Camrelizumab successfully treated a patient with hepato-pulmonary metastasis of gastric cancer: a case report and literature review

Abstract

The application of camrelizumab in gastrointestinal tumors is in ongoing clinical trials and has shown good outcomes, which provides a new idea for the diagnosis, treatment and research of gastric cancer. A 70-year-old male patient with advanced gastric cancer developed liver and lung metastasis one year after laparoscopic-assisted radical total gastrectomy, despite postoperative trastuzumab and conventional chemotherapy. To treat this metastatic tumor, camrelizumab was started on August 8, 2019. On November 11, 2020, a CT review showed significantly reduced multiple liver metastases as well as nodules in the left upper lung. At the same time, patients had achieved free progression survival of 16 months and overall survival of more than 31 months. This case report provides a new and strong evidence for the treatment of hepato-pulmonary metastasis with camrelizumab in gastric cancer.

Background

Gastric cancer (GC) is a common clinical malignant tumor characterized by high morbidity and mortality [1]. GC in the advanced stage or accompanied by distant metastasis has a poor prognosis, short survival time and short clinical treatment effect [2, 3]. In recent years, tumor immunotherapy such as tumor vaccine therapy, T-cell immunotherapy and immune checkpoint blocking therapy has got significant attention for treating a variety of tumors.

Immune checkpoints mainly include cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1). The primary ligand of PD-1 is currently considered to be PD-L1. At present, the immunotherapy for GC is still in continuous exploration, and the treatment for advanced GC mainly includes PD-1 and PD-L1 pathway inhibitors. The former treatment methods were included Nivolumab, Pembrolizumab and Camrelizumab. Nivolumab was approved by the US Food and Drug Administration (FDA) for third-line treatment in patients with PD-L1 positive cancer [4]. Camrelizumab recently received conditional approval in China for the treatment of GC [5].

In recent years, the targeted immunotherapy of PD-1/PD-L1 has been partially applied to malignant melanoma, non-small cell lung cancer, ovarian cancer, etc. The application of PD-1 in gastrointestinal tumors is undergoing clinical trials. It has shown significant effects, which provides a new idea for diagnosing, treating, and researching gastric cancer. Here we report a case of a patient with liver metastasis from gastric cancer combinedly treated with a PD-1 inhibitor (camrelizumab).

Case Presentation

The patient gave written informed consent for his case publication in line with the Commitee on Publication Ethics (COPE) best practice guidelines. A 70-year-old male with advanced gastric cancer has received laparoscopic assisted radical total gastrectomy in our hospital on April 3, 2018. Postoperative pathology showed intestinal-type adenocarcinoma with low differentiation. The tumor's size was 5cm×5cm×0.8cm, and the whole layer was infiltrated with visible vascular cancer plug, nerve invasion (Figure 1A) and lymph node metastasis (2/12). The immunohistochemical result of the tumor sample obtained from the excised gastric tumor was showed HER-2 positive (3+), and the TNM type was pT₂N₂M₁ (Figure 1B). As a routine treatment, after excluding contraindications, six cycles of regular chemotherapy and trastuzumab (HER-2 inhibitor) were started on May 3, 2018, which ended on October 2, 2018. The patients well tolerated the therapy during this period.

On June 29, 2019, CT review indicated liver metastasis and nodules in the left lung (Figures 2A and 2B). Biopsy of that nodules were performed for immunohistochemical examination (Figure 1C and 1D), and hepato-pulmonary metastasis of gastric cancer was evaluated. To overcome this problem, we initially assumed that HER-2 inhibitor might work because it was overexpressed in excised gastric tumor. In addition, an immunotherapeutic agent, PD-1 inhibitor was considered for its ongoing success report against gastric cancer treatment. To apply those inhibitors combinedly, we first took the consent of patient and his family members. Then, the regimen of camrelizumab (PD-1 inhibitor) + trastuzumab (HER-2 inhibitor) was started on August 8, 2019. Camrelizumab 200mg/ once, 21 days per cycle (last treatment on August 24, 2020) and trastuzumab 200mg/ time, 21 days per cycle were applied. In addition, after two combined medication cycles, the patient developed a common immune adverse reaction (rash), which was improved after symptomatic treatment and tolerated by the patient. We assumed that this might be because of using PD-1 inhibitor camrelizumab, which usually showed this side effect [6].

The CT review showed significantly reduced multiple liver metastases and reduced nodules in the left upper lung (Figure 2C and 2D). Patient was well tolerated and had a good quality of life during treatment. As of November 11, 2020, the patient's liver and lung metastases were further reduced ((Figure 2E and 2F), and had progression-free survival of 16 months and overall survival of more than 31 months.

