https://orcid.org/0000-0002-1733-5072
ABSTRACT
Introduction
Esophageal cancer (EC) is the ninth most common cancer in Japanese men. Esophageal squamous cell carcinoma (ESCC) is the major histological type and accounts for 90% of EC cases in Japan. The prognosis of advanced ESCC remains poor. The standard treatment for advanced ESCC was palliative chemotherapy with 5-fluorouracil plus cisplatin as first-line chemotherapy. After failure of first-line chemotherapy, taxanes were used as second-line chemotherapy. Recently, pembrolizumab monotherapy has demonstrated benefits as a second-line treatment in patients with advanced ESCC and a combined positive score of ≥10. Survival was found to be improved in patients with advanced EC who received first-line treatment with pembrolizumab plus doublet chemotherapy than in those who received doublet chemotherapy alone.
Areas covered
This overview of immune checkpoint inhibitors focuses on pembrolizumab in combination with chemotherapy and shares key clinical data relevant to the treatment of patients with EC in Japan.
Expert opinion
Pembrolizumab plus doublet chemotherapy is now an established first-line treatment for advanced EC in Japan. Recently, nivolumab plus doublet chemotherapy and nivolumab plus ipilimumab have also become first-line treatment options for patients with advanced ESCC. Further investigations are needed to identify biomarkers that would be useful for selecting candidates for these treatments.
1. Introduction
Esophageal cancer (EC) is the sixth leading cause of cancer death worldwide, with particularly high incidence in East Asia and East Africa [Citation1]. Histologically, EC can be broadly divided into squamous cell carcinoma (SCC) and adenocarcinoma. SCC is the most common organizational subtype of EC worldwide, accounting for about 90% of all EC, whereas adenocarcinoma is a common histological subtype, especially in Western populations [Citation2]. In Japan, EC is the ninth most common cancer and the tenth leading cause of cancer mortality in men, and SCC is the most common subtype [Citation3,Citation4]. EC is generally a very aggressive cancer, and patients are usually not diagnosed until an advanced stage when symptoms have appeared [Citation5]. Esophageal SCC (ESCC) and esophageal adenocarcinoma (EAC) have different risk factors. Major risk factors for ESCC are smoking, alcohol consumption, severe damage to the esophagus, and a history of head and neck cancer; those of EAC are Barrett’s esophagus, gastroesophageal reflux, and obesity [Citation6,Citation7].
The prognosis of advanced EC remains poor, with a 5-year relative survival rate of 5.2% according to the 2011–2017 data from Surveillance, Epidemiology, and End Results 18. In Japan, the median survival time for patients with ESCC who receive palliative chemotherapy is about 10 months. Furthermore, the prognosis of ESCC is worse than that of EAC [Citation8]. In Japan, systemic chemotherapy is the standard treatment for advanced ESCC. Although no randomized controlled trials have shown prolonged survival in patients who receive 5-fluorouracil plus cisplatin as first-line chemotherapy, this regimen achieves a response rate of 30–40% and progression-free survival (PFS) of 4–6 months [Citation9–11]. Taxanes have been used as second-line agents after failure of first-line chemotherapy, with response rates of 10–40% and overall survival (OS) of 8–10 months [Citation12,Citation13], although there is a lack of evidence from randomized controlled trials.
More effective cytotoxic agents are needed for patients with advanced ESCC in Japan. Immune checkpoint inhibitors (ICIs), such as pembrolizumab, have revolutionized the treatment paradigm for many types of cancer, including EC. In Japan, about 90% of all EC patients have ESCC, and EAC patients generally receive treatments according to gastric adenocarcinoma. This review provides an overview of the current role of pembrolizumab in the treatment of advanced ESCC in Japan and discusses the problems related to the use of ICIs in patients with advanced EC.
