Programmed cell death receptor 1 inhibitor Pembrolizumab in the treatment of advanced gastric cancer

Abstract

This editorial discusses Christodoulidis et al's article, which appeared in the most recent edition. The clinical trials have demonstrated the programmed cell death receptor 1 (PD-1) inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer (AGC). Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.

Key Words: Programmed cell death receptor 1 inhibitor; Pembrolizumab; Advanced gastric cancer; Chemotherapy; Trastuzumab

Core Tip: In the past decade, programmed cell death receptor 1 (PD-1) inhibitors have shown significant anti-tumor effects and good safety in the treatment of various malignant tumors such as melanoma and non-small cell lung cancer. Multiple studies on advanced gastric cancer have shown that the combination therapy of PD-1 inhibitors can improve the efficacy. Pembrolizumab combined with chemotherapy or human epidermal growth factor receptor 2 targeting therapy have showed improved prognosis. In the future, it is important to explore the reasonable treatment sequence and dosage, to maximize the efficacy of combination therapy.

INTRODUCTION

Gastric cancer (GC) is among the most common tumor and the leading causes of cancer-related death[1]. With the recent improvement of diagnosis and treatment, the comprehensive therapy of gastric malignant tumors has achieved certain results[2]. For advanced GC (AGC), platinum-based and fluorouracil-based chemotherapy as well as surgical radical resection have been in clinical practice[3]. In recent years, more and more targeted drugs, such as trastuzumab or ramucirumab, are used alone or in combination with chemotherapy for the treatment of postoperative AGC[4]. Based on the low 5-year survival rate, more effective targeting therapy for AGC is worth exploring.

With the development of research on immune checkpoint inhibitors (ICIs), including programmed cell death receptor 1 (PD-1) inhibitors, programmed cell death ligand 1 (PD-L1) inhibitors and cytotoxic T lymphocyte associated antigen 4 (CTLA-4), the treatment of most solid tumors has undergone tremendous changes[5]. ICIs mainly activate the anti-tumor immune response of effector T cells by blocking the PD-1/PD-L1 or CTLA-4 pathway. PD-1 inhibitors, including pembrolizumab, nivolumab, sintilimab, etc., have shown good efficacy in a variety of solid tumors, including malignant melanoma, non-small cell carcinoma, renal cancer, bladder cancer, etc.[6]. Studies have exhibited therapeutic effect of PD-1 inhibitors in the treatment of AGC after surgery[7].

APPLICATION OF PD-1 INHIBITOR PEMBROLIZUMAB IN AGC

A multicenter clinical trial evaluated the anti-tumor activity, safety and tolerability of pembrolizumab in patients with AGC[8]. The results showed that the median survival of patients treated with pembrolizumab was significantly longer than that of single agent chemotherapy, and pembrolizumab had good anti-tumor activity, and the toxicity level was controllable. The keynote-062 trial studied the efficacy of PD-1 inhibitors in the first-line treatment of GC[9]. The results showed that the overall survival (OS) of GC patients with a combined positive score (CPS) ≥ 1 treated with pembrolizumab monotherapy was higher than that of chemotherapy. For patients with CPS ≥ 10, the OS of the monotherapy group was significantly longer than that of the chemotherapy group. The KEYNOTE-062 trial directly compared pembrolizumab monotherapy with chemotherapy [capecitabine or 5-fluorouracil (5-FU)] in patients with AGC, with OS as the primary endpoint. In the intent-to-treat population, the OS benefit of pembrolizumab was not statistically significant when compared to chemotherapy.

PEMBROLIZUMAB COMBINED WITH CHEMOTHERAPY

Traditional chemotherapy drugs not only enhance the antigenicity of tumor cells, but also increase their sensitivity to immune effector cells[10]. PD-1 inhibitors combined with chemotherapy can enhance sensitivity to chemotherapy and further eliminate tumor cells that develop resistance to chemotherapy by enhancing anti-tumor immune responses[11]. Therefore, the combination of PD-1 inhibitors and chemotherapy drugs for AGC treatment may bring greater clinical benefits. The KEYNOTE-059 trial included 25 AGC patients who received Pembrolizumab + cisplatin + 5-FU regimen, showing an objective response rate (ORR) of 60.0% and a progression free survival of 6.6 months[12].

