ACHAIKI IATRIKI | 2023; 42(1):12–17
Division of Oncology, Department of Medicine, University Hospital of Patras, Patras, Greece
Received: 17 Feb 2022; Accepted: 06 Jul 2022
Corresponding author: Dr. Amptoulach Sousana, Division of Oncology, Department of Medicine, University Hospital of Patras, Patras, Greece, PC 26504, Tel. +30 2610999535, E-mail: email@example.com
Key words: Immunotherapy, esophageal neoplasms, stomach neoplasms
Esophageal cancer (EC) and gastric cancer (GC) are leading causes of cancer-related mortality worldwide with an increasing incidence and a poor prognosis. The management of these aggressive tumors is complex and often involves multimodality treatment including surgery, chemotherapy, and radiation. Despite advances in the management of upper gastrointestinal cancers, the biology of these tumors is complex. When EC and GC are advanced (locally or metastatic), chemotherapy remains the primary treatment and improves survival over best supportive care. The treatment of advanced EC and GC has been reshaped over the last years with the approval of several immune checkpoint inhibitors (ICIs) and mainly monoclonal antibodies targeting either the axis PD-1/PD-L1 or CTLA-4. The purpose of this review is to provide a summary of systematic treatment, to discuss updates in the molecular targeted agents and summarize significant clinical trials of locally advanced and metastatic esophagogastric adenocarcinoma (EGAC) and esophageal squamous cell carcinoma (ESCC). Due to the dynamic nature of this field, this review is not meant to be all-inclusive but rather to report the major established treatments.
Esophageal cancer (EC) is the eleventh most common cause of cancer worldwide and the sixth most common cause of cancer-related mortality . The two major histologic subtypes of esophageal cancer are adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). It is well-known that the incidence of both subtypes varies among geographic areas: SCC has a higher prevalence in East Asia, Eastern and Southern Africa, and Southern Europe, whereas AC is much more common in North America and other parts of Europe . On the other hand, gastric cancer (GC) is the fifth most common and the third most lethal cancer worldwide . Both, EC and GC, are often diagnosed at an advanced stage mainly due to the lack of early clinical symptoms. GCs can be classified into two types: early stage and advanced stage. According to the eighth edition of the American Joint Committee on Cancer TNM (8th AJCC TNM) system, early-stage gastric cancer is limited to the mucosa or submucosa regardless of the size of the lesion and the presence of lymph node metastasis. Tumors that infiltrate into or beyond the subserosa and extend to surrounding organs or metastasize are considered as advanced GC. Meanwhile, locally advanced cancer of the esophagus (stages IIb to IIIc) includes tumors that invade regional lymph nodes (N1-3) or local structures (T4 disease) . Despite the recent increase in therapeutic options, responses to systemic therapies in patients with esophagogastric cancer are most often short-lived, and less than 5% of patients with metastatic disease survive beyond 5 years .
Systemic therapy for metastatic esophageal adenocarcinoma and gastric carcinoma
First-line systemic therapy
Systemic therapy for metastatic EAC has been based on a study which included patients with gastric adenocarcinomas. Although there are global variations, the standard doublet in the first-line setting is fluoropyrimidine (5-fluorouracil or capecitabine) combined with either oxaliplatin or cisplatin . For patients with HER2-positive EAC, adding trastuzumab to fluoropyrimidine plus platinum is recommended in the first-line setting based on the ToGA trial which has shown to improve outcomes . Other molecular targeted drugs were assessed, but no additional targeted agents were found to be beneficial for EAC as first-line therapy at this point in time . Intensifying treatment by adding a third drug is controversial. The only 3-drug regimen that has demonstrated superiority in a phase 3 study is DCF (docetaxel, cisplatin, and 5-FU). DCF resulted in modestly increased response rate (RR) and overall survival (OS) over cisplatin/5-FU but was associated with significant toxicity .
Second-line or subsequent systemic therapy
Ramucirumab plus paclitaxel is the preferred regimen for second-line therapy based on the RAINBOW study. In this phase III study, Ramucirumab combined with paclitaxel improved RR (28% vs 16%; P =0.0001), progression free survival (PFS), and OS (9.6 vs 7.4 months; P =0.017) versus paclitaxel alone . Ramucirumab monotherapy is an option for patients who are not candidates for combination therapy with paclitaxel . Single-agent irinotecan or taxane (docetaxel or paclitaxel) are associated with a modest improvement in median OS over best supportive care (BSC) alone with no apparent difference in efficacy between irinotecan versus taxane . Recently, the phase III TAGS trial evaluated the efficacy of TAS-102, an orally administered combination of a thymidine based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride, in metastatic gastric and EGJ adenocarcinoma as third-line therapy . A total of 507 patients were randomly assigned to the trifluridine/tipiracil group (n = 337) and to the placebo group (n = 170). Median OS was 5.7 months in the trifluridine/tipiracil group and 3.6 months in the placebo group (HR 0.69; 95% CI 0.56–0.85; P = 0.00058). Thus, TAS-102 was approved as an option for third-line therapy. However, only a select population might be suitable for TAS-102 because of the lack of response rate.
