Pembrolizumab combined with chemotherapy has been proven effective as first-line therapy in patients with advanced esophageal cancer. Few trials have assessed the safety and efficacy of this treatment in patients with locally advanced disease.

To analyze long-term outcomes of pembrolizumab in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) in the real world.

Patients with advanced ESCC admitted to our center from October 2019 to October 2021 were enrolled in this study. Clinical staging of the patients was based on the 8^th edition of the American Joint Committee on Cancer TNM staging system. The patients received different treatments based on clinical stage. In brief, patients with locally advanced and resectable ESCC received neoadjuvant therapy combined with surgery. For those who were not candidates for resection, radical concurrent chemoradiotherapy plus pembrolizumab was more preferable. Patients with metastatic ESCC or who were unsuitable for radiotherapy underwent chemotherapy in combination with pembrolizumab. Long-term survival outcomes such as overall survival (OS), progression-free survival, disease-free survival, long-term adverse effects (AEs), immune maintenance therapy and predictors of immune checkpoint inhibitors (ICIs) efficacy were evaluated.

A total of 55 patients with advanced ESCC were enrolled in this retrospective, observational study. The median age was 61 years (range 44-74), with 47.3% (26/55) of the patients in stage IV and 45.5% of the patients had the tumor (25/55) located in the middle third of the esophagus. The median OS in all patients was not reached. The 12-mo OS rate among all patients was 78.8% and the 18-mo OS rate was 72.7%. 9 patients died due to tumor progression and 7 patients died due to treatment-related complications. The therapeutic effect evaluated at the interim evaluation was significantly reflected in the long-term outcome. Patients with complete response or partial response in all patients (P = 0.005) and in the chemoradiotherapy plus pembrolizumab group (P = 0.007) obtained a better prognosis than non-responders. A total of 20 patients (20/55, 36%) received immune maintenance therapy. Baseline peripheral blood biomarkers of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and neutrophil-to-(leukocyte-neutrophil) ratio did not predict the efficacy of ICIs.

Pembrolizumab combined with chemotherapy or radiotherapy resulted in favorable long-term survival in patients with locally advanced or metastatic ESCC, with safe and manageable long-term AEs.

Esophageal cancer is the seventh most common and the sixth leading cause of malignant tumor death worldwide[1]. In China, the incidence and mortality risk of esophageal cancer rank sixth and fourth, respectively[2]. The majority of esophageal cancer patients in China have esophageal squamous cell carcinoma (ESCC) which accounts for 90% of tissue types, and less than 10% have adenocarcinoma[3,4]. Most patients initially diagnosed with esophageal cancer have advanced disease, some patients have locally advanced disease which is inoperable, and some patients have metastases to other sites. Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the main treatment for resectable ESCC[5,6]. Radical concurrent chemoradiotherapy is an important treatment strategy for locally advanced unresectable patients[7]. For metastatic ESCC, systemic chemotherapy is the only treatment option[8,9]. In fact, for locally advanced or metastatic ESCC, treatment modalities are limited, progress in long-term survival is slow, and the efficacy is unsatisfactory. Data shows that the 5-year survival rate for locally advanced ESCC is no more than 30%. The 5-year survival rate for metastatic ESCC is less than 10%[10].

In recent years, immune checkpoint inhibitors (ICIs) combined with chemotherapy has made significant progress in the first-line treatment of advanced esophageal cancer[11-15]. In the randomized phase III KEYNOTE-590 study, ICIs therapy targeting programmed cell death protein 1 (PD-1), pembrolizumab combined with chemotherapy showed a significant survival advantage over chemotherapy alone in the first-line therapy. The median overall survival (OS) was more than 12 mo and the median progression-free survival (PFS) was 6.3 mo, significantly better than the median OS of 9.8 mo and the median PFS of 5.8 mo in the chemotherapy alone group. In addition, the safety was reliable[12]. For locally advanced patients treated with neoadjuvant therapy, a multicenter real-world study in China showed that the R0 resection rate reached 97.7% in combination with ICIs, and 25.5% of patients in the ICIs plus chemotherapy group and 42.3% of patients in the ICIs plus chemoradiotherapy group achieved pathologic complete response (pCR)[16]. Furthermore, some single-arm clinical trials have also investigated the application of ICIs combined with chemotherapy or concurrent chemoradiotherapy in the field of neoadjuvant therapy[17-20]. To date, the evidence for neoadjuvant treatment combined with ICIs remains inadequate, and results from large phase III clinical trials and long-term follow-up data are lacking. In unresectable locally advanced ESCC, a recent phase IB clinical study examined the efficacy and safety of the PD-1 inhibitor camrelizumab combined with radical radiotherapy for locally advanced ESCC which was intolerant to concurrent chemoradiotherapy[21]. The results showed that median OS and PFS were 16.7 mo and 11.7 mo, respectively. The 24-mo OS rate and PFS rate were 31.6% and 35.5%, respectively. The objective response rate (ORR) was 74%. Three randomized phase III studies (KEYNOTE-975, ESCORT-CRT and RATIONALE 311) are currently being conducted to further confirm the value of ICIs combined with concurrent chemoradiotherapy. Although these studies have demonstrated the benefit of ICIs plus chemotherapy or chemoradiotherapy in locally advanced or metastatic ESCC, there is currently a lack of reliable predictors of the efficacy of ICIs in esophageal cancer. Several retrospective studies have explored the predictors of efficacy in subsequent-lines for ESCC, and the results showed that blood cell composition can predict the efficacy of ICIs[22-24]. However, predictive results for first-line treatment of locally advanced or metastatic ESCC are still lacking.

