Investigative therapy for advanced esophageal cancer using the option for combined immunotherapy and chemotherapy

Esophageal cancer is the eighth most common cancer, and the sixth leading cause of cancer-related mortality worldwide [1] and mortality continues to rise year by year, especially in low- and middle-income countries [2]. The incidence of the disease is three- to four-times higher in males than in females, and there are two main types, squamous cell carcinoma (SCC) and adenocarcinoma. The long-term prognosis remains poor due to postoperative recurrence and metastasis. Current guidelines for first-line treatment of advanced esophageal still recommend chemotherapy [3]. Less evidences are available for esophageal SCC (ESCC) than are for adenocarcinoma, and reduced efficacy can be achieved by chemotherapy in ESCC. At present, platinum-containing chemotherapy provides response rates of 20–50% and median overall survival (mOS) duration of 8–10 months [4,5].

In recent years, immune checkpoint inhibitors (ICIs) that targeting programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) have made a breakthrough in the treatment of multiple solid tumors [6–8]. Compared with the OS of patients who are treated with conventional chemotherapeutics, PD-1/PD-L1 inhibitors-based therapies can lead to significant improvements in OS and progression-free survival (PFS) in some cancers [9,10].

Current guidelines recommend pembrolizumab for second-line or subsequent therapy for PD-L1-positive esophageal cancer [3]. While there are few reports of first-line immunotherapy for esophageal cancer. Here, we report a case of a patient who has been treated with a combination of pembrolizumab and chemotherapy as the first-line treatment. This patient achieved PR after treatment with pembrolizumab and chemotherapy, and there were no irAEs.

Case presentation

Clinical history

A 59-year-old man was admitted to our division with recurrent esophageal cancer, and who had received radical esophagectomy 11 years ago. He was diagnosed with systemic metastases before coming to our hospital. Physical examination revealed an obvious tenderness in the left shoulder. The routine laboratory parameters were found normal, except for a leukopenia and a white blood cell count of 3.15 × 109/l. The levels of tumor markers, such as the carcinoembryonic antigen and the carbohydrate antigen (CA 19-9), were 1.14 and 3.85 ng/ml, respectively (normal carcinoembryonic antigen <5 ng/ml, CA 19-9 <37 ng/ml). Blood screening for autoimmune and endocrine function, including thyroid function, before ICI therapy, showed no abnormal changes.

Further examination of the patient using CT scans, showed multiple lymphadenopathies around the right supraclavicular soft tissue, the right submaxillary and the mediastinum. Pleural nodules, in the left anterior inferior wall, and an osteolytic destruction of the left humeral head and right fifth rib, were also found. Examination with 18Ffluorodeoxyglucose positron emission tomography revealed an abnormal fluorodeoxyglucose uptake in the same lesions detected by computed tomography (Figure 1). Open right supraclavicular lymph node biopsy showed histological features that were identical to the ones observed in ESCC (Figure 2), indicating a right supraclavicular lymph node metastasis of esophageal cancer. Based on these clinical and pathological findings, the clinical stage was diagnosed as stage IV according to the Union for International Cancer Control (UICC 7th edition).

To determine potential therapeutic methods, with the patient’s consent, the tissue samples from the right supraclavicular lymph node and whole blood as control were subjected to next-generation sequencing using a 757-genes panel (Yucebio, Shenzhen, China). The genomic testing showed mutations in TP53 (R282W), and copy number (CN) variation gains in KRAS, EGFR and CCND1. Next-generation sequencing also showed microsatellite stability and moderate tumor mutational burden (4.03 Mut/Mb). Immunohistochemistry analysis showed that the PD-L1 tumor proportion score of tissue samples ranged from 6% to 10% and the combined positive score was 4.2 (Figure 3), indicating that the expression of PD-L1 was positive, but not high.

