case_images: PMC10867122_01
case_images: (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 microm. 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.
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case_images: II subtotal gastrectomy at this hospital, and the subsequent pathological examination confirmed an ulcerative type of poorly differentiated gastric adenocarcinoma. Immunohistochemical analysis showed the following parameters: HER2:3+ and mismatch repair proficiency (pMMR) phenotype(MLH1/MSH2/MSH6/PMS2) ( Figure 1A ). Figures 1B-D ). Finally, the patient was diagnosed with cTxN3M1 stage IV GC with an Eastern Cooperative Oncology Group (ECOG) performance status of 2. This treatment was combined with SBRT (24 Gy in 3 fractions) for the lesion in the inferior lobe of the left lung and (15 Gy in 3 fractions) for the partial left liver metastasis on days 2-4( Supplementary Figures 1A, B ). To investigate further, an ultrasound puncture of the hydroperitonium was performed, which revealed the presence of adenocarcinoma tumor cells in the effusion ( Figure 1C ).
case_images: (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.
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case_images: A summary of the patient's treatment history is presented in  Figure 2A . Additionally, the patient received GM-CSF (300ug on days 4-8) and camrelizumab (200mg on day 6) based on family will, HER-2 and ECOG PS 2 score ( Figure 2B ).
case_images: 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.
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case_images: This was assessed as progressive disease (PD) and suggested that the tumor had high malignant behavior and was insensitive to trastuzumab chemotherapy agents ( Figure 3  2022-05-16A-H,  Figure 4A ). The patient was again assessed as PR ( Figure 3  2022-06-23A-H).
case_images: (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.
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case_images: This was assessed as progressive disease (PD) and suggested that the tumor had high malignant behavior and was insensitive to trastuzumab chemotherapy agents ( Figure 3  2022-05-16A-H,  Figure 4A ). CT scans showed a 36% reduction in target lesions and the patient was assessed as partial remission (PR), with CEA levels decreasing to 1780 ng/mL ( Figure 4A ). However, the patient experienced grade 1 reactive cutaneous capillary endothelial proliferation (RCCEP), a novel immune-related adverse event (irAE) observed in the majority of patients treated with camrelizumab ( Figure 4B ).