Anti-PD1/PDL1 antibodies plus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma

Background: Patients with advanced esophageal squamous cell carcinoma (ESCC) have a poor prognosis with few treatment options. Immunotherapy was suggested as a promising treatment for ESCC from some clinical trials. Here we collected clinical results from 23 patients who were received anti-PD1/PDL1 antibodies (mAbs) plus chemotherapy as first line therapy with advanced ESCC, to analyze this combined therapy’s efficacy on advanced ESCC. Methods: Results of 23 Patients started treatment from December 15th, 2017 to September 27th, 2019 (12 patients were enrolled in phase II clinical trials, 11 patients were treated by physician’s choice regiment) of anti-PD1/PDL1 antibodies (mAbs) plus chemotherapy on advanced ESCC as first line treatment were collected. Regiments were either anti-PD1 or anti-PDL1 mAbs plus traditional chemotherapy (cisplatin/5-fluorouracil (5-FU), Paclitaxel/ cisplatin, Paclitaxel/carboplatin or Paclitaxel/ 5-FU) every 3 weeks for six cycles, followed by maintenance therapy with anti-PD1/PDL1 mAbs. Objective response and safety profiles were observed as well as progression-free survival(PFS), overall survival(OS) and duration of response. Results: Of the 23 patients, 18 (78.3%) responded to treatment: 15 partial and 3 complete response. 4 patients had stable disease and 1 patient had progressive disease. The median time to response was 1.4 months (range, 1.4 months – 2.8 months). Treatment-related adverse events occurred in all patients but 3-4 grade immune-mediated adverse events occurred in only one patient. As of April 10th, 2020, the Objective response rate was 78.3%, the median PFS was 15.5 months and the median OS was 21.5 months. No treatment-related deaths were observed. Conclusions: Anti-PD1/PDL1 antibodies plus chemotherapy as the first-line treatment for advanced ESCC showed promising results with manageable adverse events and worthy of further study.

4 patients had stable disease and 1 patient had progressive disease. The median time to response was 1.4 months (range, 1.4 months -2.8 months). Treatment-related adverse events occurred in all patients but 3-4 grade immune-mediated adverse events occurred in only one patient. As of April 10th, 2020, the Objective response rate was 78.3%, the median PFS was 15.5 months and the median OS was 21.5 months. No treatment-related deaths were observed.
Conclusions: Anti-PD1/PDL1 antibodies plus chemotherapy as the first-line treatment for advanced ESCC showed promising results with manageable adverse events and worthy of further study.

Background
Esophageal cancer is the sixth leading cause of cancer-related death, with an estimated 572,034 new esophageal cancer cases and 508,585 deaths occurred in 2018 worldwide 1 . Compared to western countries where the most esophageal cancer is adenocarcinoma(EAC), the subtype of squamous cell carcinoma exceeds more than 90% of esophageal cancer in Asia, where bearing 70% globule burden of esophageal cancer 23 . Moreover, ESCC is quite different from esophageal adenocarcinoma in terms of etiology, origins of tumor cells, biological behaviors, growth pattern and prognosis. Patients with ESCC have poorer survival than those with EAC 4 . The treatment goal of advanced ESCC is to palliate symptoms and prolong survival. Cisplatin and 5-fluorouracil (5-FU) (CF) have been established as the standard chemotherapy for advanced ESCC for several decades. Other regiments such as triplet, irinotecan-based, oxaliplatin-based and paclitaxel-based regimens and anti-EGFR inhibitors have been conducted in clinical trials to investigate modern therapeutic agents. However, the advantages of these strategies are limited and it often leads to a low qualities of life for patients 5 . Thus, new effective therapeutic approaches for advanced ESCC are urgently needed. Immune checkpoint PD-1 or its ligand PDL1 inhibitors have demonstrated robust and durable anti-tumor efficiency and manageable toxicity in numerous advanced solid tumors and are approved for the treatment of one or more advanced cancers in more than 60 countries. In esophageal cancer, they also indicated the durable clinical benefits and manageable safety profiles as KEYNOTE-028 6 , KEYNOTE-180 7 , KEYNOTE-181 8 , ONO-4538 9 , and ATTRACTION-03 10 clinical trials investigated, which indicated a promising option for advanced ESCC. However, the overall response rate remained low and immunotherapy in these studies were all the second or more lines therapy for esophageal cancer. In addition, these clinical trials not only focused on advanced ESCC, which leads to hard to tell the accurate response reactivity on this specific esophageal cancer subtype. Evidences indicated immunotherapy plus chemotherapy can improve the overall response rate in many cancers. In esophageal cancer, a phase III clinical trial (KEYNOTE-590) will evaluate the anti-tumor activity of two different groups [pembrolizumab + cisplatin + 5-fluoruracil (5-FU) vs. placebo + cisplatin + 5-FU] in patients with previously untreated esophageal carcinama. Early results of PFS and OS of patients will be expected in 2021 11 .
Here, we report results from 23 patients with advanced esophageal squamous cell carcinoma which was unresectable or incurable by radiotherapy received anti-PD1 /PDL1 mAbs combined with traditional chemotherapy as first line treatment. These data were reported of immunotherapy plus chemotherapy as first line treatment for advanced ESCC for the first time.

