As reported in the Journal of Clinical Oncology, Philip et al found that the phase III AVENGER 500 study showed no overall survival benefit with devimistat plus modified fluorouracil, oxaliplatin, irinotecan, and leucovorin (mFFX) vs FFX in patients with metastatic pancreatic adenocarcinoma.
As described by the investigators, “Devimistat is a lipoate analog that selectively inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic cycle in malignant cells.”
Study Details
The open-label trial included 528 patients from six countries in North America, Europe, and Asia. They were randomly assigned between December 2018 and August 2020 to receive 2-week cycles of: devimistat at 500 mg/m2 on day 1 and day 3 followed by mFFX as oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil (FU) as a 400 mg/m2 bolus followed by a 42- to 48-hour infusion at 2,400 mg/m2 (n = 266); or FFX as oxaliplatin at 85 mg/m2, leucovorin at 400 mg/m2, irinotecan at 180 mg/m2, and FU as a 400 mg/m2 bolus followed by a 42- to 48-hour infusion at 2,400 mg/m2 (n = 262 ). The primary endpoint of the trial was overall survival.
KEY POINTS
- Devimistat plus mFFX did not improve overall or progression-free survival vs FFX.
- Median overall survival was 11.10 months vs 11.73 months.
Survival Outcomes
Median follow-up for overall survival was approximately 19 months in both groups. Median overall survival was 11.10 months (95% confidence interval [CI] = 10.22–12.94 months) in the devimistat plus mFFX group vs 11.73 months (95% CI = 10.12–13.24 months) in the FFX group (hazard ratio [HR] = 0.95, 95% CI = 0.77–1.18, P = .655).
Median progression-free survival was 7.82 months (95% CI = 6.97–10.91 months) in the devimistat plus mFFX group vs 7.98 months (95% CI = 7.23–11.14 months) in the FFX group (HR = 0.99, 95% CI = 0.76–1.29, P = .94). Objective responses were observed in 39.1% vs 34.4% of patients, respectively (odds ratio = 1.23, 95% CI = 0.86–1.75).
Adverse Events
Grade ≥ 3 adverse events occurred in 88.8% of patients in the devimistat plus mFFX group vs 80.9% of those in the FFX group; those with > 10% frequency in the devimistat plus mFFX group vs the FFX group were neutropenia (29.0% vs 34.5%), anemia (13.9% vs 13.6%), hypokalemia (13.1% vs 14.9%), thrombocytopenia (11.6% vs 13.6%), diarrhea (11.2% vs 19.6%), and fatigue (10.8% vs 11.5%). Serious adverse events occurred in 54.1% vs 56.6% of patients, with 13.9% of patients experiencing serious advents attributed to devimistat.
The investigators concluded, “Devimistat in combination with mFFX did not improve long- and short-term metastatic pancreatic adenocarcinoma patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.”
Philip A. Philip, MD, PhD, FRCP, of the Department of Oncology and Department of Pharmacology, Henry Ford Cancer Institute, Wayne State University School of Medicine, Detroit, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Cornerstone Pharmaceuticals. For full disclosures of the study authors, visit ascopubs.org.