Approved by the Research Ethics Committees of Qilu Hospital (Qingdao) of Shandong University, and based on the compassionate use principle, the treatment using a combination of pembrolizumab and chemotherapy was carried on with the patient’s fully informed and agreement. After treatment with pembrolizumab (200 mg, q3w), albumin-bound taxol and nedaplatin (albumin-bound taxol 260 mg/m², d1; nedaplatin 100 mg/m², d1) for three cycles, computed tomography showed that the metastatic lesions had significantly decreased in size, and the osteolytic bone destruction of the left iliac bone became osteogenic (Figure 4). The curative effect on the patient was evaluated as PR. After the first cycle of treatment, an IV-degree bone marrow depression appeared, and the condition improved after G-CSF treatment. Following the second cycle of chemotherapy, a longer G-CSF treatment was used. A Degree III of thrombocytopenia occurred after the fourth cycle of chemotherapy, which improved after treatment with recombinant human thrombopoietin. Then, chemotherapy was adjusted using a treatment regimen with pembrolizumab and albumin-bound taxol for two cycles, resulting in the stabilization of the metastatic lesions assessed by CT scans after six cycles. Following this step, the patient was given a monotherapy as maintenance therapy. The patient received a total of six cycles of pembrolizumab and chemotherapy and then received a pembrolizumab maintenance monotherapy for two cycles, from January 2019 to July 2019. Immune-related adverse reactions were not observed. The patient was followed up till November 2019 when he died of gastrointestinal hemorrhage.

Discussion

Esophageal cancer is a clinically challenging malignancy with poor prognosis. Oncology guidelines recommend monotherapy as first-line therapy in patients with SCC, however this therapy provided patients limited survival benefits. Although chemotherapy can achieve tumor regression in the acute stage of a disease, chemotherapy alone may not be able to completely control cancer progression due to drug resistance or the presence of chemo-resistant cancer stem cells. On these conditions, other treatments, such as immunotherapy, should be combined with chemotherapy to eliminate troublesome cancer cells. At present, the strategy of immune chemotherapy has been used in other solid tumors [11]. According to the current data, adding chemotherapeutic agents to immunotherapy can stimulate host production of long-term and effective tumor antigen-specific T lymphocytes and synergistically optimize the antitumor effects [12,13]. Different drugs have different regulatory mechanisms on tumor immune microenvironment [14]. In addition, the discovery of immunogenic cell death and damage associated molecular patterns has promoted the combination of chemotherapy and immunotherapy [15], which has achieved a better and more sustained therapeutic effect than single immunotherapy.

Cancer immunotherapy aims to release the inhibition of immune surveillance to activate tumor recognition, which may result in antitumor cytotoxic activity [16]. Immunotherapy may provide cancers with an immune surveillance mechanism, regardless of drug resistance or the presence of cancer stem cells, and which would be indispensable for long-term antitumor efficacy [17,18]. So far, these inhibitors have been applied to a variety of anticancer regimens, including melanoma, non-small-cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin lymphoma [19–23]. The results of a Phase III study evaluating second-line pembrolizumab in advanced or metastatic ESCC, EAC or adenocarcinoma of gastroesophageal junction (KEYNOTE-181, NCT02564263) showed that pembrolizumab resulted in superior OS compared with second-line chemotherapy (9.3 vs 6.7 mOS; hazard ratio: 0.69; 95% CI: 0.52–0.93), and mOS for ESCC with combined positive score ≤10 was 10.3 months compared with 6.7 months [24]. In addition, ATTRACTION-3 study, a Phase III study evaluating second-line nivolumab versus chemotherapy in patients with advanced ESCC supports the use of nivolumab monotherapy. OS was significantly improved in the nivolumab group compared with the chemotherapy group (median 10.9 months, 95% CI: 9.2–13.3 vs 8.4 months, 7.2–9.9; hazard ratio for death 0.77; 95% CI: 0.62–0.96; p = 0.019) [25]. As a result of the findings of KEYNOTE-181 and ATTRACTION-3, pembrolizumab and nivolumab were granted US FDA approval as monotherapy in second-line treatment for ESCC. Several studies have shown that the efficacy of a combination immunotherapy is better than that of a single immunotherapy [26,27]. KEYNOTE-059 (NCT02335411) evaluates pembrolizumab usage in combination with chemotherapy, or as monotherapy, in the first line for advanced gastric/gastroesophageal junction cancers. The pembrolizumab demonstrates well tolerated, manageable safety and induced antitumor activity for monotherapy as well as in combination with chemotherapy. The combination of pembrolizumab and chemotherapy (cisplatin plus 5-FU) resulted in a 60% objective response rate (ORR) with 4% complete response (CR) and median PFS of 6.6 months while ORR for patients receiving pembrolizumab monotherapy was 25.8% with CR of 6.5% and median PFS of 3.3 months [28]. It is therefore imperative to explore effective therapies for ESCC. However, data from the ongoing Phase III KEYNOTE-590 study using pembrolizumab as a first-line immune chemotherapeutic treatment for advanced esophageal carcinoma have not been available and additional information is needed. This study is being conducted to investigate the safety and efficacy of pembrolizumab as the first-line treatment for advanced esophageal carcinoma [29]. Our patient repeatedly expressed his desire to improve the therapeutic effect before the start of the treatment. With the patient’s consent, we gave the patient a combination of an ICI and chemotherapy. We hope that the strategy of the ICI combined with chemotherapy in advanced esophagus will be as effective as that for other cancers, and could be added into first-line treatment. A PR was achieved and the patient did not experience irAEs, after treatments with pembrolizumab and chemotherapy.