PEMBROLIZUMAB COMBINED WITH HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 TARGETING THERAPY

Human epidermal growth factor receptor 2 (HER-2) can regulate cell proliferation, differentiation, and apoptosis. HER-2 is significantly expressed in tumor cells, and its expression is related to tumor size, invasiveness, and metastasis, directly affecting the survival rate of AGC patients[13]. At present, the standard first-line treatment for HER-2 positive AGC or recurrent GC is to add Trastuzumab to chemotherapy[14]. The anti-HER-2 antibody Trastuzumab produces anti-tumor immune effects through antibody dependent cell killing and phagocytosis. The KEYNOTE-811 trial showed that the combination of Pembrolizumab and Trastuzumab increased the ORR by 22.7% (77.4% vs 51.9%) compared to the chemotherapy group, and the complete remission rate was 11.3%, which was higher than the chemotherapy group's 3.1%[15].

PEMBROLIZUMAB IN NEOADJUVANT THERAPY

Neoadjuvant treatment, which aims to shrink tumors before surgery, has shown promise in various cancer types. In GC, neoadjuvant approaches are becoming more integral to treatment regimens, as they may improve survival rates and reduce the risk of recurrence. PD-1 inhibitors have the potential to enhance the efficacy of chemotherapy and radiation when used in the neoadjuvant setting by increasing the tumor's sensitivity to these treatments, possibly through the activation of immune-mediated tumor cell killing. Pembrolizumab would offer a new perspective of how immunotherapy can be leveraged not only as an adjuvant therapy post-surgery but also as a pre-surgical approach to reduce tumor size and possibly lead to better surgical outcomes.

TOXIC EFFECTS OF PD-1 INHIBITORS

Due to the imbalance of the immune system in the body, the toxic adverse reactions of PD-1 inhibitors occur, mainly including immune related endocrine diseases, fever, bone marrow suppression, reactive capillary hyperplasia, etc.[16]. Severe cases can involve all tissues and organs in the body, and can often recover on their own. The overall incidence is significantly lower than traditional chemotherapy, and the safety is controllable[17]. The common adverse reactions of Pembrolizumab mainly involve the endocrine system, such as hyperthyroidism and hypothyroidism, thyroiditis, pituitary inflammation, adrenal insufficiency, etc.[18]. In addition to symptomatic treatment, corticosteroids can also be given. Other immune related adverse reactions, including elevated liver enzymes, dermatitis, hepatitis, colitis, pneumonia, and pancreatitis, can be controlled by administering corticosteroids.

CLINICAL IMPLICATIONS

In the past decade, PD-1 inhibitors have shown significant anti-tumor effects and good safety in the treatment of various malignant tumors such as melanoma and non-small cell lung cancer. Multiple studies on AGC have shown that the combination therapy of PD-1 inhibitors can improve the efficacy of AGC. In future research, it is necessary to deeply understand the underlying mechanism of PD-1 inhibitors mediated immunotherapy combined with other methods to treat AGC. In order to achieve the best plan, it is important to explore the reasonable treatment sequence and dosage of combination therapy through clinical trials, so as to maximize the efficacy of synergistic therapy. In addition, it is needed to develop more novel and accurate biomarkers for predicting the efficacy of combination therapy, screen the applicable population for combination therapy, and develop individualized precision treatment plans for different AGC patients[19].

CONCLUSION

Multiple clinical trials have demonstrated that the combination therapy of PD-1 inhibitor represented by Pembrolizumab can improve the efficacy of AGC. Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting HER-2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. In future clinical trials, it is important to explore the reasonable treatment sequence and dosage of combination therapy, so as to maximize the efficacy of synergistic therapy.