Data from the phase 2 ASCEND trial, presented at the 2025 Gastrointestinal Cancers Symposium, revealed that adding certepetide to gemcitabine and nab-paclitaxel did not improve progression-free survival (PFS) in patients with untreated metastatic pancreatic ductal adenocarcinoma (PDAC). While the combination showed some signs of efficacy, the primary endpoint was not met.
The randomized, double-blind, multicenter ASCEND trial (NCT05042128) aimed to assess the impact of adding certepetide to the standard chemotherapy regimen of gemcitabine and nab-paclitaxel in patients with advanced PDAC. Certepetide, a novel cyclic peptide, is designed to enhance drug penetration into the tumor and stroma, potentially increasing antineoplastic activity.
Trial Details and Patient Population
Eligible patients had histologically confirmed advanced PDAC suitable for gemcitabine and nab-paclitaxel therapy, measurable disease per RECIST 1.1, and an ECOG performance status of 0 or 1. Participants were randomized 1:1 to receive either 3.2 mg/kg of certepetide (n = 65) or placebo (n = 30) on days 1, 8, and 15 of a 28-day cycle, in combination with 1,000 mg/m2 of intravenous gemcitabine and 125 mg/m2 of intravenous nab-paclitaxel.
The study involved a minimum 18-month follow-up period, during which data on PFS, objective tumor response rate (OTRR), overall survival (OS), safety, patient-reported outcomes (PROs), exploratory research biomarkers, and E-PRO feasibility were evaluated. Out of 198 patients screened, 66 were allocated to the certepetide arm and 29 to the placebo arm between May 2022 and December 2023. One patient from each arm did not receive the allocated intervention and were omitted from the full analysis set. The primary analysis was conducted with 70 total deaths.
Efficacy Outcomes
The 6-month PFS rate was 49.0% (95% CI, 36.4%-60.5%) in the certepetide arm versus 40.8% (95% CI, 22.6%-58.3%) in the control arm. The median PFS was 5.5 months in both arms (HR, 0.96; 95% CI, 0.60-1.53; log-rank P = .85). Median overall survival (OS) was 12.42 months in the certepetide arm compared to 9.72 months in the control arm (HR, 0.95; 95% CI, 0.56-1.60; log-rank P = .82). Objective tumor response rates (OTRRs) were 38.3% and 26.9% for the certepetide and control arms, respectively.
According to lead study author Andrew Dean, MBChB, MRCP (UK), FRACP, "The addition of certepetide is safe and despite showing no improvement in 6-month PFS, a possible signal of benefit in OS and ORR (including 4 complete responses) was observed, warranting further investigation. A further cohort (cohort B) of the ASCEND study evaluating the addition of a second dose of certepetide is ongoing."
Safety Profile
In terms of safety, grade 3/4 adverse effects (AEs) occurring in at least 10% of patients included decreased neutrophil count (certepetide: 18% vs control: 8%), anemia (14%; 4%), decreased platelet count (12%; 4%), and peripheral sensory neuropathy (9%; 4%). Other notable AEs were febrile neutropenia, lung infection, fatigue, sepsis, thromboembolic event, and increased alanine aminotransferase levels.
Baseline Characteristics
Baseline characteristics in the overall population (n = 95) indicated a mean age of 65 years (range, 37-86), with most patients being male (60%) and having an ECOG performance status of 1 (54%). The pancreatic tumor location was primarily in the head (44%), followed by the tail (31%) and body (19%). Adenocarcinoma was the most common histologic subtype (89%). Most patients had stage IV disease (96%). Common sites of metastatic disease included the liver (73%), pulmonary tract (28%), and peritoneum (21%).
Implications
While the ASCEND trial did not meet its primary endpoint of improving PFS with the addition of certepetide to gemcitabine and nab-paclitaxel, the observed trends in OS and ORR suggest potential benefits that warrant further investigation. The ongoing cohort B of the ASCEND study, evaluating a second dose of certepetide, may provide additional insights into the drug's efficacy in treating metastatic PDAC.
