Clinical outcomes are poor for patients with advanced ESCC. For stage IV ESCC, effective therapies are limited. The median OS of conventional chemotherapy for stage IV ESCC was just 7.7 months (231 days)12. And conventional treatments often lead to low life qualities of these patients.
In esophageal carcinoma, the clinical trials results of anti-PD1/PDL1 mAbs were all came from 2 or more lines of therapy, the ORR ranges from 6.7%-30%, median PFS ranges from 1.4 to 3.4 months and the OS ranges from 5.6 to 11.1 months as previously KEYNOTE‑0286, KEYNOTE-1807, KEYNOTE-1818, ONO-45389, and ATTRACTION-0310clinical trials investigated. For advanced esophageal carcinoma, conventional chemotherapy includes cisplatin and 5-fluorouracil (5-FU) (CF), triplet, irinotecan-based, oxaliplatin-based and paclitaxel-based regimens. The efficacy of these strategies was limited (ORR 15%-62.5%, median PFS 3.9-7 months, median OS 7–13 months) and the incidence of toxicities was high.
In this analysis of 23 patients with advanced esophageal squamous cell carcinoma which is unresectable or incurable by radiotherapy, we established the clinical benefit and safety of anti-PD1 /PDL1 mAbs combined with chemotherapy in this patient population. The safety profile of this combination was acceptable and manageable. The response rate was up to 78.3% (18 of 23), 3 patients (13.0%) achieved a complete response and 15 patients (65.2%) achieved a partial response. As data cutoff of April 10th, 2020, the median PFS was 15.5 months, the median OS was 21.5 months, which largely exceeded the median OS (7.7 months) of the similar conditions’ patients in conventional chemotherapy as first line therapy. As data cutoff, 7 patients (3 CR and 4 PR) PFS exceeded 15 months and 1 patient (CR) with its PFS of 25.2 months remained in treatment without progression. The time to initial response was 2 cycles after initial treatment (1.4 months) in 18 patients and another 1 patient achieved confirmed PR 4 cycles after initial treatment (2.8 months), and the median duration of response was not reached, although was anticipated to extend beyond the range 5.1–23.8 months
Although it is difficult to make direct comparisons among several trials since which had some different clinicopathological patient characteristics, with the median PFS of 15.5 months (which even exceeded the median OS for the similar conditions’ ESCC patients in other trials) and ORRs of 78.3% (which exceeded more than twice of which in almost all other trials with the similar conditions’ ESCC patients), our study showed comparable efficacy and outcomes. In addition, 7 patients died, 6 of these 7 patients’ original ECOG performance status were 1, which means these patients’ original conditions were poor. And the patient excluded because of tuberculosis responded pretty well and reached partial response criteria and even remained partial response for 1 year. These promising data demonstrated potent anti-tumor efficiency of the combination therapy.
Recent studies have shown that chemotherapy can induce favorable immunogenic compounds and stimulated immune system 13,14. The mechanism of efficacy of chemotherapy for tumor is it can destroy rapidly growing cells in the body. The neoantigens caused by platinum salts can be added to de novo mutations caused by tobacco smoke and other carcinogens in ESCC15,16. And evidence showed that mutation landscape can determine sensitivity to PD1/PDL1 blockade, the presence of these neoantigens can increase the effectiveness of anti- PD1/PDL1 mAbs and thus affect tumor regresssion17,18. Chemotherapy combined with immunotherapy, can help improve tumor antigens’ cross-presentation, thus reverse the immunosuppression to some extent, promote the proliferation of effector T cells, and enhances the anti-tumor function of the immune system19–21.
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 life22. 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 ESCC23–25. 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 expression7,8,26. Further investigation should be done to analyze the potential biomarkers for this combination therapy.