2. Overview of the market
There are two important unmet needs in the treatment of patients with ESCC in Japan. First, there are few effective agents for patients with advanced ESCC. Platinum, 5-fluorouracil, and taxanes are recognized as key agents. However, there are no effective molecular targeted agents, such as anti-epidermal growth factor receptor or anti-vascular endothelial growth factor receptor antibodies. Therefore, the prognosis of advanced ESCC remains poor, as does that of locally advanced diseases. Preoperative chemotherapy followed by surgery or definitive chemoradiotherapy are the standard treatment methods for these patients in Japan. However, patients with resectable locally advanced EC who receive standard therapy have 5-year OS of 46–62% and a recurrence rate of 25–50% [Citation14].
ICIs-containing treatments have become standard treatments in advanced melanoma, lung cancer, renal cell carcinoma, head and neck cancer, gastric cancer, malignant pleural mesothelioma, Merkel cell carcinoma, liver cancer, and so on. Preclinical research has suggested that ESCC was a potential therapeutic target for ICIs and was expected to respond well. It has also been suggested that the etiology of common polymorphisms in mismatch repair genes is influenced by environmental factors, particularly exposure to cigarette smoke. Tumors with high microsatellite instability tend to have more mutations that function as neoantigens, increased programmed cell death-1 (PD-1)-positive lymphocytic infiltration, and greater programmed cell death ligand-1 (PD-L1) expression on tumor cells [Citation15,Citation16]. Therefore, ICIs have been developed mainly for advanced ESCC.
Nivolumab is a human monoclonal antibody that targets PD-1. ATTRACTION-1 trial was the phase II trial that demonstrated the efficacy and safety of nivolumab in 65 patients with advanced EC who were refractory to or intolerant of fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. The objective response rate (ORR) was 17% (95% confidence interval [CI] 10–28), and the primary endpoint was met: median PFS was 1.51 months (95% CI 1.41–2.83 months) and median OS was 10.78 months (95% CI 7.39–13.34 months). The most frequent grade 3/4 adverse events were lung infection (3%) and dehydration (3%) [Citation17].
After ATTRACTION-1, the Phase III ATTRACTION-3 trial compared nivolumab with paclitaxel or docetaxel in patients with advanced ESCC refractory to or intolerant of fluoropyrimidine-based and platinum-based chemotherapy. All eligible patients were assigned randomly in a ratio of 1:1 to receive nivolumab or taxane as monotherapy. A total of 419 patients with advanced ESCC were included in this trial. The primary endpoint of OS was significantly better in patients who received nivolumab monotherapy than in those who received taxane monotherapy (10.9 months vs. 8.4 months, hazard ratio [HR] 0.77, 95% CI 0.62–0.96; p = 0.019); however, the ORR was similar (19% vs. 22%). The most frequent treatment-related adverse events were rash (11.0%), diarrhea (10.5%), decreased appetite (7.7%), and fatigue (7.2%) in the nivolumab group and hair loss (47%), neutropenia (37%), and leukopenia (35%) in the taxane group [Citation18].
Based on the results of ATTRACTION-3, nivolumab monotherapy for advanced ESCC refractory to fluoropyrimidine-based and platinum-based treatments was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan on 21 February 2020. Subsequently, it was approved by the US Food and Drug Administration (FDA) on 10 June 2020.
3. Introduction to the compound
3.1. Chemical structure
Pembrolizumab is a recombinant humanized immunoglobulin monoclonal antibody that targets PD-1, and consists of a complementarity-determining region derived from the mouse anti-human PD-1 monoclonal antibody. A framework region and stationary region are derived from human immunoglobulin 4 in which the amino acid residue at position 228 of the H-chain is replaced with proline. This monoclonal antibody is a glycoprotein (molecular weight approximately 149,000 Da) consisting of two H-chains (γ4-chains) with 447 amino acid residues and two L-chains (κ-chains) with 218 amino acid residues. Pembrolizumab promotes the immune response by T-cells against tumor cells by inhibiting the interaction between PD-1 and its ligands PD-L1 and PD-L2 () [Citation19].
Figure 1. Mechanism of action of pembrolizumab. MHC, major histocompatibility complex; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; TCR, T-cell receptor.
