KEY TAKEAWAYS
- The Avenger 500 trial was a phase 3 randomized, global trial conducted across 73 sites to investigate the efficacy and safety of CPI-613 in combination with mFFX.
- The trial evaluated OS in patients with mPC treated with CPI-613+mFFX vs FFX.
- The most common grade ≥ 3 treatment-emergent adverse events with ≥ 10% frequency in CPI-613 plus mFFX vs FFX arm were diarrhea (11.2% vs 19.6%), Hypokalemia (13.1% vs 14.9%), anemia (13.9% vs 13.6%), neutropenia (11.2% vs 14.0%), thrombocytopenia (11.6% vs 13.6%) and fatigue (10.8% vs 11.5%).
- Secondary endpoints of the trial included duration of response, pharmacokinetics, patient-reported outcomes, and safety.
The median overall survival (mOS) for patients with mPC treated with FFX is 11.1 months. The tricarboxylic cycle enzymes pyruvate dehydrogenase and -ketoglutarate dehydrogenase are preferentially inhibited within the mitochondria of cancer cells by CPI-613, a stable intermediate of a lipoate analog. CPI-613+mFFX showed encouraging signs of efficacy and safety in phase I research. The efficacy and safety of CPI-613 in combination with mFFX against standard dose FFX in treatment-naive patients with mPC were studied in a global, randomized phase 3 trial spanning 73 locations.
Treatment was given in cycles every two weeks when advancement or severe toxicity occurred. CPI-613 (at 500 mg/m2) was administered intravenously on days 1 and 3 to the experimental group. In the study’s experimental arm, patients received irinotecan at 65 mg/m2, oxaliplatin at 140 mg/m2, and 5-fluorouracil at 2,400 mg/2. The primary outcome measure was overall survival. Progression-free survival (PFS), overall response rate(ORR), duration of response, pharmacokinetics, patient-reported outcomes, and safety were secondary objectives.
This led to the randomization of 528 patients (266 in the test and 262 in the control arm). There were 362 deaths; the median overall survival (mOS) for those who received CPI-613+mFFX was 11.1 months, while it was 11.7 months for those who received FFX [hazard ratio (HR), 0.95; 95% CI, 0.77 to 1.18; P = 0.655]; the median progression-free survival (mPFS) was 7.8 months, while it was 8.0 months for those who received FFX [HR, 0.99; 95% CI, 0.
Grade ≥ 3 treatment-emergent adverse events with ≥ 10% frequency in CPI-613 plus mFFX vs FFX arm were diarrhea (11.2% vs 19.6%), hypokalemia (13.1% vs 14.9%), anemia (13.9% vs 13.6%), neutropenia (11.2% vs 14.0%), thrombocytopenia (11.6% vs 13.6%) and fatigue (10.8% vs 11.5%). The results showed no statistically significant ORR, PFS, or OS improvements when CPI-613 was added to mFFX. The mFFX in the study’s control group—which received the lowest doses of FFX in prospective trials—had no adverse effect on patients’ progression-free survival or overall survival.
Source:https://meetings.asco.org/abstracts-presentations/209341
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03504423
Philip Agop Philip, Nathan Bahary, Amit Mahipal, Anup Kasi, Caio Max Sao Pedro Rocha Lima, Angela Tatiana Alistar, Paul Eliezer Oberstein, Talia Golan, Vaibhav Sahai, Jean Philippe Metges, Jill Lacy, Christos Fountzilas, Charles D. Lopez, Michel Ducreux, Pascal Hammel, Mohamed E. Salem, David Lawrence Bajor, Al Bowen Benson, Marc E. Buyse, Eric Van Cutsem/Phase 3, multicenter, randomized study of CPI-613 with modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) as first-line therapy for patients with metastatic adenocarcinoma of the pancreas (AVENGER500)/J Clin Oncol 40, 2022 (suppl 16; abstr 4023)
DOI10.1200/JCO.2022.40.16_suppl.4023
