Immunotherapy for esophageal cancer: Where are we now and where can we go

Abstract

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis, and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma (ESCC) in the past decade. Monoclonal antibodies that selectively inhibit programmed cell death-1 (PD-1) activity has now become standard of care in the treatment of ESCC in metastatic settings, and has a high expectation to provide clinical benefit during perioperative period. Further, anti-cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody. Well understanding of the existing evidence of immune-based treatments for ESCC, as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant, adjuvant, and metastatic diseases, may provide future prospects of ESCC treatment for better patient outcomes.

Key Words: Esophageal cancer, Immunotherapy, Immune checkpoint inhibitor, Programmed cell death-1, Anti-cytotoxic T-lymphocyte–associated protein 4, Neoadjuvant therapy, Adjuvant therapy, Clinical trials, Combination therapy

Core Tip: Immune checkpoint inhibitor therapy alone or in combination with other cytotoxic agents has now become standard of care in the treatment of esophageal squamous cell carcinoma (ESCC) in metastatic and adjuvant settings, and has a high expectation to provide clinical benefit during perioperative period. In this editorial, we will discuss the existing evidence of immune-based treatments for ESCC, as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant, adjuvant, and metastatic diseases, which may provide future prospects of ESCC treatment for better patient outcomes.

INTRODUCTION

The concept of immune checkpoint inhibitors (ICIs) in cancer immunotherapy emerged in the late 1990s, and the clinical development has exploded in the last ten years. The development of ICIs has been a significant milestone in various cancer types including gastrointestinal malignancies such as esophageal squamous cell carcinoma (ESCC). The first ICI approved by the Food and Drug Administration (FDA) was the anti-cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), ipilimumab, which was tested for previously treated metastatic melanoma in the phase III MDX010-20 trial[1]. In this study, the median overall survival (OS) for patients receiving ipilimumab plus glycoprotein 100 (gp100) peptide vaccine (median OS, 10.0 months) or ipilimumab alone (median OS, 10.1 months) was significantly improved compared to patients after gp100 alone (median OS, 6.4 months), as this was the first study to show a survival benefit of ICI in a randomized controlled trial. The success of ipilimumab led to further research and the development of novel immunotherapies, and has paved the way for the approval of other ICIs, in particular, ICIs targeting programmed cell death-1/programmed cell death 1 ligand 1 (PD-1 / PD-L1) pathway, which have been utilized as one of the standard treatment across many cancer types including ESCC.

CURRENT EVIDENCE OF ICIS FOR ESCC

Later-line therapy

The earliest approval of ICI for ESCC was as later-line therapy by single-agent anti-PD-1 monoclonal antibody pembrolizumab, after KEYNOTE-180 and KEYNOTE-181 studies[2,3]. KEYNOTE-180 is a phase II single-arm study which enrolled 121 patients with advanced/metastatic esophageal cancer (EC) that progressed after 2 or more lines of treatment. Objective response rate was 14.3% (95%CI: 6.7%-25.4%) among patients with ESCC (9 of 63), and 13.8% (95%CI: 6.1%-25.4%) among patients with PD-L1-positive tumors (8 of 58). Fifteen patients (12.4%) had grade 3 or higher treatment-related adverse events (TRAE), including 5 patients (4.1%) which experienced discontinuation due to adverse events. In the following randomized phase III KEYNOTE-181 study which enrolled 628 patients with advanced/metastatic EC which progressed after one prior therapy, OS was prolonged with pembrolizumab than chemotherapy for patients with combined positive score (CPS) ≥ 10 [median OS, 9.3 months vs 6.7 months, hazard ratio (HR), 0.69 (95%CI: 52%-93%), P = 0.0074], and the median OS was 8.2 months vs 7.1 months [HR, 0.78 (95%CI: 63%-96%), P = 0.0095] in patients with ESCC. The 18.2% of patients suffered grade 3-5 TRAE with pembrolizumab vs 40.9% after chemotherapy. After these 2 studies, the FDA approved single-agent pembrolizumab for ICI naive advanced ESCC with CPS ≥ 10.

