Rapid progression during or after the standard chemotherapy in patients with advanced esophageal cancer indicates that a new effective treatment diagram is in urgent need[32]. Recently, it is worth noting that the successive discovery and further study of immune checkpoints, such as PD-1, make immunotherapy served as the fourth antitumor strategies following surgery, radiotherapy and chemotherapy[33]. Single agent PD-1 inhibitors have been explored as treatment strategies for advanced esophageal cancer patients. We conducted this meta-analysis to investigate the efficacy and safety of anti-PD-1 therapy for advanced esophageal cancer patients.
In this study, we first compared the efficacy of PD-1 inhibitors with chemotherapy in advanced esophageal cancer patients. OS, PFS and ORR were selected as the primary endpoints. We observed that PD-1 inhibitors significantly improved OS in advanced esophageal cancer when compared with chemotherapy, however, no significant improvement in PFS and ORR was found. Similar results were found in patients with ESCC. In the subgroup analysis, squamous cell carcinoma was more effective than adenocarcinoma for anti-PD-1 therapy. Hence, it was concluded that the anti-PD-1 therapy significantly improved the OS rather than the PFS and ORR when compared with chemotherapy, especially in ESCC. In addition to histology, overall survival assessed consistently favoured PD-1 inhibitors versus chemotherapy in all subgroups. Although significant interactions were observed for age ≥ 65, female and ECOG PS = 0, the HRs were less than 1, suggesting there was no change in the direction of the treatment effect. Then, we compared the safety of PD-1 inhibitors with chemotherapy in esophageal cancer patients. On the basis of the observed results, no significant difference was found in the incidence of all treatment-related adverse effect events. However, our results show that PD-1 inhibitors had a lower incidence of grade 3 to 5 treatment-related adverse events than the chemotherapy, which demonstrated patients receiving PD-1 inhibitors had a significant overall improvement in quality of life.
Several recent trials demonstrated that PD-L1 expression had a significant correlation with OS, PFS, and ORR, however, the significance of PD-L1 expression level for anti-PD-1 therapy is still controversial[34]. Here, we conducted a subgroup analysis to clarify the OS benefit of PD-1 inhibitors in esophageal cancer patients with different PD-L1 expression. The OS benefit with PD-1 inhibitors occurred for patients in whom the PD-L1 TPS was at least 1% (OR = 0.83; 95% CI: 0.67–1.02; P = 0.07), and when the PD-L1 TPS was less than 1%, the OS benefit with PD-1 inhibitors was not statistical difference(OR = 0.64; 95% CI: 0.51–0.79; P < 0.001). However, the magnitude of OS benefit was not significantly different among subgroups of PD-L1 TPS which indicated the survival benefit with PD-1 inhibitors occurred regardless of patients’ level of tumor PD-L1 expression. Therefore, exploratory clinical trials and extended follow-up are needed to fully evaluate the role of PD-L1 expression in immunotherapy.
The results of our study are consistent with previous studies. KEYNOTE 180 showed that pembrolizumab had long-term clinical benefits with controlled adverse events, which provided treatment options for patients with esophageal cancer who had previously failed treatment[23]. KEYNOTE 181 achieved the main-OS endpoint, which has demonstrated a survival benefit in esophageal cancer immunotherapy[24]. In ATTRACTION-03 trial, nivolumab group showed a statistically significant improvement in OS compared with chemotherapy group, and the survival benefit of nivolumab was observed regardless of the expression level of PD-L1 in tumors. In terms of PFS and ORR, there was no significant improvement between the nivolumab group and the chemotherapy group[25]. The subgroup analyses in Huang et al. showed that PD-L1 was not significantly associated with ORR in the clinical trial of SHR-1210 for esophageal cancer[27].
There were some exploratory biomarker analyses to evaluate the role of PD-1 inhibitors in patients with esophageal cancer, in whom treatment options have been very limited for decades and the prognosis remains poor. Some esophageal cancer patients were reported to carry frequent amplification of chromosome 11q13 and those patients without 11q13 amplification, had significantly better ORR and PFS when compared with 11q13 amplified individuals[35]. Several studies have shown that both PFS and OS are prolonged with the increase of tumor mutation burden (TMB) with immunotherapy, and TMB has the potential to be a biomarker to evaluate the efficacy of immunotherapy[36–38]. Greally et al analyzed the relationship between TMB and survival in 62 patients of immunotherapeutic esophageal cancer and this clinical study found that patients in the high TMB group obtained significant survival benefits.[39] Microsatellite instability (MSI) is usually caused by deficiencies mismatch repair (dMMR) [40]. The microenvironment of dMMR made it more likely to express PD-L1, which influenced the efficacy of PD-1 inhibitors, and dMMR tumors were associated with prolonged PFS compared with mismatch repair-proficient tumors, regardless of the origin tissue of cancer[41]. Although the incidence of MSI-H in ESCC is rare and only about 8%, this biomarker is very important and may affect the efficacy of immune checkpoint inhibitors.[42] This may explain why patients with advanced esophageal cancer might benefit from improved on OS when treated with PD-1 inhibitors and the difference of PFS and ORR in these studies.
To the best of our knowledge, this is the first meta-analysis to explore the efficacy and safety of PD-1 inhibitors for advanced esophageal cancer patients. The topic of this paper is novel and the high quality of the data included in the meta-analysis. We observed several limitations in this research. The number of included studies is limited. At the same time, one study were limited from the abstract of ASCO meeting abstract.
Anti-PD-1 therapy has showed initial efficacy in the treatment of advanced esophageal cancer and become one of the main research directions in the treatment of advanced esophageal cancer. With the increase of biomarker analysis and clinical experience, anti-PD-1 therapy will have a broader application prospect in esophageal cancer. It is imperative to comprehensively carry out more randomized controlled studies to further explore the immune mechanism of esophageal cancer and screen out reasonable biomarkers to identify the beneficial population.