Complete Remission of a Patient With HER-2 amplification Gastric Cancer Treated With Sintilimab Combined With Trastuzumab

doi:10.21203/rs.3.rs-2797687/v1

Background Gastric cancer (GC) is one of the most common malignant tumors in China and is also a major cause of cancer deaths worldwide, for which treatment strategies are extremely limited. Patients Susually lose the opportunity of therapeutic surgery because the lesions cannot be completely removed, although it can greatly prolong their survival time. Human epidermal growth factor receptor-2（HER-2）is the diagnostic criterion that determines whether patients can be the therapy with target in gastric cancer. However, the effect of targeted therapy on improving patient over survival (OS) is not significant. In recent years, immune checkpoint inhibitors (ICIs) sintilimab has shown significant efficacy in the treatment of gastric cancer.

Case presentation A 50-year-old man was diagnosed with adenocarcinoma of GC with multiple lymph node metastases. Positron emission tomography-computed tomography (PET-CT) shows retroperitoneal, ileocecal, ascending colon, pelvic peritoneum, and mesangial metastasis. Then, the patient underwent genetic testing.The results indicated that MSS, PD-L1 CPS = 2, HER-2(3+). Therefore, the first choice was chemotherapy combined with immunotherapy and targeted therapy. The regimen was chosen with sintilimab plus trastuzumab with chemotherapy SOX as first-line therapy for patients. After two cycles of treatment, the expression of CA199 was decreased, and lymph node metastases were smaller than before. The treatment was continued, and CT scans suggested complete response (CR) was achieved for both the lymph node metastases and gastric lesions after of 4 cycles treatment on 31 January 2023. Maintenance sintilimab plus trastuzumab was selected because of his stable CR status. During the treatment period, there was no occurrence of relatively serious adverse effects due to chemotherapy.

ConclusionHER-2-positive GC of patients who receives target combined with immune therapy may be an efficient and safe decision-making therapeutic choice. The case provides a treatment regimen for patients with HER-2-positive, whether to choose combination therapy as a new treatment regimen. This is the first reported case of gastric cancer with multiple lymph node metastases with complete remission with sintilimab plus trastuzumab.

GC

human epidermal growth factor receptor 2 (HER2)-positive

immunotherapy

Gastric cancer (GC) is one of the most common digestive malignancies worldwide with the fourth most common cause of cancer-related death^[1]. The reported 5-year survival rates of metastatic advanced GC are from 8.8–14.9%^[2–4]. The median OS of patients with advanced GC is less than one year with combination chemotherapy^[5]. Human epidermal growth factor receptor 2 (HER-2) is the most prominent therapeutic target in GC. Since 2010, combination therapy with the HER-2-positive trastuzumab and chemotherapy has become the standard first-line treatment^[6]. But in recent years, trastuzumab in GC has largely been unsuccessful^[7]. The ICIs play an emerging role in the treatment of GC. ICIs including programmed cell death peotein-1 (PD-1), anti-PD-L1, and anti-cytotoxicT lymphocyte antigen-4 (CTLA-4). It is usually thought that PD-L1-positive GC with a high tumor mutation burden (TMB-H) and high microsatellite instability can obtain a good response. Although the case we discuss here was PD-L1-positive and had microsatellite stability (MMS), there was still an encouraging prognosis. Sintilimab is a monoclonal antibody against PD-1. Sintilimab can bind to PD-1, block the interaction of PD-1 with its ligands, and help to recover the anti-tumor response of T cells^[8]. Recently, sintilimab has been reported in plenty of literature and shows a satisfying anti-tumor effect. By 2020, sintilimab has been approved by the National Medical Products Administration (NMPA) of China to treat relapsed or refractory classical Hodgkin lymphoma (r/r cHL)^[9]. In digestive system cancers, sintilimab showed favorable anti-tumor effects as well. In a phase I study NCT02937116, 20 patients of gastric/gastroesophageal junction(G/GEJ) adenocarcinoma was enrolled among them, sintilimab was administered intravenously in combination with every 21 days for up to six cycles; after combination treatment. The combination therapy resulted in progression-free survival (PFS) of 7.5 months, and an objective response rate (ORR) of 85% ^[10]. Immunotherapy brings a light of hope for patients with failed chemotherapy, and immunotherapy combined with targeted therapy will bring better efficacy for patients. However, large-scale prospective trials are needed to further in the future.

