 months vs. 6.5 months, P = 0.003). Age and history of radical surgery were significantly associated with OS in patients receiving camrelizumab combined with chemotherapy as second-line treatment (P < 0.05).

Conclusion

Second-line treatment with camrelizumab combined with chemotherapy is well-tolerated and associated with favorable oncological outcomes in patients with locally advanced, recurrent, or metastatic ESCC. Furthermore, younger patients and those who have undergone radical surgery may derive greater benefit from camrelizumab combined with chemotherapy as a second-line treatment.

Highlights

Camrelizumab combined with chemotherapy as a second-line treatment significantly extended progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone.

Younger patients and those with a history of radical surgery showed greater benefits from the immunotherapy combined regimen, with significant OS improvement.

The combination of camrelizumab and chemotherapy showed a manageable safety profile, with adverse events similar to chemotherapy alone.

Introduction

Esophageal cancer (EC) is a prevalent malignant tumor of the digestive system worldwide [1]. Early-stage EC often presents with non-specific symptoms, leading to over 70% of patients being diagnosed at an advanced stage [2]. Although surgery, radiotherapy, and chemotherapy can enhance survival in patients with esophageal squamous cell carcinoma (ESCC), factors such as local recurrence, regional lymph node involvement, extensive metastasis, and drug resistance result in a 5-year survival rate of only 20–30% for those with unresectable, locally advanced, recurrent, or metastatic ESCC [3]. These patients typically receive chemotherapy-based treatments; however, the benefits remain limited [4]. Before the advent of immunotherapy, treatment for advanced EC primarily relied on chemotherapy. Regardless of whether paclitaxel combined with platinum agents or fluorouracil combined with platinum agents was used, median overall survival (OS) was less than one year [5,6,7].

Currently, immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) checkpoints have been approved for the treatment of various malignancies [8]. Advances in tumor immunotherapy have led to the widespread application of immune checkpoint inhibitors in EC. Multiple anti-PD-1 antibodies, such as pembrolizumab, camrelizumab, and nivolumab, combined with chemotherapy are recommended for first-line treatment. Clinical trials indicate that first-line chemotherapy combined with immunotherapy can improve the prognosis of patients with advanced EC [9,10,11]. However, due to factors such as treatment costs and patient selection criteria, some patients with advanced EC do not receive immunotherapy in the first-line setting. Clinical studies of various anti-PD-1 antibodies, including pembrolizumab, camrelizumab, nivolumab, and tislelizumab, have demonstrated that immunotherapy alone as a second-line treatment can still benefit patients who did not receive immunotherapy initially. However, the overall response rate (ORR) of second- or third-line immunotherapy monotherapy for EC remains low, at only 16–20%, with over 80% of patients not achieving tumor remission [12,13,14,15]. Therefore, providing more effective subsequent treatment options for these patients remains an important research direction. Given the significantly higher efficacy of first-line immunotherapy combined with chemotherapy for EC compared to chemotherapy alone, it is reasonable to hypothesize that combined chemotherapy may improve efficacy and prognosis in second-line treatment for EC patients who did not receive immunotherapy initially.

Camrelizumab is currently approved in China for second-line immunotherapy for ESCC. However, its monotherapy ORR is approximately 20%, with 80% of ESCC patients not achieving tumor remission [16]. In contrast, the ORR of camrelizumab combined with chemotherapy in first-line treatment for advanced ESCC can reach 72%, yielding favorable outcomes [17]. For ESCC patients who did not receive immunotherapy in the first-line setting, combined chemotherapy in second-line treatment, if tolerable, may enhance treatment efficacy [18]. Therefore, we conducted this retrospective study to evaluate the efficacy and safety of camrelizumab combined with chemotherapy as a second-line treatment for advanced ESCC at our center.

Materials and methods

Study participants and study design

This retrospective, single-center observational study included medical records of patients with ESCC who received at least two cycles of camrelizumab combined with chemotherapy or chemotherapy alone as second-line treatment at our center between July 1, 2019, and May 31, 2023. Inclusion criteria were as follows: patients aged between 18 and 75 years; pathologically confirmed ESCC; locally advanced, recurrent, or metastatic ESCC with disease progression during or after first-line systemic treatment; Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; measurable lesions as defined by RECIST 1.1 criteria; and traceable cases, including baseline data, safety data, baseline imaging, and at least one post-treatment imaging examination. Exclusion criteria included: patients who received anti-PD-1, anti-PD-L1, anti-PD-L2, or any targeted T-cell co-stimulation or checkpoint pathway antibodies or drugs during first-line treatment; patients participating in interventional studies; and patients with grade 2 or higher anemia, hypoalbuminemia, or esophageal fistula as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