3.2. Pharmacodynamics
The relationship between the efficacy of pembrolizumab and its toxicity has been evaluated in patients with advanced melanoma and lung cancer. There was no clinically significant difference in efficacy or toxicity between doses of 200 mg or 2 mg/kg administered every 3 weeks [Citation20].
3.3. Pharmacokinetics and metabolism
Pembrolizumab pharmacokinetic data were collected on 2993 patients with various types of cancer who received 1–10 mg/kg every 2 weeks, 2–10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Steady-state concentrations of pembrolizumab were reached after 16 weeks of repeated dosing at 3-week intervals, with a 2.1-fold increase in systemic accumulation [Citation20]. The Phase I KEYNOTE-555 study of pembrolizumab 400 mg every 6 weeks in patients with metastatic melanoma showed that the concentration with this regimen was well within the 90% prediction interval of the simulated concentration with short-term efficacy that appeared to be comparable to that reported previously [Citation21]. Based on the findings of this study, the FDA approved pembrolizumab at a dose of 400 mg every 6 weeks on 28 April 2020.
4. Clinical efficacy: first-line chemotherapy in Japanese patients
KEYNOTE-590 was a randomized, double-blind, placebo-controlled Phase III study. In this study, patients with untreated advanced ESCC or EAC were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo by intravenous infusion every 3 weeks in combination with chemotherapy (80 mg/m2 cisplatin intravenously plus 800 mg/m2 of 5-fluorouracil by continuous intravenous infusion on days 1–5 every 3 weeks). The primary endpoints were PFS and OS in all patients including in a subgroup of PD-L1-positive patients with a combined positive score (CPS) ≥10. The secondary endpoints were safety, tolerability, ORR, duration of response, and health-related quality of life in all patients including in the PD-L1-positive subgroup [Citation22].
The study included 749 patients (ESCC, 73%; PD-L1-positive, 51%), 141 (19%) of whom were Japanese. Median age of the Japanese patients was 67.5 years in the pembrolizumab group and 68.0 years in the chemotherapy group. The Eastern Cooperative Oncology Group performance status (PS) score was 1 in 35.1% of Japanese patients in the pembrolizumab group and 20.9% of Japanese patients in the chemotherapy group; these proportions tended to be lower than in the intent-to-treat population. The proportion of Japanese patients with ESCC was 90.5% in the pembrolizumab group and 88.1% in the chemotherapy group, which tended to be higher than in the intention-to-treat population. Furthermore, the proportion of Japanese patients with an Eastern Cooperative Oncology Group PS score of 1 and those with PD-L1-positive (CPS ≥ 10) tumors tended to be higher in the pembrolizumab group than in the chemotherapy group.
In the Japanese subgroups, patients with PD-L1-positive ESCC had significantly improved median OS in the pembrolizumab group (15.8 months; 95% CI 12.8–NE) than in the chemotherapy group (10.9 months; 95% CI 7.8–14.6; HR 0.55, 95% CI 0.32–0.94). Among the total Japanese population, patients in the pembrolizumab group had significantly improved median OS (17.6 months; 95% CI 13.9–NE) than those in the chemotherapy group (11.7 months; 95% CI 9.5–19.0; HR 0.71, 95% CI 0.47–1.09). Among the global populations, patients with ESCC had significantly improved median OS in the pembrolizumab group (12.6 months; 95% CI 10.2–14.3) than in the chemotherapy group (9.8 months; 95% CI 8.6–11.1; HR 0.72, 95% CI 0.6–0.88; p < 0.0006) and patients with PD-L1 positive EC also had significantly improved median OS in the pembrolizumab group (13.5 months; 95% CI 11.1–15.6) than in the chemotherapy group (9.4 months; 95% CI 8.0–10.7; HR 0.62, 95% CI 0.49–0.78; p < 0.0001). The trend for OS in the Japanese population was similar to that in the global population.
