Encyclopedia
Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Mian Xi.
Esophageal cancer has a high mortality rate and a poor prognosis, with more than one-third of patients receiving a diagnosis of locally advanced cancer. Esophageal squamous cell carcinoma (ESCC) is the dominant histological subtype of esophageal cancer in Asia and Eastern Europe. Although neoadjuvant or definitive chemoradiotherapy (CRT) has been the standard treatment for locally advanced ESCC, patient outcomes remain unsatisfactory, with recurrence rates as high as 30–50%. The combination of immune checkpoint inhibitors (ICIs) and CRT has emerged as a novel strategy to treat esophageal cancer, and it may have a synergistic action and provide greater efficacy.
- esophageal squamous cell carcinoma
- immune checkpoint inhibitors
- immunotherapy
- chemoradiotherapy
1. ICIs Combined with Neoadjuvant CRT
1. Immune Checkpoint Inhibitors (ICIs) Combined with Neoadjuvant Chemoradiotherapy (CRT)
Several phase I and II studies have investigated the safety and efficacy of programmed death receptor 1 (PD-1) inhibitors combined with neoadjuvant CRT in ESCC(CRT) in esophageal squamous cell carcinoma (ESCC). In addition, several ongoing trials have explored the benefits of this combination (Table 1).
Table 1. Immunotherapy combined with neoadjuvant chemoradiotherapy for resectable esophageal squamous cell carcinoma: ongoing trials.
| Registration | Phase | Study Cohort | Control Cohort | Primary Endpoints |
Secondary Endpoints |
|---|---|---|---|---|---|
| NCT04435197 (PALACE-2) |
II | Pembrolizumab + CRT (Paclitaxel + Carboplatin) | pCR | DFS, OS | |
| NCT04437212 | II | Toripalimab + CRT (Paclitaxel + Cisplatin) |
[2]. Grade 3 or higher treatment-related adverse events occurred in 65% of the enrolled patients, with lymphocytopenia accounting for most of these occurrences (92%). The pCR rate was 55.6% in 18 patients who underwent surgery, which was higher than that of historical results from traditional neoadjuvant CRT [17,18][3][4]. A subsequent ongoing multicenter phase II clinical study (PALACE-2) will further confirm the efficacy of this treatment [19][5].
A phase II single-arm trial evaluating neoadjuvant CRT in combination with perioperative toripalimab for ESCC was presented at the ASCO Annual Meeting in 2022 (NCT04437212) [20][6]. In 13 patients who underwent the procedure, the overall pCR rate was 54%, and 7 patients (54%) experienced grade 3–4 treatment-related adverse events.
In addition, SCALE-1 was a single-center, single-arm, exploratory phase Ib study that enrolled 23 patients with locally advanced ESCC. A short course of neoadjuvant radiotherapy combined with toripalimab was used, with a total radiation dose of 30 Gy in 12 fractions and two cycles of paclitaxel/carboplatin chemotherapy administered concurrently. After surgery, 11 patients exhibited pCR (47.8%), suggesting adequate safety and efficacy of short-course CRT combined with immunotherapy.
Collectively, the available data suggest that the combination of immunotherapy and neoadjuvant CRT in ESCC has the potential to achieve a higher rate of pCR and manageable safety, but it lacks long-term follow-up results. More evidence from phase III trials is required to confirm these findings.
2. ICIs Combined with Neoadjuvant Chemotherapy
Although neoadjuvant CRT is the standard treatment for resectable locally advanced ESCC, it is also associated with higher postoperative complications and mortality than surgery alone. Neoadjuvant chemotherapy and nivolumab showed encouraging results, including a major pathologic response (MPR) rate of 83% in resectable lung cancer in the NADIM study [21][7]. Therefore, several researchers have investigated the efficacy of neoadjuvant treatments combining PD-1 inhibitors and chemotherapy in ESCC, excluding radiotherapy (Table 2).