The study cohort was divided into two groups: the chemotherapy group and the immunotherapy combined with chemotherapy group. Patients in the chemotherapy group received only chemotherapy as second-line treatment, with chemotherapy drugs selected based on individual patient conditions. Patients in the immunotherapy combined with chemotherapy group received camrelizumab in combination with chemotherapy as second-line treatment, with chemotherapy drugs similarly tailored to the patient’s specific condition. Camrelizumab was administered at a dose of 200 mg via intravenous infusion every 21 days, on day 1 of each cycle, until disease progression, unacceptable toxicity, or a maximum treatment duration of two years. No dose reductions or adjustments were made for camrelizumab.

Clinical cases and treatment-related data of patients with locally advanced, recurrent, or metastatic ESCC who received second-line treatment were retrieved from electronic medical records. Follow-up with patients was conducted via telephone, WeChat, and other methods to obtain data on progression-free survival (PFS) and OS. The follow-up period concluded on April 30, 2024.

Assessments

Efficacy in both groups was evaluated every two treatment cycles according to RECIST 1.1 criteria, utilizing enhanced CT scans. The evaluation criteria included complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD). Definitions were as follows: CR denotes the disappearance of all target lesions; PR indicates at least a 30% reduction in the sum of diameters of target lesions; PD signifies more than a 20% increase in the sum of diameters of target lesions; and SD refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, with no new lesions. CR and PR cases require efficacy confirmation 4 weeks after the initial evaluation. ORR = (CR + PR) / total cases * 100.00%. Disease control rate (DCR) = (CR + PR + SD) / total cases * 100.00%.

Outcomes

We recorded and analyzed PFS and OS for both groups. PFS was defined as the time from the first date of medication to the first occurrence of tumor progression or death from any cause. OS was defined as the time from the first date of medication to death from any cause. Patients who were lost to follow-up were censored at the date of last contact, and surviving patients were censored at the end of the study date. We collected follow-up and laboratory examination data before and after treatment with chemotherapy alone or camrelizumab combined with chemotherapy. Follow-up methods included physical examinations, telephone calls, WeChat messages, and interviews to obtain safety data. Laboratory tests encompassed complete blood counts, blood biochemistry, free thyroid function tests, urinalysis, stool examinations, ECGs, and myocardial enzyme tests. Adverse events (AEs) were recorded based on the Common Terminology Criteria for Adverse Events (CTCAE) and classified into grades 1 through 5.

Statistical analysis

Continuous variables were presented as medians (ranges) and compared using the Student’s t-test. Categorical variables were presented as numbers and percentages and compared using the χ² test. The impact of different factors on PFS and OS was assessed using the Kaplan-Meier method and the Log-Rank test. A Cox proportional hazards model was used for univariate analysis of OS, and variables with statistical significance (P < 0.05) were included in a multivariate Cox proportional hazards model analysis, which provided hazard ratios (HR) and 95% confidence intervals (CI). All statistical tests were two-sided, with a significance level set at α = 0.05. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 27.0 (IBM Corp., Armonk, N.Y., USA).

Results

Baseline characteristics

A total of 60 patients with locally advanced, recurrent, or metastatic ESCC were included (Fig. 1). Patients who underwent concurrent radical radiotherapy were excluded. However, a small number of patients in the chemotherapy group (3 cases) received palliative radiotherapy for non-target lesions, such as bone metastases, primarily for pain relief. Of the included patients, 30 received immunotherapy combined with chemotherapy, and 30 received chemotherapy alone. The median age was 59 years (range, 45–73) in the combination therapy group and 60 years (range, 43–75) in the chemotherapy group. The median number of treatment cycles was 4 (range, 2–32) in the combination group and 3.5 (range, 2–15) in the chemotherapy group. There were no statistically significant differences between the two groups regarding gender, age, disease stage, tumor location, degree of differentiation, or history of radical chemoradiotherapy or surgery (P > 0.05) (Table 1).

Fig. 1

A flowchart of the patient selection process

Table 1 Comparison of clinical and pathological data in two groups (n, %)

Short-term efficacy

No CR patients were observed in either group. The differences in ORR and DCR between the immunotherapy combined with chemotherapy group and the chemotherapy group were not statistically significant (P > 0.05) (Table 2).