Based on this, our center conducted a real-world clinical study to examine the efficacy and safety of pembrolizumab in neoadjuvant therapy, concurrent chemoradiotherapy and first-line therapy for ESCC[25]. Early results showed that the combination with pembrolizumab demonstrated considerable ORR and acceptable adverse effects (AEs). We here report the long-term survival such as OS, disease-free survival (DFS) ,PFS, long-term toxicities and ICIs completion rates. We also assess the relationship between baseline blood cell composition indices such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-(leukocyte-neutrophil) ratio (dNLR) and long-term survival in order to determine the predictive factors of ICIs.

Our previous results showed that PD-1 inhibitor plus chemotherapy or chemoradiotherapy had a good ORR and manageable safety[25]. We used lobaplatin and albumin-paclitaxel as the chemotherapy regimen instead of cisplatin, as cisplatin has AEs on renal function. The trial proved that lobaplatin had favorable results in ESCC[26]. The present study reported the results of long-term follow-up.

For advanced ESCC, especially locally advanced disease, neoadjuvant chemotherapy plus immunotherapy followed by surgery or chemoradiotherapy combined with immunotherapy warrants further studies, as current clinical studies are confined to phase I-II trials, and long-term follow-up data are lacking. In the present study, relatively good long-term outcomes were achieved with tolerable side effects, and evidence for PD-1 inhibitor combined with chemotherapy or radiotherapy used in ESCC has been provided.

In this study, 21 patients received neoadjuvant therapy plus pembrolizumab followed by surgery. The results demonstrated that the 12-mo DFS rate was 85%, the 18-mo DFS rate was 75%, the 12-mo OS rate was 95% and the 18-mo OS rate was 89.7%. The median OS or DFS was not reached. The results of the NEOCRTEC 5010 study indicated that the 1-year OS rate in the nCRT group was 90% and the 2-year OS rate was 75.1%[5]. Our results were similar to those of the NEOCRTEC 5010 trial. However, during a median follow-up of 24 mo in our study, patients were found to have local recurrence in mediastinal lymph nodes, anastomotic stoma and retroperitoneal lymph nodes. Lung, pleural effusion, and supraclavicular lymph node metastases were found in 23.8% of patients (5/21). The 10-year pattern of recurrence and metastasis in the CROSS study showed that the proportion of isolated local recurrence in the neoadjuvant group was 8% (15/178). The percentage of patients with both local recurrence and distant metastasis were 13% (23/178). In addition, the ratio of patients with simple distant metastasis was 27% (48/178)[27]. In our study, the recurrence pattern was dominated by distant metastasis, but there was still a high local recurrence rate. Therefore, it remains unclear whether the local recurrence risk with neoadjuvant chemotherapy plus ICIs is non-inferior to neoadjuvant concurrent chemoradiotherapy. Furthermore, the relatively high recurrence rate in the short follow-up period in our study requires further verification in large clinical trials. In the CHECKMATE-577 trial, the median DFS for patients who did not reach pCR after nCRT was significantly better in the maintenance treatment group with nivolumab than in the placebo group[28]. In our study, the postoperative immune maintenance rate was only 14.3% (3/21), which may also be one of the reasons for the increased rate of distant metastasis. In the future, neoadjuvant therapy for locally advanced esophageal cancer requires continuous optimization of protocols to reduce the risk of distant metastasis and improve survival. In addition, on the premise of ensuring local control, eliminating radiotherapy to reduce AEs is also worth further exploration.