Result of ATTRACTION-3[4] delivered PD-1 inhibitor nivolumab as an alternative option in the later-line setting. In this study, 419 patients with advanced/recurrent ESCC after one prior treatment were either randomized into nivolumab or chemotherapy group, regardless of PD-L1 expression. At a minimum follow-up time of 17.6 months, OS was significantly improved in the nivolumab group compared to the chemotherapy group [median OS, 10.9 months vs 8.4 months, HR, 0·77 (95%CI: 62%-96%), P = 0.019]. Grade 3 or higher TRAE occurred in 38 (18%) of 209 patients in the nivolumab group compared with 131 (63%) of 208 patients in the chemotherapy group. As a result, nivolumab monotherapy was approved in the second-line treatment setting for ESCC regardless of PD-L1 status.

First-line therapy

KEYNOTE-590[5] and Checkmate-648[6] studies have established a new standard of care for chemo-immunotherapy and doublet-immunotherapy in the first-line setting for patients with advanced ESCC. In the phase III KEYNOTE-590 study, 749 patients with locally advanced/unresectable/metastatic EC were randomly assigned to pembrolizumab or placebo plus chemotherapy. At the first interim analysis, pembrolizumab group was superior to placebo group regarding OS in the patients with PD-L1 CPS ≥ 10 ESCC [median OS, 13.9 months vs 8.8 months, HR, 0.57 (95%CI: 43%-75%), P < 0.0001], ESCC [median OS, 12.6 months vs 9.8 months, HR, 0.72 (95%CI: 60%-88%), P = 0.0006], PD-L1 CPS ≥ 10 [median OS, 13.5 months vs 9.4 months, HR, 0.62 (95%CI: 49%-78%), P < 0.0001], and in the entire cohort [median OS, 12.4 months vs 9.8 months, HR, 0.73 (95%CI: 62%-86%), P < 0.0001]. The 72%, 266 of the patients in the pembrolizumab group compared to 68%, 250 patients in the placebo group suffered grade 3-5 TRAEs, respectively. In the Checkmate-648, 970 previously untreated/unresectable advanced/recurrent/metastatic ESCC patients were randomly assigned to receive nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone. At a 13-month minimum follow-up, OS was significantly longer with nivolumab plus chemotherapy than with chemotherapy, both among patients with tumor proportion score (TPS) ≥ 1% [median OS, 15.4 months vs 9.1 months, HR, 0.54 (99.5%CI: 37%-80%), P < 0.001] and in the overall population [median OS, 13.2 months vs 10.7 months, HR, 0.74 (99.1%CI: 58%-96%), P = 0.002]. OS was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with TPS ≥ 1% [median OS, 13.7 months vs 9.1 months, HR, 0.64 (98.6%CI: 46%-90%), P = 0.001] and in the overall population [median OS, 12.7 months vs 10.7 months, HR, 0.78 (98.2%CI: 62%-98%), P = 0.01]. The incidence of TRAEs of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. Accordingly, anti PD-1 therapy with chemotherapy or ipilimumab became one of the first choice for advanced ESCC patients.

Adjuvant therapy

ICI therapy has also become one of the standard treatments in adjuvant settings according to the results of Checkmate-577[7]. In this randomized phase III trial, 794 patients with stage II or III EC or esophagogastric junction cancer (EGJC) after complete resection were randomly assigned to receive nivolumab or matching placebo. Median disease-free survival (DFS) was superior for those after nivolumab compared to placebo [median DFS, 22.4 months vs 11.0 months, HR, 0.69 (96.4%CI: 56%-86%), P < 0.001]. Grade 3 or 4 TRAEs occurred in 71 of 532 patients (13%) in the nivolumab group and 15 of 260 patients (6%) in the placebo group. As a result, adjuvant nivolumab was approved by the FDA since 2021.

Recent development of ICI therapy for ESCC

As discussed above, nivolumab or pembrolizumab alone or combination therapy has been approved for ESCC in the first-line, later-line, and in adjuvant treatment. Recent studies have focused on the utility of other checkpoint inhibitors targeting PD-1 in the first-line and later-line settings. Recent large phase III studies for ICI in advanced/metastatic ESCC patients are summarized in Table 1[8-14]. Utility of novel anti-PD-1 antibodies such as camrelizumab and tislelizumab, alone or in combination with chemotherapy have been tested, and favorable survival outcomes with acceptable safety profiles compared to conventional treatment have been reported. In most studies, patient recruitment was mostly performed from a single country, except for two global trials RATIONALE-302[8] and RATIONALE-306[9].