Table 2 Comparison of short-term efficacy in two groups [n, %]

Long-term efficacy

The median progression-free survival (mPFS) was 3.4 months (95% CI, 2.4–4.3) in the chemotherapy group and 4.7 months (95% CI, 1.6–7.8) in the immunotherapy combined with chemotherapy group. The mPFS was significantly longer in the combination therapy group compared to the chemotherapy group (P = 0.048) (Fig. 2). The 6-month PFS rate was 23.3% in the chemotherapy group versus 49.8% in the combination therapy group. The median overall survival (mOS) was 6.5 months (95% CI, 5.6–7.4) in the chemotherapy group and 11.7 months (95% CI, 6.7–16.7) in the immunotherapy combined with chemotherapy group. The mOS was significantly longer in the combination therapy group compared to the chemotherapy group (P = 0.003) (Fig. 3). The 12-month OS rate was 23.3% in the chemotherapy group versus 49.6% in the combination therapy group.

Fig. 2

Comparison of PFS between the two groups of ESCC patients (C: Chemotherapy group, CC: Chemotherapy plus camrelizumab group)

Fig. 3

Comparison of OS between the two groups of ESCC patients (C: Chemotherapy group, CC: Chemotherapy plus camrelizumab group)

Analysis of risk factors associated with PFS and OS

Using the Kaplan-Meier method, we conducted a univariate analysis to evaluate the impact of clinical and pathological characteristics on PFS in patients with locally advanced, recurrent, or metastatic ESCC. The results indicated that factors such as sex, age stratification, staging, tumor location, pathological differentiation, prior radical radiotherapy, post-treatment prognostic nutritional index (PNI) after two cycles, and pre-treatment PNI were not significantly associated with PFS in patients receiving second-line treatment (P > 0.05). However, factors such as whether the anti-tumor treatment regimen included immunotherapy, tumor response (ORR and DCR), and whether prior radical surgery had been performed were significantly associated with PFS (P < 0.05) (Table 3). Based on these findings, factors with statistical significance in the univariate analysis were included in the multivariate Cox regression analysis. The multivariate analysis demonstrated that tumor shrinkage to stable disease (SD) or better was independently associated with improved PFS in patients receiving second-line treatment for locally advanced, recurrent, or metastatic ESCC (P < 0.05) (Table 4).

Similarly, a univariate analysis using the Kaplan-Meier method was performed to assess the impact of clinical and pathological characteristics on OS in the same patient population. The analysis showed that factors such as gender, age stratification, stage, tumor location, degree of pathological differentiation, prior radical surgery, prior radical radiotherapy, and pre-enrollment PNI were not statistically related to OS in patients receiving second-line treatment (P > 0.05). In contrast, tumor treatment response (ORR, DCR), inclusion of immunotherapy in the anti-tumor treatment regimen, and PNI value after two cycles of treatment were significantly associated with OS (P < 0.05) (Table 5). Consequently, variables demonstrating statistical significance in the univariate analysis were incorporated into the multivariate Cox regression analysis. The multivariate analysis identified that the inclusion of immunotherapy in the treatment regimen and achieving a PR or higher tumor regression were independently associated with better OS in patients with locally advanced, recurrent, or metastatic ESCC undergoing second-line treatment (P < 0.05) (Table 6).

Table 3 Univariate analysis of PFS for second-line treatment in advanced ESCC patients $(\bar x \pm s)$

Table 4 Multivariate analysis of PFs for second-line treatment in advanced ESCC patients

Table 5 Univariate analysis of OS for second-line treatment in advanced ESCC patients($(\bar x \pm s)$)

Table 6 Multivariate analysis of OS for second-line treatment in advanced ESCC patients

Further stratified analysis revealed no statistically significant difference in OS between patients aged over 60 years in the two treatment groups (P = 0.714) (Fig. 4). However, among patients aged 60 years or younger, there was a statistically significant improvement in OS for those receiving second-line immunotherapy combined with chemotherapy compared to those receiving chemotherapy alone (P < 0.001) (Fig. 5). Additionally, patients with a history of radical surgery exhibited significantly better survival outcomes in the immunotherapy combined with chemotherapy group compared to the chemotherapy-only group (P = 0.042) (Fig. 6). In contrast, no statistically significant difference in OS was observed among patients without a history of radical surgery (P = 0.103) (Fig. 7).

