ABSTRACT
Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide. Under the standard of care, patients with advanced GC (AGC) have a median survival time of approximately 12–15 months. With the emergence of immunotherapy as a key therapeutic strategy in medical oncology, relevant changes are expected in the systemic treatment of GC. In the phase III ATTRACTION-2 trial, nivolumab, a monoclonal anti-programmed cell death 1 (PD-1) antibody, as a third- or later-line treatment improved overall survival (OS) compared with placebo in patients with AGC. Furthermore, nivolumab in combination with 5-fluorouracil and platinum as a first-line treatment improved OS in patients with human epidermal growth factor receptor-2 (HER2)-negative AGC in the global phase III CheckMate-649 study. Another anti-PD-1 antibody, pembrolizumab, in combination with trastuzumab and cytotoxic chemotherapy as a first-line treatment, significantly improved the overall response rate in patients with HER2-positive AGC. Therefore, immune checkpoint inhibitors (ICIs) are essential components of the current treatment of GC. Subsequent treatments after ICI combination therapy, such as ICI rechallenge or combination therapy with agents having other modes of action, are being actively investigated to date. On the basis of the success of immunotherapy in the treatment of AGC, various clinical trials are underway to apply this therapeutic strategy in the perioperative and postoperative settings for patients with early GC. This review describes recent progress in immunotherapy and potential immunotherapy biomarkers for GC.
ABSTRACT
Purpose@#Up to 20% of patients with biliary tract cancer (BTC) have alterations in DNA damage response (DDR) genes, including homologous recombination (HR) genes. Therefore, the DDR pathway could be a promising target for new drug development in BTC. We aim to investigate the anti-tumor effects using poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors in BTC. @*Materials and Methods@#We used 10 BTC cell lines to evaluate an anti-tumor effect of olaparib (a PARP inhibitor) and AZD1775 (a WEE1 inhibitor) in in vitro. Additionally, we established SNU869 xenograft model for in vivo experiments. @*Results@#In this study, we observed a modest anti-proliferative effect of olaparib. DNA double-strand break (DSB) and apoptosis were increased by olaparib in BTC cells. However, olaparib-induced DNA DSB was repaired through the HR pathway, and G2 arrest was induced to secure the time for repair. As AZD1775 typically regulates the G2/M checkpoint, we combined olaparib with AZD1775 to abrogate G2 arrest. We observed that AZD1775 downregulated p-CDK1, a G2/M cell cycle checkpoint protein, and induced early mitotic entry. AZD1775 also decreased CtIP and RAD51 expression and disrupted HR repair. In xenograft model, olaparib plus AZD1775 treatment reduced tumor growth more potently than did monotherapy with either drug. @*Conclusion@#This is the first study to suggest that olaparib combined with AZD1775 can induce synergistic anti-tumor effects against BTC. Combination therapy that blocks dual PARP and WEE1 has the potential to be further clinically developed for BTC patients.
ABSTRACT
Purpose@#Hypoxia is widely known as one of the mechanisms of chemoresistance and as an environmental condition which triggers invasion and metastasis of cancer. Evofosfamide is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard conjugated with 2-nitroimidazole. Biliary tract cancer (BTC) is known to contain large hypoxic area. This study evaluated the efficacy and safety of evofosfamide as a second-line treatment of advanced BTC. @*Materials and Methods@#Patients received evofosfamide at a dose of 340 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Primary end-point was progression-free survival (PFS) rate at 4-months (4m-PFSR). Secondary end-points included overall survival (OS), PFS, disease control rate (DCR), metabolic response by 18F-fluorodeoxyglucose positron emission tomography (PET), hypoxic parameters evaluated by 18F-fluoromisonidazole (FMISO) PET and toxicity. @*Results@#Twenty patients were treated with evofosfamide, with 16 response-evaluable patients. There was no objective response; stable disease was observed in nine patients, with a DCR of 56.25%. 4m-PFSR was 40.6%. Median PFS was 3.60 months (95% confidence interval [CI], 1.68 to 5.52). Median OS was 6.37 months (95% CI, 3.94 to 8.79). Reduction of tumor metabolic activity was observed in eight of 15 patients (53.3%). High baseline hypoxic parameters were associated with poor PFS. Change of hypoxic parameters between pretreatment and post-treatment reflected hypoxic-activated drug response. There was no treatment-related death. @*Conclusion@#Evofosfamide as second-line treatment of advanced BTC showed acceptable safety and comparable efficacy to other agents. Changes in volumetric parameters measured with FMISO PET, showing the degree of tumor hypoxia, reflected the response to evofosfamide based on the mode of action.
ABSTRACT
Purpose@#Hypoxia is widely known as one of the mechanisms of chemoresistance and as an environmental condition which triggers invasion and metastasis of cancer. Evofosfamide is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard conjugated with 2-nitroimidazole. Biliary tract cancer (BTC) is known to contain large hypoxic area. This study evaluated the efficacy and safety of evofosfamide as a second-line treatment of advanced BTC. @*Materials and Methods@#Patients received evofosfamide at a dose of 340 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Primary end-point was progression-free survival (PFS) rate at 4-months (4m-PFSR). Secondary end-points included overall survival (OS), PFS, disease control rate (DCR), metabolic response by 18F-fluorodeoxyglucose positron emission tomography (PET), hypoxic parameters evaluated by 18F-fluoromisonidazole (FMISO) PET and toxicity. @*Results@#Twenty patients were treated with evofosfamide, with 16 response-evaluable patients. There was no objective response; stable disease was observed in nine patients, with a DCR of 56.25%. 4m-PFSR was 40.6%. Median PFS was 3.60 months (95% confidence interval [CI], 1.68 to 5.52). Median OS was 6.37 months (95% CI, 3.94 to 8.79). Reduction of tumor metabolic activity was observed in eight of 15 patients (53.3%). High baseline hypoxic parameters were associated with poor PFS. Change of hypoxic parameters between pretreatment and post-treatment reflected hypoxic-activated drug response. There was no treatment-related death. @*Conclusion@#Evofosfamide as second-line treatment of advanced BTC showed acceptable safety and comparable efficacy to other agents. Changes in volumetric parameters measured with FMISO PET, showing the degree of tumor hypoxia, reflected the response to evofosfamide based on the mode of action.