20 patients with unresectable locally advanced or limited supraclavicular lymph node metastases received chemoradiotherapy combined with pembrolizumab. The results showed that the 12-mo OS rate was 65%, the 18-mo OS rate was 60% and the median OS was not reached. The 12-mo PFS rate was 55%, the 18-mo PFS rate was 50% and the median PFS was 17 mo. The median survival time following radical concurrent chemoradiotherapy recommended by current guidelines was 18 mo, and the 2-year survival rate was about 40%[29]. The long-term survival in the radical chemoradiotherapy plus pembrolizumab group in our study was slightly better than that in the standard radical concurrent chemoradiotherapy group. The addition of ICIs to chemoradiotherapy likely increased the efficacy and prolonged survival. However, randomized phase III studies are needed to verify this. A phase IB clinical study is currently examining the efficacy and safety of the PD-1 inhibitor camrelizumab combined with radical radiotherapy in patients with locally advanced ESCC who are intolerant to concurrent chemoradiotherapy[21]. The median OS and PFS were 16.7 mo and 11.7 mo, respectively. The 24-mo OS rate and PFS rate were 31.6% and 35.5%, respectively. The ORR rate was 74%. Our results showed a more beneficial outcome, probably because we used the combination of radiotherapy and chemotherapy, which strengthened the intensity of treatment and improved survival outcomes. Studies have shown that the incidence rate of esophageal fistula caused by radiotherapy and chemotherapy is approximately 15%, of which T4 and esophageal stenosis increase the risk of fistula with a poor prognosis[30]. In our study, 20% (4/20) patients died from esophageal fistula. The patients with fistula in the radiotherapy plus pembrolizumab group were all T4 and the tumor was closely related to the trachea, which was suspected to have invasion. Furthermore, the radiotherapy dose in this group was 63 Gy, and the high radiotherapy dose was also the main cause of fistula. Studies have shown that higher 60 Gy did not improve long-term survival and simultaneously increased AEs[31]. Therefore, in the era of ICIs, for locally advanced patients with T3-T4, radiotherapy dose should be carefully selected and safety should be taken into account in the absence of clear evidence of benefit. The data and results of randomized phase III studies on the combination therapy of radiotherapy and ICIs are lacking at present. There are still some problems to be solved such as the timing of combination therapy, selection of the combination chemotherapy regimen, clinical target volume and so on. The results of KEYNOTE-975, ESCORT-CRT, RATIONALE-311 and other randomized phase III studies are expected.

A total of 14 patients in our study received chemotherapy combined with pembrolizumab. The 12-mo OS rate was 75% and the 18-mo OS rate was 66.7%. The 12-mo PFS rate and 18-mo PFS rate were 67.7%. In the randomized phase III JUPITER-06 study, toripalimab combined with chemotherapy significantly prolonged PFS in patients with a 42% reduction in the risk of disease progression and resulted in a significant benefit in median OS (17 mo vs 11 mo) compared with placebo plus chemotherapy. The 1-year PFS rate was 27.8% and the 1-year OS rate was 66% in the toripalimab-based group[11]. The long-term survival results in our study were better than those in the JUPITER-06 study, and even better than those in the radiotherapy plus pembrolizumab group. There are several possible reasons for this result: (1) The tumor burden in the chemotherapy combined with pembrolizumab group was relatively low. Some patients with stage III refused radiotherapy due to toxicity, while others had single liver metastasis or small nodules in lung metastasis; (2) In the radiotherapy plus pembrolizumab group, 4 patients died due to esophageal fistula after radiotherapy and survival outcomes were negatively affected; and (3) Small sample size and short follow-up time may have led to deviations in the results.

As indicators of systemic inflammation, the NLR, PLR and dNLR can reflect the microenvironment of inflammation. Neutrophils can promote tumor invasion and progression by secreting cytokines, vascular endothelial cell growth factors and chemokines[32]. However, lymphocytes play an important role in the immune system and can inhibit tumor proliferation[33]. Studies have reported that in patients with non-small cell lung cancer and a higher baseline NLR, ICIs had poor efficacy, which had a negative predictive value on PFS and OS[34]. Our study found that low baseline NLR, dNLR and PLR showed a trend for OS benefit, but a statistically significant difference was not observed. This result may have been limited by the small sample size. Thus, a larger sample size is needed to examine this issue in the future.

This study also had some limitations: (1) This was a single-arm, single-center retrospective clinical study, with a small number of patients and did not include a control group; (2) The follow-up period should have been longer, as there is a lack of 3-year and 5-year long-term survival outcomes; and (3) Prospective randomized controlled studies with long-term follow-up data are needed.

Our real-world results revealed that pembrolizumab combined with chemotherapy or radiotherapy resulted in a favorable long-term survival outcome in patients with locally advanced and metastatic esophageal cancer. Long-term toxicities associated with these regimens were manageable.

We thank Dr. Run-Kun Yang from Merck Sharp and Dohme Medical Affairs for his scientific comments on the manuscript.