In the Japanese populations with ESCC, the median PFS was 6.4 months in pembrolizumab group (95% CI: 6.0–8.4) versus 6.1 months in chemotherapy group (95% CI: 4.2–6.3) (HR: 0.65 [95% CI: 0.55–0.76]; p < 0.0001). In the global population of patients with ESCC, the median PFS was 6.3 months in pembrolizumab group (95% CI 6.2–6.9) versus 5.8 months in chemotherapy group (95% CI: 5.0–6.1) (HR: 0.65 [95% CI: 0.54–0.78]; p < 0.0001). PFS in the Japanese population tended to be similar to that in the global study population. The secondary endpoint of ORR was also improved (56.8% vs. 38.8%, respectively) [Citation23], indicating a similar trend for ORR in the Japanese population.
These data point to some trends in the Japanese population. First, there were some differences in baseline characteristics, such as PS, and in histopathology between the Japanese population and the global population. The difference in histopathology may reflect the epidemiology of EC in Japan, and the difference in PS might reflect the specific criteria used to select patients for participation in clinical trials in Japan. Second, the results for PFS in the Japanese population and global population were similar but OS tended to be improved in the Japanese population than in the global population. This discrepancy might reflect a difference in subsequent treatment for patients with advanced EC.
The clinical efficacy of pembrolizumab plus doublet chemotherapy in the Japanese population was similar to that in the global population ().
Table 1. Clinical efficacy in the Japanese population and global population in the KEYNOTE-590 trial.
5. Safety and tolerability
The safety data in KEYNOTE-590 showed that adverse events occurred in 98% of patients (364/370) and grade ≥3 treatment-related adverse events occurred in 72% of patients (266/370) in the pembrolizumab plus doublet chemotherapy group. Immune-mediated adverse events and infusion reactions, including hypothyroidism (11%), pneumonitis (6%), and hyperthyroidism (6%), occurred in 26% of patients (95/370) and were grade ≥3 in 7% (26/370). Grade 5 immune-mediated events (pneumonitis) occurred in two patients [Citation22].
In the Japanese population, treatment-related grade ≥3 adverse events were reported in 74.3% of patients (55/74). The most common treatment-related adverse events were decreased appetite, nausea, and a decreased neutrophil count in the pembrolizumab plus doublet chemotherapy group [Citation23].
Although detailed safety data were not reported specifically for the Japanese population in this study, the frequency of treatment-related grade ≥3 adverse events (72% vs. 74.3%) and the frequency of immune-mediated adverse events and infusion reactions (26% vs. 28.4%) in the pembrolizumab plus doublet chemotherapy group were similar for the Japan and global populations.
6. Regulatory affairs
The KEYNOTE-590 trial showed pembrolizumab plus doublet chemotherapy as a new standard first-line treatment for advanced EC patients, and the FDA approved pembrolizumab plus platinum and fluoropyrimidine-containing chemotherapy as a first-line treatment for advanced EC patients regardless of the types of histology or PD-L1 expression on 23 March 2021. In Japan, the PMDA approved pembrolizumab plus doublet chemotherapy on 25 November 2021.
7. Conclusion
The results of KEYNOTE-590 trial established pembrolizumab plus doublet chemotherapy as a first-line standard treatment for advanced ESCC. PD-L1 expression was evaluated by the CPS, and efficacy was confirmed in all patients, not just those with a CPS score ≥10.
8. Expert opinion
In Japan, EC is known to be common in men, with a typical age of onset of 60–70 years. ESCC is the main histological type, accounting for 90% of cases. The prognosis of patients with advanced ESCC remains poor, and the efficacy of cytotoxic agents such as 5-fluorouracil, platinum, and taxanes is limited. ICIs have been developed mainly for advanced EC patients, and the KEYNOTE-590 trial finally established pembrolizumab plus doublet chemotherapy as a standard first-line treatment for advanced EC in many countries, including Japan.