Table 1 Recent phase III studies for immune checkpoint inhibitor therapy in patients with advanced/metastatic esophageal squamous cell carcinoma.

Trail	Line	Phase	n	Country	Intervention	Programmed cell death 1 ligand 1 status	Primary endpoints	Treatment-related adverse events
RATIONALE-302[8]	Later	III	512	Global	Tislelizumab vs CT	Overall	OS (improved in treatment arm)	Fewer in treatment arm
RATIONALE-306[9]	First	III	649	Global	Tislelizumab + CT vs placebo + CT	Overall	OS (improved in treatment arm)	Similar between groups
JUPITER-06[10]	First	III	514	China	Toripalimab + CT vs placebo + CT	Overall	PFS, OS (improved in treatment arm)	Simiral between groups
ORIENT-15[11]	First	III	659	Global (mainly China)	Sintilimab + CT vs placebo + CT	Overall, CPS ≥ 10	PFS, OS (improved in treatment arm)	Simiral between groups
ASTRUM-007[12]	First	III	551	China	Serplulimab + CT vs placebo + CT	CPS ≥ 1	PFS, OS (improved in treatment arm)	Simiral between groups
ESCORT-1st[13]	First	III	596	China	Camrelizumab + CT vs CT	Overall	PFS, OS (improved in treatment arm)	Simiral between groups
ESCORT[14]	Later	III	457	China	Camrelizumab vs CT	Overall	OS (improved in treatment arm)	Similar between groups

CT: Chemotherapy; PFS: Progression-free survival; OS: Overall survival; CPS: Combined positive score.

In the RATIONALE-302[8] study, 512 patients across 11 countries/regions with advanced/metastatic ESCC who progressed after first-line therapy were randomly assigned for tislelizumab or chemotherapy. OS was significantly improved with tislelizumab versus chemotherapy in the overall population [median OS, 8.6 months vs 6.3 months, HR, 0.70 (95%CI: 57%-85%), P < 0.0001] and in patients with TPS ≥ 10% [median OS, 10.3 months vs 6.8 months, HR, 0.54 (95%CI: 36%-70%), P = 0.0006]. Further, tislelizumab treatment was associated with higher OR (20.3% vs 9.8%), more durable response (median, 7.1 months vs 4.0 months), and fewer TRAEs (18.8% vs 55.5%). In the following RATIONALE-306[9] study, 649 patients with unresectable, locally advanced, recurrent, or metastatic ESCC from Asia, Europe, Oceania, and North America were randomly assigned to receive tislelizumab or placebo together with a doublet chemotherapy comprising a platinum agent (cisplatin or oxaliplatin) plus fluoropyrimidine/capecitabine/paclitaxel. At the time of data cutoff, median follow up was 16.3 months vs 9.8 months in the tislelizumab and control arm, respectively. Median OS was significantly improved in the tislelizumab group [median OS, 17.2 months vs 10.6 months, HR, 0.66 (95%CI: 54%-80%), P < 0.0001], with equivalent safety profile. These two studies indicate the utility of another ICI tislelizumab for ESCC in the first-line and later-line setting, and that ICIs may be of utility regardless of the paired chemotherapeutic regimen.

Utility of ICIs has been recently discussed also in the perioperative settings, and multiple prospective studies have been conducted as shown in Table 2[15-20]. Anti-PD-1 antibodies camrelizumab, sintilimab, and tislelizumab combined with cytotoxic regimens have been tested in multi-institutional or single-institutional phase II studies held in China. Although the number of participating patients is limited, preoperative combination therapies have shown ideal pathological complete response (PCR) rate, ranging 21.2%-40.0%, with an acceptable safety profile. Effect of neoadjuvant camrelizumab-containing regimens have also been studied in a multicenter observational study[21], which showed a complete resection and PCR rate of 86.4% and 21.3%, respectively, among 255 patients with ESCC. Although the survival benefit for patients after neoadjuvant combination ICI + chemotherapy remain unknown, follow-up data was reported in several trials. In the study by Zhang et al[15], the median follow-up for the surviving patients was 14.6 months at the time of analysis. Median OS and DFS for the overall cohort were not reached, and the 1-year OS and DFS were reported to be 90.8% and 68.3%, respectively. In the study by Yang et al[16], one-year OS and DFS were both 97.6% at the database cutoff (median follow-up, 24.3 months) for the patients who received surgery, however, survival outcomes for the entire cohort was not reported. As stated above, most of the resent studies regarding perioperative ICI combination therapies are phase II clinical trials, thereby the long-term clinical benefit of ICI in the perioperative settings remain unknown. Large-scale multicenter phase III studies are awaited.

