PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma: A case report

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with limited effective treatment especially after first-line chemotherapy. The human epidermal growth factor receptor 2 (HER-2) immunohistochemistry (IHC) positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.

Case summary: We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn't have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment. A novel combination therapy PRaG 3.0 of RC48 (HER2-antibody-drug conjugate), radiotherapy, PD-1 inhibitor, granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month. She had not developed any grade 2 or above treatment-related adverse events at any point. Percentage of peripheral CD8⁺Temra and CD4⁺Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.

Conclusion: PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Keywords: Case report; Human epidermal growth factor receptor 2; Novel combination therapy; PRaG 3.0 therapy; Pancreatic ductal adenocarcinoma.

Figure 1

Treatment schedule of the PRaG3.0 therapy and treatment efficacy evaluation of the patient. A: Hematoxylin and eosin staining and immunohistochemistry assay for CK19, human epidermal growth factor receptor 2 (HER-2), Hepar1, MLH1, MSH2, MSH6 and PMS2 of liver lesions. CK19 was expressed in tumor cells but Hepar1 was not expressed. HER-2 was weakly expressed in tumor cell membranes. MLH1, MSH2, MSH6 and PMS2 were expressed in tumors indicating mismatch repair proficient; B: Treatment schedule of the PRaG3.0 therapy. The patient received two activation cycle and six maintenance cycle. The time of positron emission tomography-computed tomography (PET-CT) was also indicated; C: Serum carbohydrate antigen 19-9 (Ca 19-9), Ca 50 and Ca 242 levels of the patient during the treatment; D: Peripheral cytokines [interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17A, tumor necrosis factor and interferon-γ] levels changes of the patient during the treatment. E: The PET-CT evaluation of the patient at baseline and after cycle 2, 4, 7 and 8. ADC: Antibody-drug conjugate; Ca: Carbohydrate antigen; GM-CSF: Granulocyte-macrophage colony-stimulating factor; HE: Hematoxylin and eosin; HER-2: Human epidermal growth factor receptor 2; IFN: Interferon; IL: Interleukin; SBRT: Stereotactic body radiotherapy; TNF: Tumor necrosis factor.

Figure 2

The percentage and absolute numbers of lymphocyte subsets at baseline and after each cycle. A: The percentage of peripheral lymphocytes, including CD4⁺Temra, CD8⁺Temra, activated CD4⁺Temra, activated CD8⁺Temra, activated CD4⁺Tem, activated CD8⁺Tem and Tregs at baseline and after each cycle; B and C: Absolute numbers of peripheral lymphocytes subsets at baseline and after each cycle.