Table 2. Immunotherapy combined with neoadjuvant chemotherapy for resectable esophageal squamous cell carcinoma: ongoing trials.
| Registration | Phase | Study Cohort | Control Cohort | Primary Endpoints |
Secondary Endpoints | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| NCT04280822 (HCHTOG1909) |
III | Toripalimab + CT (Paclitaxel + Cisplatin) | Placebo + CT (Paclitaxel + Cisplatin) |
EFS | pCR, DFS, OS, ORR, R0 resection rate, MPR, AEs, QoL | ||||||
| MPR | |||||||||||
| NCT04506138 | DFS, OS, AEs | ||||||||||
| II | Camrelizumab + CT (Nab-paclitaxel + Carboplatin) | pCR, MPR | OS, EFS | NCT03044613 | Ib | Nivolumab + CRT (Paclitaxel + Carboplatin) |
Nivolumab + Relatlimab + CRT (Paclitaxel + Carboplatin) | AEs | |||
| NCT04177797 | pCR, OS, RFS | ||||||||||
| II | Toripalimab + CT (Paclitaxel + Carboplatin) | pCR | DCR, ORR, AEs | NCT03064490 (PROCEED) |
II | Pembrolizumab + CRT (Paclitaxel + Carboplatin) | pCR | ||||
| NCT03914443 | AEs | ||||||||||
(FRONTiER) |
I | Nivolumab + CT (5-FU + Cisplatin) (Cohort A/B) |
Nivolumab + CT (5-FU + Cisplatin + Docetaxel) (Cohort C/D) |
DLT | NCT04006041 | II | Toripalimab + CRT (Paclitaxel + Cisplatin) |
pCR | OS, DFS, AEs, R0 resection rate | ||
| pCR, AEs, PFS, OS | |||||||||||
| NCT04389177 (KEYSTONE-001) |
II | Pembrolizumab + CT (Paclitaxel + Carboplatin) | MPR | NCT04177875 | II | Toripalimab + CRT (Docetaxel + Nab-paclitaxel + Cisplatin) | MPR, ORR | DFS, OS, AEs | |||
| NCT04229459 | II | Nivolumab + Cetuximab + CRT (Cisplatin + 5-FU) | pCR, PFS, AEs | OS | |||||||
| NCT04568200 | II | Durvalumab + CRT (Paclitaxel + Carboplatin) |
Placebo + CRT (Paclitaxel + Carboplatin) | Tumor response, pathological response | R0 resection rate, AEs, PFS, OS | ||||||
| ORR, DFS, OS, R0 resection rate | |||||||||||
| NCT03437200 (CRUCIAL) |
II | Nivolumab + CT (FOLFOX) |
Nivolumab + Ipilimumab + CT (FOLFOX) | PFS | FFS, OS | ||||||
| NCT04460066 | Ib/II | ZKB001 + CT (Nab-paclitaxel + Cisplatin) |
Placebo + CT (Nab-paclitaxel + Cisplatin) |
MPR | R0 resection rate, pCR, DFS, EFS, OS, AEs | ||||||
| NCT04767295 | II | Camrelizumab + CT (Nab-paclitaxel + Carboplatin) |
pCR | OS, PFS, DCR, ORR | NCT04644250 | II | Toripalimab + CRT (Paclitaxel liposome + Carboplatin) | pCR | AEs, OS, DFS, MPR, ORR, R0 resection rate | ||
| NCT04804696 | II | Toripalimab + CT (Paclitaxel + Cisplatin) | pCR | ORR, R0 resection rate, MPR, DFS, OS, AEs | NCT04776590 | II | Tislelizumab + CRT (Nab-paclitaxel + Carboplatin) | pCR | DFS, OS | ||
| NCT04848753 | III | Toripalimab + CT (Paclitaxel + Cisplatin) | Placebo + CT (Paclitaxel + Cisplatin) |
EFS | pCR, EFS, OS | NCT04888403 | II | Toripalimab + CRT (Nab-paclitaxel + Nedaplatin) | pCR | MPR, DFS, R0 resection rate | |
| NCT03917966 | II | Camrelizumab + CT (Docetaxel + Nedaplatin) | Camrelizumab + Apatinib | MPR | pCR, OS, DFS, LNR, R0 resection rate | NCT04929392 | II | Pembrolizumab + Lenvatinib + CRT (Nab-paclitaxel + Carboplatin) | pCR, cCR | ||
| NCT03946969 | AEs, DFS, OS | ||||||||||
| II | Sintilimab + CT (Nab-paclitaxel + Cisplatin + S-1) | AEs | MPR, R0 resection rate, RFS, OS | NCT04974047 | II | Tislelizumab + CT (Paclitaxel + Cisplatin) |