Table 2 Recent phase II studies for perioperative immune checkpoint inhibitor therapy in patients with esophageal squamous cell carcinoma, n (%).

Trail	Line	Phase	n	Country	Intervention	Population	Primary endpoints	TRAE ≥ Grade 3
Zhang et al[15]	NA	II	47	China	Sintilimab + CT	cStage II-IVA	PCR (22.2)	40.4
Yang et al[16]	NA	II	47	China	Camrelizumab + CT	cStage II-III	PCR (33.3) and MPR (64.3)	8.5
NICE[17]	NA	II	60	China	Camrelizumab + CT	cT1b-4aN2-3M0-1	PCR (39.2)	56.7
ESONICT-1[18]	NA	II	30	China	Sintilimab + CT	cT3-4aN0-3M0	PCR (21.7) and TRAE	3.3
KEEP-G 03[19]	NA	II	30	China	Sintilimab + CT	cT1b-3NanyM0 or cT4aN0-1M0	Safety and Surgical feasibility	36.7
TD-NICE[20]	NA	II	45	China	Tislelizumab + CT	cT2-4aNanyM0	PCR (40.0) and MPR (57.5)	42.2

CT: Chemotherapy; PCR: Pathological complete response; MPR: Major pathological response; TRAE: Treatment-related adverse events.

CONCLUSION

As a result of large global phase III studies, PD-1 inhibitor pembrolizumab/nivolumab, and CTLA-4 inhibitor ipilimumab, have become one of the standard treatment options for ESCC in the first-line, later-line, and adjuvant settings. Recent trials have indicated the utility of other ICIs targeting PD-1, and further, use of ICI combination therapy in the perioperative settings may enable high PCR rate, complete resection rate, and thus lead to better survival outcomes. Furthermore, due to the high PCR rate, ICI combination induction therapy may enable curative resection for initially unresectable cases[22,23], and may overcome the treatment results of the current standard chemoradiotherapy.

Future of ICIs in ESCC seems promising, however, various challenges remain. First, is the optimal biomarker to predict treatment responses in individual ICIs. Several scoring systems such as CPS and TPS have been established, however, the ideal scoring system is not yet revealed, and biomarkers to select individual ICIs remain unknown. Recently, novel biomarkers to predict the treatment response and prognosis after ICI therapy such as tumor-genome biomarkers, tumor immune microenvironment-related biomarkers, and liquid biopsy biomarkers have been reported in several gastrointestinal diseases[24], and the combination of several biomarkers is noteworthy. Future prospective trials and the development of novel technologies, such as single-cell analysis and machine learning, may lead to the development of optimal ICI biomarker. Second, is the ideal chemotherapeutic regimen to be paired with ICIs. Although patients after different cytotoxic therapies have been included in the RATIONALE-306 study[9], the study was not designed to determine the most effective option. Finally, but most importantly, safety of ICI is critical to expand the use of ICI, and novel biomarkers to predict severe immune-related TRAEs is awaited. In a recent meta-analysis which analyzed TRAEs in esophageal and EGJC[25], although not significant, the rate of serious TRAEs were relatively higher in the ICI group compared to chemotherapy group (22.66% vs 11.46%, P = 0.059), and further, ICI significantly increased the rates of immune-related TRAES in both all grade (44.6% vs 11.09%, P < 0.001) and grade 3-5 (7.35% vs 2.25%, P < 0.001). Although the safety of ICIs was manageable in most studies included in this article, severe cardiovascular, respiratory, and endocrine disorders have been reported, thus long-term and perioperative effect of ICI should be further discussed. Results of ongoing trials, and future studies are awaited to further broaden treatment options, and contribute to better survival outcomes for ESCC patients.