Fig. 4

Comparison of OS in ESCC patients aged > 60 years (C: Chemotherapy group, CC: Chemotherapy plus camrelizumab group)

Fig. 5

Comparison of OS in ESCC patients aged ≤ 60 years (C: Chemotherapy group, CC: Chemotherapy plus camrelizumab group)

Fig. 6

Comparison of OS in ESCC patients with radical surgery (C: Chemotherapy group, CC: Chemotherapy plus camrelizumab group)

Fig. 7

Comparison of OS in ESCC patients with no history of radical surgery (C: Chemotherapy group, CC: Chemotherapy plus camrelizumab group)

Safety

Treatment-related AEs were documented in 100% of patients in both groups. The incidence rates of RCCEP (80%) and hypothyroidism (33%) were significantly higher in the immunotherapy combined with chemotherapy group compared to the chemotherapy-only group (P < 0.05). The incidence rates of other AEs, including pneumonia, myelosuppression, hyponatremia, hypoalbuminemia, and hypokalemia, were comparable between the two groups, with no statistically significant differences (P > 0.05) (Table 5). The immunotherapy combined with chemotherapy group reported irAEs such as RCCEP, hypothyroidism, rash, immune pneumonia, and immune enteritis.

Table 7 Comparison of common AEs in two groups (n, %)

Discussion

In China, EC ranks sixth in incidence among malignant tumors and fourth in mortality, which is significantly higher than the global average and still rising [19]. Traditional chemotherapy-based treatments have limited effectiveness for advanced EC, with OS not exceeding one year [20]. In recent years, the introduction of immunotherapy has led to more favorable clinical outcomes compared to traditional chemotherapy [21]. However, the efficacy of immunotherapy alone as a second-line treatment for patients who did not receive immunotherapy as a first-line treatment remains unsatisfactory. The potential for subsequent immunotherapy combined regimens to enhance efficacy warrants further investigation.

This retrospective study demonstrated that, in terms of safety, the overall incidence of AEs and major grade 3–4 AEs in the immunotherapy plus chemotherapy group was comparable to that in the chemotherapy-only group. The primary grade 3–4 AEs in the immunotherapy plus chemotherapy group were similar to those in the chemotherapy group, predominantly consisting of hematologic toxicities such as anemia, decreased white blood cell count, decreased neutrophil count, and decreased lymphocyte count. Wang et al. reported that camrelizumab combined with chemotherapy or as monotherapy in the treatment of advanced ESCC can cause adverse reactions including abnormal liver function and decreased appetite, though most are mild and manageable with symptomatic treatment [22]. Xu et al. also noted that adverse reactions are tolerable when using camrelizumab for advanced tumor patients [17]. Overall, camrelizumab combined with chemotherapy exhibits high tolerability in patients with advanced ESCC.

Although the immunotherapy plus chemotherapy group showed higher ORR (33.33%) and DCR (73.33%) compared to the chemotherapy group (ORR 13.33%, DCR 56.67%), these differences were not statistically significant, potentially due to the small sample size. Notably, the ORR and DCR in the chemotherapy group of this study were higher than those reported in previous phase III clinical trials (ORR 6-10%, DCR 35-42%), which may be attributed to factors such as the use of dual chemotherapy agents and the inherent selection bias of retrospective studies [13, 15]. The ORR of 33.33% in the immunotherapy plus chemotherapy group exceeds previously reported data for second-line immunotherapy monotherapy (12-20%) [12,13,14,15, 23]. A prospective study involving 238 patients with advanced EC receiving second-line treatment (68.5% combined with chemotherapy) reported an ORR of 31.4% [24], which aligns closely with our findings.