A 50-year-old man was hospitalized on 15 September 2022 with abdominal discomfort without obvious incentive. There was no tobacco or alcohol dependence, no nausea and vomiting, no hematemesis and melena, no fever and chills, and no familial genetic disease. Physical examination showed no tenderness in the abdomen without abnormalities of other organ systems. He had a gastroscopy on 29 August 2022 and the examination result showed that the color of the esophageal mucosa was not abnormal, the mucosa of the gastric sinus was edema, two ulcers were visible in the small bend of the gastric sinus, thick moss on the surface, and pathology was taken in the larger ulcer (Fig. 1A). The pathological examination of the specimen proved to be a well-differentiated adenocarcinoma (Fig. 1b). To clarify examination, subsequently, patients underwent PET-CT that image with increased F-deoxyglucose (FDG) metabolism and lymph node metastasis considered. The inspection result showed FDG metabolism in multiple lymph nodes in the gastric antrum and the gastric antrum was increased, with increased FDG metaboism and etroperitoneal, ileocecal, ascending colon, and pelvic peritoneum and mesangial lymph gland metastasis were considered. The base on the current situation of the patient, conversion therapy is considered the greatest benefit to the patients(Figs. 1C, D, and E). After being carefully informed and with the patient’s content, we performed genetic testing of the pathological tissue removed from the patient. The results show the tumor microenvironment (TME) of the patient was microsatellite stability, PD-L1 CPS = 2, and HER-2 (3+) (Fig. 2). Thus, immunotherapy combined with targeted was selected as the first-line therapy. In 2019, ESCO reported a clinical trial in showed that compare with the Capox regimen, SOX would more beneficial for Chinese patients^[11]. We treated the patients with sintilimab plus trastuzumab and SOX (sintilimab 20ml once on day 1, trastuzumab 480mg/m2 once on day 1, oxaliplatin 200 mg/m2 once on day 1, S-1 60 mg twice a day on days 1–14) was initiated on 16 September 2022 (Fig. 3). The patient was examined during therapy for routine blood, liver, and kidney function, as well as coagulation and serum tumor markers. During the three of cycles treatment, The liver and kidney function : ALT 101 U/L and AST 79 U/L. We delivered liver preservation therapy and, on 3 January 2023, retested liver function: ALT 45 U/L and AST 36 U/L. The effectiveness of immunotherapy combined with target treatment led us to decide to maintain the treatment regimen. Gastroscopy was repeated after the fourth cycle of combined treatment on 31 January 2023. And the imaging result showed that patky ulcers were seen in the gastric antrum with white moss attached(Fig. 4A). The pathological examination of the specimen proved to be chronic mucosal inflammation of the gastric antrum, associated with glandular hyperplasia. On 29 January 2023, the abdominal enhanced CT showed gastric antral occupancy, the scope is slightly reduced and the small abdominal lymph nodes are reduced compared with the front(Fig. 4B). After four cycles, CA199 from 369 ng/ml decreased to 25.24 ng/ml (Fig. 5). The efficacy evaluation showed a large partial response. The potential mechanism of complete remission was discussed through clinical, genomic, and immune characteristics.