Immunotherapy in gastric cancer
In the last decade, immunotherapy has revolutionized the oncology landscape by targeting the host immune system. Cancer cells have the ability to evade the anti-tumor immune response by expressing PD-L1 (programmed cell death ligand 1) on the cell surface which inhibits the cytotoxic T-cells through binding and blockade of the T-cell receptor PD-1 (programmed cell death receptor 1). By overexpression of PD-L1 on their surface or inducing PD-L1 expression on immune cells, cancer cells exploit the PD-1/PD-L1 pathway to further promote immune escape and tumor growth. Furthermore, cancer cell-mediated upregulation of CTLA-4 (anti-cytotoxic T-lymphocyte-associated antigen 4) on T-cells enhances the recruitment of immunosuppressive T-cells and constitutes a co-inhibitory pathway to elude host immune responses. Blocking immune checkpoint such as programmed cell death protein 1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4), has emerged as a new treatment strategy in several solid cancers .
Immunotherapy has also been added to HER2-directed therapy. In a phase III double-blind trial KEYNOTE-811 it was demonstrated that the addition of pembrolizumab to trastuzumab and chemotherapy significantly improved objective response rate in HER2-positive gastric cancer suggesting that there may be a synergistic benefit of combining checkpoint blockade with standard trastuzumab plus chemotherapy. Objective response was observed in pembrolizumab group compared with the placebo group (74.4% vs 51.9%, p≥ 0.00006) and complete responses were more frequently observed in the pembrolizumab group than in the placebo group (11.3% vs 3.1%) .
Assessment of microsatellite instability (MSI) status and programmed death ligand 1 (PD-L1) expression is recommended. In gastric cancer, deficiency mismatch repair gene (dMMR tumors) represent around 20% of patients, however, MSI tumors are rare in EC, and PD-1 or PD-L1 blockade is marginally effective in EAC. Since 2017, pembrolizumab has been approved as a second-line regimen for patients with MSI-high/deficient mismatch repair (MMR) solid tumors, regardless of tumor type, based on several trials, such as KEYNOTE-016 , KEYNOTE-164 , KEYNOTE-012 , KEYNOTE-028 , and KEYNOTE-158 . Le et al., reported that objective radiographic response (ORR) was observed in 53% of patients, and complete response was achieved in 21% of patients with deficient MMR tumor . The KEYNOTE-059 study showed that ORR was as high as 57% in patients with MSI-high tumors, which is significantly higher than the 9% in the case of microsatellite stable tumors . The MMR status seems to be a helpful tool to better select patients who may benefit from immunotherapy.
Another biomarker that is currently under investigation is TMB (tumor mutations burden). TMB quantifies the number of somatic mutations per coding area of a genome. It has been hypothesized that a heavily mutated tumor can produce a large number of neoantigens, resulting in T-cell infiltration and potentially increased responsiveness to checkpoint blockade. In June 2020, the FDA granted accelerated approval for the treatment of patients with unresectable or metastatic TMB-high (TMB-H) (≥10 mutations per megabase) solid tumors that progressed after prior treatment and had no satisfactory alternative treatment options. This was based upon a prospectively planned retrospective analysis of previously treated patients with advanced solid tumors and TMB-H enrolled on KEYNOTE-158. In this nonrandomized trial, of 790 evaluable patients, 102 (13%) were had TMB-H status and an ORR of 29% .
Nivolumab is another humanized monoclonal antibody that inhibits PD-1. In the randomized CheckMate-649 trial, the largest international phase III trial with 1581 patients suffering from locally advanced or metastatic Her2/neu negative adenocarcinoma of the gastroesophageal junction or stomach the effect of nivolumab plus chemotherapy (XELOX (capecitabine plus oxaliplatin) or FOLFOX (5-FU, folinic acid, oxaliplatine) versus chemotherapy alone was evaluated as the first-line regime. The results of the prespecified interim analysis of OS and PFS in this study were presented at ESMO 2020. The combination of nivolumab plus 5-FU/oxaliplatin significantly improved OS and PFS in patients with PD-L1 CPS ≥ 5 (primary endpoint, n = 955 patients, 60%). Improvement of median OS was 14.4 months versus 11.1 months (HR 98% CI = 0.71 (0.59–0.86), p < 0.0001). Differences were also statistically significant for all patients with PD-L1 CPS ≥ 1 (HR = 0.77, p = 0.0001) and for all randomly assigned patients irrespective of their PD-L1 CPS score (HR = 0.80, p = 0.0002). Because 70% of all patients have CPS ≥ 1 and 60% CPS ≥ 5, the positive results for these groups are likely to be driven by the CPS ≥ 5 population. In the group of patients with PD-L1 CPS ≥ 5, the median progression-free survival was 7.7 versus 6.0 months, respectively (HR 98% CI = 0.68 (0.56–0.81), p < 0.0001) . Based on the results of this trial, the implementation of nivolumab as a first-line therapy option for advanced GEJ or stomach cancer with PD-L1 CPS ≥ 5 is now approved.