Tislelizumab + CRT (Paclitaxel + Cisplatin/5-FU + Cisplatin) | pCR | MPR, R0 resection rate, DFS, EFS, ORR, AEs | ||
| NCT03165994 | II | Sotigalimab + CRT (Paclitaxel + Carboplatin) |
pCR | R0 resection rate, pathologic stage, radiographic/metabolic response, AEs | |||||||
| NCT03490292 | I/II | Avelumab +CRT (Paclitaxel + Carboplatin) |
DLT, pCR | AEs, DFS, R0 resection rate | |||||||
| NCT03857763 | II | Apatinib + CRT (Paclitaxel + Cisplatin) |
pCR | R0 resection rate, DFS, OS, AEs | |||||||
| NCT04426955 | III | Camrelizumab + CRT (Paclitaxel + Cisplatin) | Placebo + CRT (Paclitaxel + Cisplatin) | PFS | OS, ORR, DoR, AEs |
CRT, chemoradiotherapy; pCR, pathological complete response; DFS, disease-free survival; OS, overall survival; MPR, major pathologic response; AEs, adverse events; RFS, recurrence-free survival; ORR, objective response rate; PFS, progression-free survival; cCR, clinical complete response; EFS, event-free survival; CT, chemotherapy; DLT, dose-limiting toxicity; DoR, duration of response.
In a single-arm phase II clinical trial (NCT02844075) reported at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, 28 patients with locally advanced ESCC received a combination of neoadjuvant pembrolizumab and CRT (paclitaxel + cisplatin), followed by surgery and postoperative pembrolizumab maintenance up until two years, disease progression, or intolerable toxicity [15][1]. With a median follow-up of 11.7 months, the pathological complete response (pCR) rate was 46.1%, and the one-year OS rate was 89.3%.
Similarly, in a phase I study (PALACE-1), preoperative pembrolizumab combined with neoadjuvant CRT resulted in an acceptable safety profile and anti-tumor efficacy in 20 patients with locally advanced ESCC [16]
CT, chemotherapy; EFS, event-free survival; pCR, pathological complete response; DFS, disease-free survival; OS, overall survival; ORR, objective response rate; MPR, major pathologic response; AEs, adverse events; QoL, quality of life; DCR, disease control rate; DLT, dose-limiting toxicity; PFS, progression-free survival; FFS, failure-free survival; LNR, lymph node ratio; RFS, recurrence-free survival.
A prospective study of neoadjuvant camrelizumab in combination with paclitaxel and carboplatin (ChiCTR2100051903) reported pCR and R0 resection rates of 31.3% and 93.8%, respectively [22][8]. After a one-year follow-up, progression-free survival (PFS) and OS were 83% and 90.9%, respectively, with manageable adverse events.
Neoadjuvant chemotherapy has poor outcomes in patients with multisite lymph node metastases, and the NICE study is the first to focus on neoadjuvant therapy in this cohort globally. This prospective, single-arm, single-center, exploratory phase II trial assessed the effectiveness and safety of camrelizumab combined with carboplatin and albumin paclitaxel (ChiCTR1900026240) [23][9]. This study showed a pCR rate of 39.2% and complete remission of the primary tumor in five patients with residual lesions in the lymph nodes (ypT0N+). As the long-term efficacy of the NICE regimen is lacking, a phase III randomized controlled trial is underway.
