Second-line HR070803 Plus 5-FU/Leucovorin Improves OS in Gemcitabine-Refractory Pancreatic Cancer

The liposome formulation of irinotecan, HR070803, in combination with 5-fluororacil (5-FU) and leucovorin provided a statistically significant overall survival (OS) benefit to patients with gemcitabine-refractory locally advanced or metastatic pancreatic cancer, according to data from the phase 3 HR-IRI-APC trial (NCT05074589) presented during the 2022 ESMO Congress.¹

At a median follow-up of 12.81 months, the median OS achieved with HR070803 plus 5-FU/leucovorin (n = 149) was 7.39 months (95% CI, 6.05-8.41) vs 4.99 months (95% CI, 4.27-6.01) with 5-FU/leucovorin alone (n = 149), translating to a 37% reduction in the risk of death in this patient population (HR, 0.63; 95% CI, 0.48-0.84; P = .0019).

Moreover, the median progression-free survival (PFS) in the investigative arm was 4.21 months (95% CI, 2.92-5.59) vs 1.48 months (95% CI, 1.41-1.58) in the control arm, translating to a 64% reduction in the risk of disease progression or death (HR, 0.36; 95% CI, 0.27-0.48; P < .0001).

“The observed antitumor activity is worth further investigation in more tumor types,” the study authors wrote in a presentation delivered at the meeting. “[The regimen was] more moderate in safety, with no new safety signals identified.”

Limited options are available for patients with locally advanced pancreatic cancer or metastatic disease that has progressed after gemcitabine-based treatment. HR070803 is hypothesized to allow for passive targeting, sustained-release, and irinotecan that is well protected.

The double-blind, multicenter trial enrolled patients with locally advanced or metastatic pancreatic cancer in whom frontline gemcitabine-based therapy has failed. To be eligible for enrollment, patients were required to be at least 18 years of age and to have an ECOG performance status of 0 or 1.

A total of 298 participants were randomly assigned 1:1 to HR070803 at 56.5 mg/m² plus 5-FU/leucovorin at 2000/200 mg/m² every 2 weeks or 5-FU/leucovorin alone. Stratification factors included serum albumin levels (<40 g/dL vs ≥40 g/dL), treatment history of fluorouracil (yes vs no), and treatment history of gemcitabine (monotherapy vs combination).

The primary end point of the trial was OS, and key secondary end points included PFS, objective response rate, time to treatment failure, reaction of CA19-9, and safety.

The data cutoff date for the OS analysis was November 18, 2021.

The median age of patients in the investigative arm was 60 years (range, 32-78) vs 59 years (range, 40-76) in the control arm. Most patients were male (64% vs 62%, respectively) and had an ECOG performance status of 1 (83% vs 83%). In the HR070803 arm, 40% of patients had their tumor located in the head and 60% had it in another place; in the placebo arm, these rates were 44% and 56%, respectively.

In the investigative arm, CA-199 levels were 40 u/mL or higher in 85% of patients and less than 40 u/mL in 15% of patients; in the control arm, these rates were 84% and 16%, respectively. Moreover, most patients in the HR070803 and placebo arms had metastatic lesions present in the liver (74% vs 67%, respectively).

In the HR070803 arm, 7% of patients received prior gemcitabine monotherapy, 93% had a gemcitabine-based combination, and 26% had a fluorouracil-based treatment; these rates were 7%, 93%, and 32%, respectively, in the placebo arm.

Safety was examined in 147 patients in the investigative arm and 149 patients in the control arm. Any-grade adverse effects (AEs) occurred in 99.3% of those who received HR070803 vs 97.3% of those who did not; these effects were grade 3 or higher in 53.1% and 46.3% of patients, respectively. Serious AEs were reported in 24.5% of those in the investigative arm and 17.5% of those in the control arm.

The most common grade 3 or higher treatment-emergent toxicities reported in the HR070803 and placebo arms, respectively, were nausea (1.4% vs 0%), vomiting (4.8% vs 2.0%), fatigue (4.1% vs 2.0%), diarrhea (4.1% vs 2.7%), anorexia (2.7% vs 1.3%), neutropenia (12.9% vs 0%), and elevated alanine aminotransferase (4.1% vs 2.0%).

In the investigative arm, 4.1% of patients experienced AEs that resulted in dose discontinuation and 21.1% experienced toxicities that required dose adjustments; these rates were 9.4% and 5.4%, respectively, in the control arm.

Reference

Wang L, Qin S, Zhou Y, et al. HR070803 plus 5-FU/LV versus placebo plus 5-FU/LV in second-line therapy for gemcitabine-refractory locally advanced or metastatic pancreatic cancer: a multicentered, randomized, double-blind, parallel-controlled phase III trial (HR-IRI-APC). Ann Oncol. 2022;33(suppl 7):S1426. doi:10.1016/j.annonc.2022.08.063