This phase 2 study revealed that sintilimab monotherapy resulted in an evidently prolonged survival outcome and had a favorable safety profile versus chemo in patients with advanced ESCC refractory to previous chemotherapy.
Both nivolumab and pembrolizumab showed encouraging results in patients with advanced ESCC refractory or intolerant to chemo (median OS > 6 mo).7,19 The KEYNOTE-181 study demonstrated a favorable survival benefit for pembrolizumab over chemo in second line (2L) patients with ESCC (HR = 0.75, P = 0.0035, median OS 8.2 vs. 7.1 mo), although the primary endpoint was not significantly reached.20 In the ATTRACTION-3 study, nivolumab remarkably improved the median OS in 2L patients with ESCC when compared with chemo (HR = 0.77, P = 0.019, median OS 10.9 vs. 8.4 mo).8 In the ESCORT study, camrelizumab also significantly improved the median OS in 2L patients with ESCC when compared with chemo (HR = 0.71, P = 0.001, median OS 8.3 vs. 6.2 mo).8 Although the median OS in the aforementioned studies varied based on different populations and baseline characteristics, our study showed a significant survival benefit of sintilimab over chemo, either for the overall population or several subgroups based on age, ECOG PS, and smoking status, consistent with these studies.8 Both the OS and PFS KM survival curves were shown to cross at an early stage and diverge beyond 5 mo, in favor of sintilimab. This was similar to the results obtained in studies on nivolumab and pembrolizumab in ESCC and other indications,5,8,21 suggesting a delayed response and more durable benefit of immunotherapies with these indications. In addition, the survival advantage of sintilimab was demonstrated via a prolonged follow-up duration. The superior RMST of sintilimab over chemo was increased from 0.3 mo at 9 mo to 1.6 mo at 18 mo, further suggesting a delayed survival benefit of sintilimab.
Patients in the sintilimab group had an ORR of 12.6 %, comparable to the contemporary phase 2 studies of PD-1 inhibitor monotherapies in ESCC (14–17 %).6,7 Moreover, the ORR of patients with sintilimab was twice higher than those with chemo, similar to the findings in the Chinese population of the KEYNOTE-181 study and the patients in the ESCORT study.9,22 Notably, for patients who were initially evaluated as PD per RECIST v1.1 in the sintilimab group, those continuing to receive sintilimab had a remarkable increase on median OS, compared with those that discontinued treatment. This finding suggested that continuous treatment with sintilimab could have a long-term survival benefit and should be further explored for patients after initial PD by RECIST v1.1.
Sintilimab showed a favorable safety profile over chemo, with a substantially reduced incidence of TRAEs (54.3 vs. 90.8 %) and TRAEs of grade 3 or worse (20.2 vs. 39.1 %). Most toxic effects were comparable to the historical data on treatment with sintilimab in relapsed or refractory classical Hodgkin lymphoma and to that of treatments with other PD-1 inhibitors in EC or solid tumors.6,20,23 In particular, three treatment-related deaths, which were due to upper gastrointestinal bleeding, pneumonitis, and lung infection, occurred in the sintilimab group. Pneumonitis and lung infection were previously reported in pembrolizumab- or nivolumab-treated patients with ESCC or EC.7,8 While upper gastrointestinal bleeding is regarded as a common cause of death in ESCC, the estimate of cause of death from researchers might be biased as this was an open-label study.
In this trial, comprehensive biomarker studies were performed, including for tumor PD-L1 expression, tumor transcriptome analysis, NLR and peripheral blood TCR, and ctDNA analysis. Similar to the ESCORT study, none of the TPS or CPS could predict any benefit from the treatment with sintilimab, implying that alternative biomarkers are needed.
Analyzing tumor transcriptomes revealed two immune cell signatures, including infiltration of T-follicular helper cells and activated B–cells, which were significantly related to PFS in immunotherapy but not in the chemotherapy arm. On the basis of the well-established function of T-cells in cancer immunotherapy, an emerging role of B-cells and tertiary lymphoid structures in tumors has been recently reported and associated them with patient survival.26–28 Furthermore, T-follicular helper cells have been shown to play important roles in the generation of tertiary lymphoid structures in the tumor microenvironment.29 Thus, our results underscoring a potential relevance of tertiary lymphoid structures in the mode of action of cancer immunotherapy warrant further investigation.
Baseline peripheral TCR clonality alone did not predict the efficacy of sintilimab in this study, potentially because the PD-1 inhibitor-mediated antitumor responses relied less on T-cell quantity rather than tumor antigen specificity, which could not be reflected by TCR sequencing. Conflicting results from previous studies using TCR clonality or diversity to predict the efficacy of immunotherapy30,31 might have been due to the dilution effect of nontumor specific TCR.32 The mTBI is a reflection of the percentage of ctDNA detected in blood cell free DNA, and might be considered an indicator of tumor burden. Compared with TCR clonality, the mTBI index was significantly associated with clinical efficacy in the treatment with sintilimab. When mTBI was combined with TCR, the prediction was further enhanced: patients with high TCR clonality and low mTBI exhibited the longest survival. The higher TCR clonality and lower mTBI in these patients implied an existing and expanded tumor-killing immune response, which might be suppressed by the PD-1 axis, and is thus important for the response of patients to treatment with sintilimab.
As is known, NLR can reflect differences in the immune status during cancer development and progression.24 Our results revealed that a low NLR (< 3) prior to or at 6 wk after treatment with sintilimab was significantly correlated with a longer OS and PFS. So, NLR together with TCR and mTBI supported the validation of peripheral blood biomarkers in future clinical trials for improved patient selection.
This study had several limitations. First, the patient sample size in the phase 2 study was relatively small. Second, the open-label design of the study might have influenced the assessment of the incidence of adverse effects. Nevertheless, this design was deemed acceptable because both dose regimens and toxicities in the two groups were disparate. Third, due to limited tumor samples available for the assessment of PD-L1 expression, it was hard to evaluate its correlation with the survival benefit of sintilimab.
In conclusion, our data favored the use of sintilimab over chemo in Chinese patients with advanced ESCC refractory to previous chemotherapies, as it suggested a prolonged survival benefit and a favorable safety profile. Both NLR (< 3) at 6 wk post-treatment and the combination of high TCR clonality with low mTBI might be potent biomarkers for the prediction of improved OS and PFS in patients with ESCC treated with sintilimab. A phase 3 study (NCT03748134), which could provide potent evidence for the potential use of sintilimab in patients with ESCC, is currently ongoing.