Toripalimab plus neoadjuvant chemotherapy (paclitaxel + carboplatin) showed anti-tumor effectiveness in locally advanced ESCC in a phase II trial (NCT04177797) [24][10]. The MPR and pCR rates were 43.8% and 18.8%, respectively, in the 16 patients who underwent surgery.
FRONTiER is a phase I clinical study that aims to evaluate the safety of nivolumab in combination with neoadjuvant chemotherapy regimens (5-fluorouracil + paclitaxel or 5-fluorouracil + docetaxel) [25][11]. The ASCO Gastrointestinal Cancer Symposiums Annual Meeting in 2021 and 2022 reported the preliminary results of the FRONTiER study, which showed that two patients (33.3%) in cohort A achieved pCR, and the pCR rates in cohorts C and D were 16.7% and 50.0%, respectively [26,27][12][13]. Only one patient in cohort D had dose-limiting toxicity (grade 3 dyspnea and rash).
In previous studies, patients usually received concurrent chemotherapy and anti-PD-1 monoclonal antibody treatment; however, chemotherapy drugs can kill anti-PD-1 antibody-activated T cells, hindering the effects of the ICI [28][14]. A recent phase II study showed that administering toripalimab 48 h after administering chemotherapy (paclitaxel + cisplatin) resulted in a higher pCR rate than concurrent administration (NCT03985670) [29][15].
In summary, neoadjuvant PD-1 inhibitors combined with chemotherapy may be effective against resectable ESCC. However, the superiority of this modality to neoadjuvant CRT remains unclear and warrants further investigation.
3. Adjuvant Immunotherapy after Neoadjuvant CRT and Surgery
Recurrence risk remains significant for patients with esophageal cancer who have residual disease after neoadjuvant CRT followed by surgery. Until recently, high-level evidence-based recommendations for adjuvant treatment were lacking. Currently, a novel adjuvant nivolumab maintenance therapy after surgery is recommended in these cases, based on the results of the CheckMate 577 trial.
CheckMate-577 is a randomized, double-blind, multicenter phase III study that enrolled 1085 patients who had esophageal or gastroesophageal junction cancer (ESCC 29%) without pCR after neoadjuvant CRT [30][16]. Patients were randomized in a 2:1 ratio to receive adjuvant nivolumab or placebo. The primary endpoint of disease-free survival (DFS) was reached. According to the findings, the median DFS for the 532 patients who received nivolumab was 22.4 months, which was significantly longer than the 11.0 months for the 262 patients in the placebo group. Additionally, compared with 15 (6%) of 260 patients in the placebo group, 71 (13%) patients in the nivolumab group experienced treatment-related grade 3 or 4 adverse events. The findings of this trial have now been endorsed by treatment guidelines, which indicate that adjuvant treatment with nivolumab significantly prolongs DFS compared with placebo and has an adequate overall safety profile. However, a clinical study conducted by Park et al. in 2022 (European Society for Medical Oncology—ESMO) contrasted with Checkmate577 (NCT02520453) [31][17]. This placebo-controlled, randomized, double-blind, phase II clinical study included 86 ESCC patients undergoing neoadjuvant chemoradiotherapy, staged T3-4N0M0 or T1-4N1-3M0 according to the American Joint Committee on Cancer (AJCC) 7th edition, and it evaluated the efficacy of adjuvant durvalumab compared to placebo. There was no statistically significant difference between the two groups in terms of DFS or OS after a median follow-up of 38.7 months.
CheckMate-577 was a multicenter phase III study with a large sample size and excluded patients who achieved pCR postoperatively. Conversely, the study conducted by Park et al. was a relatively small single-center trial that enrolled both postoperative pCR and non-pCR patients. With a higher recurrence risk after trimodality therapy, patients with non-pCR were more likely to benefit from adjuvant therapy. Therefore, the negative results from the Korean phase II trial are to be expected.
Additionally, a multicenter, randomized, controlled phase III clinical study (AIRES) is currently ongoing to assess the efficacy and safety of adjuvant chemotherapy combined with tislelizumab versus tislelizumab alone for patients with ESCC at high risk of postoperative recurrence (ypN+).
References
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