Furthermore, this study observed that the median OS in the immunotherapy plus chemotherapy group was 11.7 months, compared to 6.5 months in the chemotherapy group, indicating a significant 5.2-month increase in median OS for the combination treatment (P = 0.003). The second-line regimen of camrelizumab combined with chemotherapy appears to prolong OS in patients with locally advanced, recurrent, or metastatic ESCC compared to chemotherapy alone, potentially due to the synergistic effects of immunotherapy and chemotherapy [25]. Chemotherapy not only eradicates tumor cells but also releases tumor antigens, thereby stimulating the immune system and enhancing the efficacy of camrelizumab. Key phase III studies on second-line treatments have reported mOS for immunotherapy monotherapy ranging from 8 to 10 months, while chemotherapy alone yielded an mOS of 6 to 8 months. The ESCORT study, for instance, reported an mOS of 8.3 months for the immunotherapy group versus 6.2 months for the chemotherapy group [12,13,14,15, 23]. Additionally, the 12-month OS rate in the immunotherapy plus chemotherapy group was 49.6%, compared to 34% for immunotherapy monotherapy in the ESCORT study, suggesting a trend toward long-term OS benefits. Given that our study is a real-world retrospective analysis with more complex baseline conditions, further investigation is needed to determine whether combination immunotherapy can consistently outperform monotherapy. In addition, in our study, a total of 15 patients were categorized as locally advanced (stage IIIB and IVA). Among these, 8 patients had disease progression following prior radical radiotherapy, 3 patients were deemed unsuitable for radiotherapy due to high tumor burden and risk of esophageal fistula, 2 patients were not recommended for radical radiotherapy due to poor lung function, and 2 patients refused curative radiotherapy for financial reasons.

In stratified analyses, patients aged ≤ 60 years receiving immunotherapy combined with chemotherapy showed a statistically significant OS benefit compared to those receiving chemotherapy alone, whereas no significant difference was observed in patients aged > 60 years. In the chemotherapy group, OS stratified by age was not significant; however, in the immunotherapy plus chemotherapy group, age stratification revealed significant differences, consistent with previous research [26, 27]. Thus, age is a crucial predictive factor for survival in second-line chemotherapy combined with immunotherapy for EC patients. Younger patients typically have better organ function, enhanced tolerance, and stronger immune responses, making them more suitable candidates for combination therapy [28]. Conversely, the short-term benefits of combination therapy in patients aged > 60 years may be limited by reduced treatment tolerance [29]. These findings suggest that treatment plans should consider patient age and other factors to tailor individualized therapy. Multivariate Cox regression analysis confirmed that the inclusion of immunotherapy was a major influencing factor for OS in second-line treatment patients, aligning with previous studies on second-line immunotherapy for ESCC [12,13,14,15].

Moreover, stratified analysis indicated that patients with a history of radical surgery experienced improved survival benefits from immunotherapy combined with chemotherapy compared to those receiving chemotherapy alone. These patients often present with regional lymph node recurrence and distant metastasis, with a low incidence of local esophageal recurrence. This results in less impact on swallowing and better nutritional intake during treatment, thereby reducing the risk of anemia and grade 2 or higher hypoalbuminemia [30]. Additionally, PNI values improved after treatment (average increase from 46.2 to 58.7), and the risk of esophageal fistula was lower compared to non-surgical patients. This allows for more complete courses of immunotherapy combined with chemotherapy, enhancing immune responses and providing greater survival benefits [31].

This study has several limitations. Firstly, the retrospective nature of the present study may have introduced potential biases into the results. Secondly, the single-center design limits the generalizability of the findings. Thirdly, PD-L1 testing was performed in only a small fraction of patients in our cohort, with two patients showing a Combined Positive Score (CPS) less than 5 and one patient being negative in the chemotherapy group; in the immunotherapy combined with chemotherapy group, PD-L1 testing was conducted in 21 patients, of whom eight patients had a CPS more than 5, five patients had a CPS less than 5, and eight patients were negative. Given the limited data available from PD-L1 testing, we are unable to conduct a subgroup analysis to evaluate the efficacy of immunotherapy based on PD-L1 status. Additionally, the relatively small sample size (n = 60) may not provide sufficient statistical power to detect all clinically relevant differences, particularly in subgroup analyses. Despite these limitations, the study holds significant clinical implications. The observed survival benefits of camrelizumab combined with chemotherapy suggest that this regimen could be a viable second-line treatment option for ESCC patients, especially those who did not receive immunotherapy as part of their first-line treatment. Further large-scale, multicenter, prospective, randomized controlled trials are warranted to validate these results and provide more robust evidence for clinical guidelines. Additionally, future studies should explore the underlying mechanisms enhancing the efficacy of the combined regimen and investigate biomarkers that could predict treatment response.

In conclusion, compared to chemotherapy alone, the second-line treatment regimen of camrelizumab combined with chemotherapy improves overall survival in patients with locally advanced, recurrent, or metastatic ESCC, while maintaining a favorable safety profile. Moreover, younger patients and those with a history of radical surgery are particularly recommended to receive camrelizumab combined with chemotherapy as a second-line treatment. Further large-scale, multicenter, prospective, randomized controlled trials are necessary to confirm these findings.