Discussion

Camrelizumab is a selective, humanized, high affinity IgG4 monoclonal antibody [12]. The drug can bind with PD-1 on the surface of CD4⁺ and CD8⁺T cells, B lymphocytes, Natural killer cells and dendritic cells [13] to block their interaction among themselves. It also inhibits the interaction between PD-L1 and PD-L2 on various immune cell surfaces, including malignant tumor cells, tumor-infiltrating dendritic cells, tumor-infiltrating lymphocytes, and antigen-presenting cells [14]. Therefore, this might be the relevant reason why camrelizumab achieved a good therapeutic effect in this elderly patient with hepato-pulmonary metastasis of gastric cancer.

Wang K, et al reported an overall survival of 14 months in a 53-year-old patient with liver metastasis from gastric cancer treated with camrelizumab [7]. Lin J, et al reported a 65-year-old patient with gastric cancer who had an overall survival of 26 months after camrelizumab treatment and developed Hypothyroidism complications [8]. Wang D, et al reported a 32-year-old young patient with gastric cancer who developed Mimicking Behcet's disease after using carrelizumab [9]. Up to now, there has been no reported case of simultaneous liver and lung metastasis of gastric cancer with camrelizumab in the case reports of gastric cancer. Moreover, the patient we reported was the oldest with a longer overall survival, and the complication was only rash, as shown in Table 1.

A Phase 2 clinical trial involved 10 patients with gastric cancer metastasis, including only liver, bone, peritoneum and lymph node metastasis. Moreover, reactive dermal capillary endothelial hyperplasia, fatigue, hypothyroidism, hyperthyroidism, and rash complications were also reported [10]. According to the existing clinical trial results of carrelizumab in gastric cancer, there is no successful case of camrelizumab in the treatment of gastric cancer with hepato-pulmonary metastasis.

From the IHC assay of excised gastric tumor biopsy, we found that HER-2 expression was significantly higher compared to adjacent cells. In this perspective, we have chosen HER-2 inhibitor for the treatment of this patient, but it didn't work well. On the other hand, at present, conventional surgery and chemoradiotherapy are not effective in treating advanced GC. In recent years, immunotherapy has shown promising prospects in the treatment of advanced GC. The objective response rate (ORR) of patients with advanced GC treated with Pembrolizumab was 11.6%, and the median duration of response (DOR) was 8.4 months and the ORR and DCR of Toripalimab were 20% and 60%, respectively [15]. The PD-1 inhibitor Camrelizumab showed sound anti-tumor effects in patients with advanced or metastatic GC.[16] So, we have chosen camrelizumab as a combination therapy with trastuzumab, based on previous studies and intending to help promote patient survival. Although pneumonia, diarrhea, hepatitis problems, etc., have been reported as adverse effects of the camrelizumab, we have only seen rash in this combination treatment which was easily managed . The follow-up CT scanning report provided evidence that this combination treatment significantly reduced the tumor size and metastasis in both lung and liver organs. When the combination of traditional chemotherapy and HER-2 inhibitor failed, we reported that PD-1 inhibitor as an effective treatment method against gastric cancer metastasis with the minimal adverse reaction which requires preclinical studies to compare the effectiveness of both drugs alone or combined to treat cancer metastasis. Of course, there are still many challenges in the application of camrelizumab in gastric cancer. Camrelizumab has shown good efficacy and safety in gastric cancer, and a series of 28 phase Ⅰ, Ⅱ and Ⅲ clinical trials are being carried out, Table 2.

In our study, the hepato-pulmonary's distant metastasis occurred one year after the surgery in an elderly patient with gastric cancer. With the patient and his family's consent, the patient's distant hepatic and pulmonary metastasis was significantly reduced after the treatment of camrelizumab. This treatment regimen achieved outstanding efficacy in this patient, whose free progression survival was 16 months and overall survival was over 31 months. This case report provides new and strong evidence for the use of camrelizumab in  patients with hepato-pulmonary metastasis of gastric cancer.

Declarations

Conflicts of interest The author declares that they have no competing of interest.

Ethical approval This case report was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2020-KY-386).

Consent for publication The authors have obtained consent to publish from the participants to report individual patient data. 

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Tables

Table 1 Clinical report of camrelizumab in gastric cancer

Abbreviations: No., number; FPS, free progression survival; OS, overall survival.

Table 2 Camrelizumab ongoing clinical trials as of January 15, 2022

Note: This form is from ClinicalTrials.gov (https://www.clinicaltrials.gov/).