Study Design
In this study, patients received 3 mg/kg (weight ≤ 60 kg) or 200 mg (weight 60 kg) of anti-PD1 or anti-PDL1 mAbs plus traditional chemotherapy (cisplatin/5-fluorouracil (5-FU), Paclitaxel/ cisplatin, Paclitaxel/carboplatin or Paclitaxel/ 5-FU) every 3 weeks for six cycles, followed by maintenance therapy with anti-PD1 or anti-PDL1 mAbs respectively until progression, death or unacceptable toxicity. The specific indications of chemotherapy were 5-FU 750 mg/m2, cisplatin 75 mg/m2, paclitaxel 175 mg/m2 and carboplatin 75 mg/m2. The primary outcomes of this trial were objective response and safety. Key secondary outcomes including PFS, OS and tolerability, duration of response.

Assessments
Tumor imaging was performed every 2 cycles (1.4 months). Response was assessed per RECIST v1.1 and per irRC by investigator. PFS was calculated as the time between day1 (treatment started) and disease progression defined by RECIST v1.1 or last follow-up date. Patients were followed up for survival until death or study closure. Adverse events (AEs) were assessed for up to 30 days after treatment (90 days for serious AEs) and were graded according to Common Terminology Criteria for Adverse Events, version 4.0.

Statistical Analyses
Safety and efficacy analyses were performed in all patients. The response rate was assessed by point estimate. Duration of response, progression-free survival, and overall survival was estimated using the Kaplan-Meier method. 95% CIs were calculated using the Clopper-Pearson method.

Results Patients
From December 15th, 2017, to September 27th, 2019, 23 patients with advanced esophageal squamous cell carcinoma which was unresectable or incurable by radiotherapy were collected ( Fig. 1).
Baseline characteristics were list in Table 1. All patients received anti-PD1/PDL1 mAbs plus chemotherapy as first line therapy. The median duration of follow-up time (defined as the time from start of treatment to death or the date of data cutoff for those who were alive) was 11.9 months (range, 6.0-27.2 months) as of April 10th, 2020. As of April 10th, 2020, 7 patients (30.4%) had completed at least 12-months treatment, 12 patients (52.2%) had discontinued treatment because of progressive disease or death, one patient (4.3%) discontinue treatment because of other diseases (tuberculosis), and 10 patients remained on treatment (Fig. 1).  had a progression disease (PD) by Lugano criteria (Table 3). Early and durable responses were observed (Fig. 3B, C), the median time to response was 1.4 months (range, 1.4 months -2.8 months).
The median duration of response of these patients was not reached, although was anticipated to extend beyond the range 5.1-23.8 months, and the 6 months disease control rate was 91.3% (Table 3). Twenty two (95.7%) of 23 evaluable patients had target lesion size reduced from baseline ( Fig. 3A, B). One of these patients, while on study treatment, had partial response (according to criteria pre investigator) 1.4 months after treatment, discontinued treatment because of tuberculosis.
At data cutoff, among 3 CR patients, 1 patient still on the treatment with its PFS of 25.2 months, another 2 CR patients had cancer recrudesced in retroperitoneum and adrenal gland, defined as disease progression with its PFS of 17.3 and 18.4 months respectively. At data cutoff, the median PFS was 15.5 months, the median OS was 21.5 months (Table 3). At data cutoff, 7 patients (30.4%) had died, and the overall survival of them were 27. 2, 21.5, 18.3, 15.5, 9.8, 9.2, 6.0 months respectively.   For patients with metastatic/recurrent or advanced ESCC, the primary treatment goal is to alleviate cancer-related symptoms, minimize treatment-related toxicity, prolong survival time, and improve quality of life 22 . In our study, the life quality of patients was good and at the data cutoff of April 10th, 2020, in 12 patients (the patient with tuberculosis was excluded) who have received the combination treatment more than 12 months, they all completed 6 cycles of chemotherapy, which is hard to achieve in conventional chemotherapy. It is partial because of the shrinking of the major lesion of esophageal promoted patients' nutrition conditions since they can eat more.
There were also some limitations of this study. The sample size was too small and the patients enrolled were all Asian and male, which could lead to selection basis. A phase III of large data sets and muti-centre were warranted in the future and the results of KEYNOTE-590/MK-3475-590 were expected. Our study also did not focus on biomarkers to predict the effect of this combination therapy. PD-L1 overexpression is associated with worse clinical outcomes in ESCC 23-25 . However, the higher ORR of anti-PD1 mAb and longer median OS were also observed in PD-L1 overexpression patients when compared to the patients with low PD-L1 expression 7,8,26 . Further investigation should be done to analyze the potential biomarkers for this combination therapy.

Conclusion
In summary, this is the first report of immunotherapy plus chemotherapy as the first line treatment of  We wish to acknowledge our colleagues for their valuable efforts. We also appreciate the study patients, and their families for their cooperation.

Availability of data and materials
The datasets generated during the current study are available

Authors' contributions
JQ, WL, HW, LT and NX were involved in the conception and design of the work. CM and HJ collected the data. JQ, WL, HW, LT and NX did the data analysis and interpretation. JQ, WL and HW were major contributors in writing the manuscript, and CM revised the manuscript. All authors approved the final manuscript. JQ, WL and HW contributes equally, LT and NX are the Co-corresponding authors.

Ethics approval and consent to participate
This study was approved by the Ethics Committee of the first affiliated hospital of Zhejiang University.