In the phase III, ATTRACTION-2 trial, evaluated the efficacy of nivolumab in patients with advanced gastric or EGJ adenocarcinoma who underwent at least two previous chemotherapy regimens. Here, 493 patients were randomly assigned to receive nivolumab (n = 330) or placebo (n = 163) . Median OS was 5.26 months in the nivolumab group and 4.14 months in the placebo group (HR 0.63; 95% CI 0.51–0.78; P<0.001). Moreover, the survival benefit with nivolumab was independent of PD-L1 expression. Thus, nivolumab is accepted as third-line therapy regardless of PD-L1 expression in Japan. (Table 1: list of currently approved immune check point inhibitors).
Systemic therapy for advanced ESCC
First-line systemic therapy
As with EAC, fluoropyrimidine (5-fluorouracil or capecitabine) combined with either oxaliplatin or cisplatin has been the most commonly used first-line regimen for advanced ESCC . In the presidential session at ESMO 2020, the combination of pembrolizumab with CF as first-line treatment (a Phase III trial -KEYNOTE-590) showed a significant improvement in the overall survival in patients with ESCC. In the KEYNOTE-590 trial, a randomized international double-blind phase III study of pembrolizumab plus chemotherapy (cisplatin + 5-FU) versus chemotherapy alone, 749 patients with locally advanced or metastatic esophageal cancer (including Siewert type 1 adenocarcinoma of the esophago-gastric junction) were randomized 1:1 with 73% ESCC and 25% EAC patients. Independent of CPS (combined positivity score) and tumour histology, there was a significant benefit in OS (overall survival) in the combination group of pembrolizumab plus chemotherapy [OS all patients (pts) 12.4 vs. 9.8 months, HR 0.73 (95% CI 0.62–0.86, p < 0.0002); PFS (progression-free survival) all pts 6.3 vs. 5.8 months, HR 0.65 (95% CI 0.55–0.76)]. In particular, ESCC patients with CPS ≥ 10 benefitted most from the combination of immune checkpoint inhibition and chemotherapy (median OS 13.9 vs. 8.8 months, HR 95% CI = 0.57 (0.43–0.75), p = 0.012). The CPS score seems to be decisive for response in subgroups .
Second-line or subsequent systemic therapy
Single-agent chemotherapy with taxanes or irinotecan is an option for second-line therapy [27-29]. However, results with second-line chemotherapy in ESCC are inferior to those in EAC.
Immune checkpoint inhibitors have been approved as second line or subsequent therapy for advanced ESCC. Pembrolizumab has been accepted as a second-line therapy for patients with advanced ESSC with PD-L1 expression levels by CPS of >10. The phase III KEYNOTE-181 trial compared pembrolizumab versus investigator’s choice chemotherapy (docetaxel, paclitaxel, or irinotecan) as second-line therapy in 628 patients with advanced EC . Pembrolizumab significantly improved median OS (9.3 months vs. 6.7 months; HR 0.69; 95% CI 0.52–0.93; P = 0.0074) and 12-month OS rates (43% vs. 20%) compared with chemotherapy in patients whose tumors had a PD-L1 CPS >10. Recently, nivolumab has been accepted as a second-line therapy for ESCC in Japan based on ATTRACTION-3 outcome . A total of 419 previously treated patients with ESCC were randomly assigned to nivolumab (n = 210) and chemotherapy (n = 209). OS was significantly improved in nivolumab; median OS in the nivolumab and chemotherapy group was 10.9 months and 8.4 months, respectively (HR 0.77; 95% CI 0.62–0.96; P = 0.019) . In the KEYNOTE-180 trial, 121 patients with EC (63 ESCC and 58 EAC) who progressed after two or more prior therapies were assessed. Pembrolizumab monotherapy showed that ORR was 14.3% (95% CI 6.7–25.4%) in patients with ESCC and 5.2% (95% CI 1.1–14.4%) in patients with EAC . ORR was higher in patients with PD-L1-positive tumor (13.8% vs. 6.3%) . These results demonstrated the efficacy and tolerability of pembrolizumab as a third-line or subsequent therapy option in patients with heavily pretreated ESSC with high PD-L1 expression. (Table 1: list of currently approved immune check point inhibitors).
Esophageal and gastric cancer remains a significant cause of all cancer-related deaths worldwide. With a spiked increase in incidence being observed in certain Western countries, 5-year survival rates have been shown at rates of 10–15%. Most patients have already manifested advanced disease at diagnosis and are therefore precluded from curative surgical resection.
Esophageal and gastric cancer is challenging to treat and requires a multidisciplinary approach to improve outcomes. The management of these diseases in the advanced setting has advanced the use of immune checkpoint inhibitors. The future challenge is to identify molecular targets based on tumor profiling. The results of further and ongoing clinical trials will contribute to establishing the most appropriate interdisciplinary strategy for each stage of each histologic subtype.
Conflict of interest disclosure
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Declaration of funding sources
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AS is responsible for conception, writing, data interpretation and review of the final draft of the article.
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