A recent study published in Nature highlights the potential of HR070803, a liposomal formulation of irinotecan hydrochloride, in combination with 5-fluorouracil (5-FU) and leucovorin, for the treatment of advanced pancreatic cancer. The study demonstrated a significant extension in overall survival (OS) among patients with unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) who had previously failed gemcitabine-based therapy.
The trial compared HR070803 plus 5-FU and leucovorin to placebo plus 5-FU and leucovorin in this patient population. Results indicated a 37% reduction in the risk of death in the HR070803 group, with a median OS extension of 2.4 months compared to the placebo group. The HR070803 arm also exhibited numerically superior progression-free survival (PFS), objective response rate (ORR), time to treatment failure (TTF), and CA19-9 response.
Efficacy and Safety Profile
The efficacy of HR070803 combined with 5-FU and leucovorin appears comparable to Onivyde (nanoliposomal irinotecan) combined with FU and folic acid, a standard of care in this patient population, despite a lower dose of liposomal irinotecan (56.5 mg/m2 vs. 70 mg/m2). The promising efficacy of HR070803 may be attributed to the long median drug exposure time (17.4 weeks) and the small liposome particle size (approximately 80–90 nm), potentially improving drug penetration to the target tumor lesion.
The adverse event (AE) profile of HR070803 plus 5-FU and leucovorin was manageable. Common AEs occurring more frequently (≥10%) in the HR070803 group compared to the placebo group included nausea, vomiting, diarrhea, decreased white blood cell count, decreased neutrophil count, loss of appetite, and fatigue. These AEs were consistent with those known for irinotecan, and no new toxicities were observed. The slow-release nature of HR070803 liposome maintains stable, lower blood concentrations of the active metabolite SN-38 and total irinotecan, resulting in relatively lower incidences of decreased neutrophil count and diarrhea compared to irinotecan hydrochloride.
Impact of UGT1A1 Polymorphism
UGT1A1 is a crucial enzyme in irinotecan metabolism, and gene mutations in the UGT1A1 gene can lead to an increased incidence of diarrhea and decreased neutrophil count caused by irinotecan. In this study, a limited number of patients with UGT1A1 mutations were included, and the polymorphism had a limited impact on neutropenia incidence.
Quality of Life Considerations
Despite the increased incidence of certain AEs associated with HR070803, there was no significant difference in quality of life between the HR070803 and placebo groups, suggesting that the AEs related to HR070803 combination therapy are acceptable and manageable.
Study Limitations
One limitation of this study is the small number of patients with UGT1A1 mutations, which did not allow for the exploration of the necessity of dose adjustment of irinotecan hydrochloride liposome in this population. Another limitation is the 5-FU dosing regimen, which may result in less potent outcomes when extrapolating the efficacy of this HR070803 combination therapy to a global population. The dose and schedule of 5-FU in both arms were chosen based on clinical practice in Chinese pancreatic cancer patients, who generally have poor tolerance, to improve patient tolerance while ensuring efficacy.
Clinical Implications
The study concludes that HR070803 plus 5-FU and leucovorin significantly extended OS and improved other efficacy endpoints in unresectable, locally advanced, or metastatic PDAC who have received gemcitabine-based therapy, compared to placebo plus 5-FU and leucovorin. The safety was acceptable and manageable, suggesting that this HR070803 combination therapy might represent a novel standard second-line treatment option for this patient population.