At present, as the primary treatment modality, chemotherapy, targeted molecular therapy or immunotherapy play an important role in currently gastric therapy^[12]. Whether comprehensive treatment can provide longer survival times or more adverse effects still needs to be tested in more clinical trials. Based on the ToGA research result, trastuzumab was the first target medicinal for HER-2-positive patients^[6]. However, its efficacy is not obvious in patients with advanced GC in recent trails. ICIs include anti-PD-1, anti-PD-L1 and CTLA-4, which are increasingly administered to those late-stage malignant tumor patients who have failed multiple treatments, such as melanoma, non–small-cell lung cancer, and colorectal cancer ^[12–14], and have produced a higher antitumor response. In recent years, ICIs have emerged as promising therapeutic agents in GC. Sintilimab can bind to PD-1, block the interaction of PD-1 with its ligands, and help to recover the anti-tumor response of T cells. As one of the immune checkpoint membrane proteins, PD-1 is synthesized in the endoplasmic reticulum and then delivered to the cell membrane surface to play inhibitory roles. Structurally, PD-1 is a type I transmembrane protein that belongs to the CD28 immunoglobulin subfamily and is an important immunosuppressive protein. By 2020, Sintilimab has been approved by the National Medical Products Administration (NMPA) of China to treat r/r cHL. Sintilimab could effectively activate T cells, as evidenced by the enhanced interleukin-2 and IFN-secretion among T cells co-incubated with it^[15]. PD-1 is expressed on activated T cells but not expressed on resting T cells^[16]. In a human tumor xenograft mice model reconstituted with human immune cells or a PD-1 knock-in tumor mouse model. In 2021 ASCO China reported a II-stage clinal trial (NCT04065282)^[17], this phase 2 study aimed to evaluate Sintilimab plus CapeOx as a neoadjuvant regimen in patients with advanced respectable G/GEJ adenocarcinoma. In this study, pCR and major pathological responseS were achieved in 7 and 17 patients. Another II-stage trial (ChiCTR2000030414)^[10] was reported as the same as in China. To evaluate the efficacy and safety of the anti-PD-1 antibody Sintilimab plus XELOX regimen. Thirty patients were enrolled from March 2020 to July 2021. The pathology complete remission (PCR) rate was 33.3%. Similarly, the trial had four cycles of conversion therapy in the same patients we reported, and the guidelines do not specify the specific amount of chemotherapy. It is hoped that the report of this experiment can provide some reference for the most suitable cycle of the conversion therapy. In conclusion, we report a successful clinical case of chemotherapy combined with immunotherapy for advanced GC, this combination of regimens might provide a new option for patients with GC. In this case, after fours cycles of combined therapy, the patient’s CT scan revealed that the tumor at the perigastric lymph nodes had dwindled, which suggests that sintilimab and trastuzumab have synergistic effects in advanced and metast GC, and a significant decrease was also observed for CA199. The patient did not develop serious complications due to chemotherapy during the treatment period, which could indicate a good safety profile of sitilimab. Based on the ORIENT-16 study, NMPA approved the first-line treatment indication for advanced GC, opening a new chapter of immunotherapy for GC and bringing hope to more GC patients.

Combinations of PD-1 are specific immunotherapy with HER-2-positive outcomes for the patients with advanced GC. It provides a choice patients with MSS HER-2 (3+) CPS = 2 subtype gastric cancer. This case illustrates the clinical benefit of this regimen, which may become a first-line therapy option for HER-2-positive patients. However, the limitation of the case is that it is a single case report, so preliminary evidence on the efficacy and safety of this strategy need to be confirmed to support the development of more large randomized controlled trials. In addition, the present case report is the absence of staging laparoscopy to diagnose and confirm the situation of perigastric lymph node metastases. The patient are supposed to be followed up in the future to determine his disease-free survival and OS.

CR	complete response
CTLA-4	cytotoxicT lymphocyte antigen 4
FDG	F-deoxyglucose
GC	gastric cancer
G/GEJ	gastric/gastroesophageal junction
HER-2	human epidermal growth factor receptor-2
ICIs	immune checkpoint inhibitors
NMPA	National Medical Products Administration
MMS	microsatellite stability
ORR	objective response rate
OS	over survival
PCR	pathology complete remission
PD-1	programmed cell death protein-1
PET-CT	positron emission tomography-computed tomography
PFS	progression-free survival
r/r cHL	relapsed or refractory classical Hodgkin lymphom
TMB-H	high tumor mutation burden
TME	tumor microenvironment

Ethics approval and consent to participate

The informed consent to participate in this study was obtained from this patient.

Consent for publication

Informed consent was obtained from the patient to report the case.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

There is no fnancial support associated with this study.

Authors’ contributions

JX , KW, GZ treat the patient and discussed the treatment stratefies.YW, XL, ZL,WZ made the preoperative diagnoses and performed.CQ, YJ performed manuscript editing. All authors have read and approved the fnal manuscript.

Acknowledgements

We would like to thank Editage (www.editage.cn) for English language editing.

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No competing interests reported.

Complete Remission of a Patient With HER-2 amplification Gastric Cancer Treated With Sintilimab Combined With Trastuzumab

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Abstract

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Introduction

Case Report

Discussion

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