The checkpoint inhibitors based immunotherapy brings solid tumor treatment into a new era. However, this approach also brings new clinical challenges, such as predicting the efficacy, adverse reactions, hyperprogressive disease associated with immunotherapy and irAEs. The antitumor immune response is a complex process, involving several types of immune cells and molecules. Seeking predictive biomarkers for the efficacy of an immunotherapy is more challenging. In clinical practices and researches, PD-L1 is used as a biomarker for efficacy predicting. Overexpression of PD-L1 in tumor cells may cause immune escape, by inhibiting the function of cytotoxic T cells [30–32]. Therefore, the expression of PD-L1 is considered as a biomarker for predicting the efficacy of ICIs. Researchers found that patients with low or no expression of PD-L1 in non-small-cell lung cancer tumors, could also be benefit from anti-PD-L1 therapy [33].

The overexpression rate of EGFR in ESCC patients is as high as 60–70%, and EGFR CN variation can be detected in 28% of patients. However, because EGFR may not be the dominant upstream driving gene, it can be effectively intervened with some targeted drugs, its clinical effect is not very satisfactory, so immunotherapy is very necessary [34]. But in one hyperprogression study, five patients with immunotherapy hyperprogression, two of whom were esophageal cancer patients, were found to have MDM2/MDM4 gene amplification, EGFR gene amplification and CCND1/FGF3/FGF4/FGF19 gene amplification [35]. In another study of patients with head and neck SCC, authors explored the potential genetic markers associated with hyperprogressive disease following immunotherapy and the results showed that the changes of EGFR were related to the ‘hyperprogressive disease’ of PD-1/PD-L1 inhibitors after treatment [36]. Furthermore, EGFR and CCND1 copy number were amplified in this patient, but the efficacy of PR was still achieved. Therefore, it may be one of the directions for future research to explore whose markers that can predict validly immunotherapy ‘hyperprogressive disease’.

Conclusion

The development of immunotherapy improves the prognosis of several cancers. However, the benefits of ICIs for primary advanced esophageal cancer are still unclear. We report results obtained in one patient who was diagnosed with primary advanced esophageal cancer and was treated with a combination of an ICI and chemotherapy. We believe that a larger clinical trials investigating checkpoint inhibitor based immunotherapy as a first-line treatment for advanced esophageal cancer will be promising and help the people who succumbed to this disease.

Future perspective

At present, monotherapy is recommended by oncology guidelines as first-line therapy in patients with SCC, however this therapy provided patients limited survival benefits, and pembrolizumab for second-line or subsequent therapy for PD-L1-positive esophageal cancer. At present, many studies have shown that immunotherapy and chemotherapy have synergistic interaction, and some clinical trials have verified it. Phase III KEYNOTE-590 study, which was used as a first-line treatment of advanced esophageal carcinoma with immune chemotherapy, has been still ongoing. The treatment effect of the case we reported is very good and with no irAEs. We believe the large-scale clinical trials will be successful and improve the first-line treatment for esophageal cancer patients in the future.