State-of-the-art therapy and innovative treatment strategies in esophageal squamous cell cancer

Esophageal cancer is the eleventh most common cancer worldwide, with over 510,000 newly diagnosed cases and over 440,000 recorded deaths in 2022 [1]. The highest regional incidence is observed in Eastern Asia and Eastern Africa [1]. ESCC represents the predominant histologic subtype globally. However, increased esophageal adenocarcinoma (AC) diagnoses have been recently detected, particularly in more developed countries. Smoking and alcohol consumption are well-known major risk factors for ESCC in Western countries. In contrast, those associated with ESCC cases in lower-income countries have yet to be uncovered [2].

As ESCC represents a major clinical challenge for physicians and the prognosis remains poor, it is indispensable to offer suitable treatment strategies. This article focuses on current treatment possibilities in the European subpopulation, while still aiming to depict other geographically dependent treatment perspectives. Figure 1 illustrates the treatment approaches discussed in this review.

In contrast to the FDA label, the current European guidelines suggest immunohistochemical staining of programmed death-ligand 1 (PD-L1) to determine the eligibility for the administration of immune checkpoint inhibitors (ICI) [3]. PD-L1 scoring can be evaluated using several assessments including the tumor proportion score (TPS) or the combined positive score (CPS). TPS investigates viable tumor cells with either partial or complete membrane staining at any intensity, while CPS also comprises lymphocytes and macrophages. Tumor area positivity (TAP) score, which is determined by visually estimating positive tumor cells and tumor-associated immune cells, is already frequently used in clinical trials for ESCC and might become the baseline for future approvals, as it is suggested to be less time-consuming and more visually estimated than CPS and TPS [4].

The evaluation of other molecular markers associated with response to immunotherapy (IO; i.e., high microsatellite instability [MSI-H], mismatch repair deficiency [MMRD] or high tumor mutational burden [TMB-H]) is only mentioned in American National Comprehensive Cancer Network guidelines and should be performed for all newly esophageal cancers, whereas there is no mention in European guidelines [3, 5]. For these specific subgroups, the anti-PD‑1 antibody pembrolizumab has already been approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in advanced stages lacking other suitable treatment options. Although these molecular markers are rarely detected and ESCC is not specifically included in the EMA’s approval, pembrolizumab may still be considered for use in advanced ESCC cases under a “tissue-agnostic” approach [6‐8]. Another key point is the various antibodies used for immunohistochemical staining of PD‑1 in clinical trials, which are not specifically highlighted by approval authorities and may indicate that antibodies such as 22C3 (Keynote590) or 28‑8 (Checkmate577) are exchangeable [9, 10].

ESCC is considered advanced when there is no possibility of having curative-intended/definitive CRT or when metastases are present. Treatment strategies in this setting are shown in Fig. 1b.

Novel drugs inhibiting the PD‑1 pathway such as camrelizumab (ESCORT-1st [23]), toripalimab (JUPITER-06 [24]), or sintilimab (ORIENT-15 [25]) have already proved their efficacy in Asian populations with advanced ESCC. Tislelizumab (RATIONALE-306 [26]) provided superior survival both in Asian and Caucasian patients, which might lead to approval in Europe as first-line therapy. Anti-epidermal growth factor receptor (EGFR) antibodies, i.e., nimotuzumab, were also reported to increase pCR combined with CRT in unresectable ESCC [27]. Tiragolumab (SKYSCRAPER-08), a novel T‑cell immunoreceptor with immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibitory motif) domain (TIGIT) inhibitor, led to significantly elevated PFS and OS, when combined with atezolizumab and CHT, compared to CHT alone [28]. In pretreated ESCC expressing EGFR and/or mesenchymal epithelial transition (MET), the bispecific antibody amivantamab showed antitumor activity, another promising novel treatment strategy [29].

Regarding curative treatment, camrelizumab, another novel PD‑1 inhibitor, showed promising results in the phase III ESCORT NEO trial (n = 391) in neoadjuvant administration with CHT in locally advanced ESCC, leading to much higher pCR rates compared to CHT alone [30].

Treatment strategies after definitive CRT are still not defined, engendering the phase III trials KEYNOTE-975 and SKYSCRAPER-07. In the first trial, pembrolizumab is administered for 1 year, whereas in the other trial, atezolizumab ± tiragolumab is given to patients who have not progressed following definitive CRT ([31, 32]; Table 1).

In recent years, the landscape of systemic therapeutic options for localized and metastatic esophageal squamous cell cancer (ESCC) has been revolutionized by novel drugs and numerous randomized controlled trials. Nevertheless, prognosis in advanced stages remains poor, which necessitates further research. Particularly some patient subgroups with specific biomarkers might profit from targeted therapies that are currently under investigation. As treatment options are still limited, therapeutic decisions should always be made after discussion in an interdisciplinary tumor board and in accordance with the patients’ wishes.