Combination treatment with anti-HER2 therapeutic antibody RC48, PD-1 inhibitor, radiotherapy, and granulocyte macrophage-colony stimulating factor (GM-CSF) in patient with metastatic gastric cancer: a case report

Abstract

HER2 overexpression/amplification is a prevalent driver in various types of cancer, including gastric cancer (GC). Limited options are available for patients with HER2-positive metastatic gastric cancer, particularly those who do not respond to the standard therapy of HER2 antibody trastuzumab combined with chemotherapy. Previous research suggests that combining a PD-1 inhibitor with radiotherapy and granulocyte macrophage-colony stimulating factor (PRaG regimen) may enhance the antitumor effects in patients with chemotherapy-resistant metastatic solid tumors. In this case study, we presented a potential treatment strategy of a patient having HER2-positive and PD-L1-negative gastric adenocarcinoma. The patient showed rapid tumor progression even after surgery and multiple trastuzumab plus chemotherapy treatments. To address this, we employed a novel anti-HER2 antibody called RC48 in combination with PRaG regimen therapy (PRaG3.0). The patient demonstrated a positive response after two treatment cycles and achieved a progression-free survival time of 6.5 months. This case highlights the potential of four-combination therapies for treating refractory, multiorgan, HER2-positive, PD-L1-negative metastatic gastric cancer. Additionally, varying radiation doses in targeting dual foci is critical to enhance tumor immunotherapy.

Keywords: GM-CSF; HER2-positive; PD-1 inhibitor; RC48; gastric cancer; stereotactic body radiotherapy.

Figure 1

(A) HER2 and H&E staining of the primary tumor. (B) PD-L1 immunohistochemistry of mediastinal lymph nodes. (C) Adenocarcinoma tumor cells in the effusion. Scale bars: 25 µm. H&E: hematoxylin and eosin. (D) The next-generation sequencing (NGS) analysis of tumor DNA from the enlarged lymph nodes showed negative expression of PD-L1, gene mutations of TP53, gene amplification of ERBB2 and MET.

Figure 2

(A) Timeline of the whole treatment process for the patient. The patient experienced PD with the new emergence of mass in the left lobe of the liver during postoperative adjuvant chemotherapy on 01 November 2021.Two treatment cycles after trastuzumab with docetaxel plus cisplatin, the CT scan revealed metastases in both lungs, liver, thoracic cavity, hilar liver, head of pancreas, retroperitoneum, and parietal aorta on 15 January 2022.The treatment regimen was changed to trastuzumab plus irinotecan, but due to the COVID-19 pandemic, no further treatment was administered after only one cycle. On 16 May 2022, Baseline CT scans showed significant enlargement of tumor lesions in both lungs, mediastinal lymph nodes, liver metastases lesions. After 2 cycles of PRaG3.0 therapy, the sum of diameters of the unirradiated target metastases decreased by 58% from baseline. The patient was assessed as PR on 23 June 2022.The patient continue receiving RC48 and camrelizumab as maintenance treatment, with each cycle lasting for 2 weeks. Until 3 December 2023, when the patient suffered PD again and opted for supportive care. PD, progressive disease; PR, partial response; PFS, progression-free survival. (B) The patient underwent the first cycle of RC48 treatment (120mg on day 1) in combination with SBRT (24 Gy in 3 fractions for lung metastasis and 15 Gy in 3 fractions for partial liver metastasis on days 2-4). Additionally, GM-CSF (300ug on days 4-8) and camrelizumab (200mg on day 6) were administered. This treatment course was repeated every 3 weeks. Two courses of four-combination therapy were administered in total, targeting different metastases with SBRT. Subsequently, the patient received twelve cycles of RC48 (120mg on day 1) in combination with camrelizumab (200mg on day 1) after completing the four-combination therapy.

Figure 3

CT scans were conducted before (2022-05-16), during (2022-22-02), and after (2122-12-03, 2021-05-12) the PRaG3.0 therapy. The baseline inspection was performed on 2022-05-16 (A–H): the red area indicates the first cycle of radiation, the yellow area represents the second cycle of radiation. The radiographic changes after two cycles of treatment were observed on 2022-06-23 (A–H): the blue area indicating tumor regression in the unirradiated area. During maintenance treatment. On 2022-11-02 (A–H): changes in the patient’s lesion were noted. On 2022-12-03 (A–H), the tumor lesion progressed and thoracic and abdominal effusion developed.

Figure 4

(A) Dynamics of cancer carcinoembryonic antigen (CEA) (ng/mL) levels during the entire disease course. (B) Management of irAE during the four-combination therapy. Representative images showing irAEs of (B) RCCEP, RCCEP, reactive cutaneous capillary endothelial proliferation.