There are two major clinical questions concerning the use of ICI-containing regimens for patients with advanced ESCC in Japan. The first question is which regimen is optimal for these patients – pembrolizumab plus doublet chemotherapy, nivolumab plus doublet chemotherapy, or nivolumab plus ipilimumab. The CheckMate 648 trial showed the statistical superiority of nivolumab plus doublet chemotherapy and nivolumab plus ipilimumab over doublet chemotherapy in terms of OS [Citation24]. Therefore, the PMDA approved nivolumab plus doublet chemotherapy and nivolumab plus ipilimumab on 26 May 2022. Three ICI-containing first-line treatments are available for patients with advanced ESCC in Japan. However, there have been no direct comparisons of the clinical efficacy and safety of these three treatments. Compared with pembrolizumab plus doublet chemotherapy and nivolumab plus doublet chemotherapy, nivolumab plus ipilimumab does not contain cisplatin, which requires hydration to prevent renal damage. Therefore, patients with advanced ESCC and heart failure or renal impairment might be suitable candidates for nivolumab plus ipilimumab as a first-line treatment. However, these frail patients were not included in the CheckMate 648 trial. Further investigations are needed to obtain real-world data on first-line treatments for patients with advanced ESCC.
The second clinical question concerns the most useful biomarker(s) for identifying patients with advanced ESCC who can be considered candidates for first-line ICI-containing treatments. PD-L1 expression was used as a candidate biomarker for ICI-containing treatments in the KEYNOTE-590 and CheckMate 648 trials but was evaluated by the CPS in KEYNOTE-590 and by the tumor proportion score in CheckMate 648. The KEYNOTE-590 trial found an HR of 0.72 in patients with ESCC and an HR of 0.57 in patients with PD-L1-positive ESCC (CPS ≥10) [Citation22], while the CheckMate 648 trial found respective HRs of 0.74 and 0.54 [Citation24]. Although these two trials used different PD-L1 scoring methods, their findings indicate that PD-L1 expression status might be a useful biomarker for identifying candidates for ICI-containing treatments. In any case, these trials demonstrated the clinical efficacy of ICI-containing treatments regardless of PD-L1 expression, and PD-L1 expression is recognized as a complementary biomarker rather than an essential one in Japan. Therefore, further translational research is needed to find more useful biomarkers that can be used to identify patients likely to benefit from ICI-containing treatments.
Pembrolizumab plus doublet chemotherapy has become one of the new first-line standard treatments for advanced ESCC patients, however the median OS in this population is still reported at about 12 months. To improve the clinical outcomes for these patients, the LEAP-014 phase III trial, which evaluates efficacy and safety of an investigational first-line treatment consisting of pembrolizumab and fluoropyrimidine, platinum, and lenvatinib, is ongoing (NCT04949256). Additionally, the KEYMAKER-06 phase I/II trial, which evaluates the safety and efficacy of some investigational second-line treatments consisting of cytotoxic chemotherapy and/or pembrolizumab, anti-LAG3 antibody, anti-ILT4 antibody, and lenvatinib, is ongoing too (NCT05342636).
Article highlights
The prognosis of Japanese patients with advanced esophageal squamous cell carcinoma is still poor, and a few drugs such as platinum and fluoropyrimidine and taxane are effective for these patients.
Pembrolizumab is a recombinant humanized immunoglobulin monoclonal antibody that targets PD-1.
Pembrolizumab plus doublet chemotherapy as a first-line treatment showed clinical efficacy for patients with advanced esophageal cancer based on the results of the KEYNOTE-590 trial.
In Japanese subgroup analysis of the KEYNOTE-590 trial, efficacy and safety of pembrolizumab plus doublet chemotherapy were similar for Japan and globally.
Clinical trials related to pembrolizumab-containing treatments such as the LEAP-014 trial and KEYMAKER-06 trial are developing.
Drug summary box
Declaration of interest
K Kato has received research funds from ONO, Bristol Myers Squibb, Merck Sharp & Dohme, Beigeen, Shionogi, and Oncolys Biopharma, and honoraria from ONO, Eli Lilly and Taiho. S Yamamoto has received honoraria from ONO and Bristol Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Company review
Merck Sharp & Dohme provided a scientific accuracy review at the request of the journal editor.
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