In a European phase Ib/II study (OPTIMIZE-1) reported in The Lancet Oncology, Jean-Luc Van Laethem, MD, and colleagues found that the combination of the CD40 agonist antibody mitazalimab with mFOLFIRINOX (modified fluorouracil, leucovorin, oxaliplatin, and irinotecan) showed activity in previously untreated patients with metastatic pancreatic ductal adenocarcinoma.
As stated by the investigators, “CD40 is a co-stimulatory receptor expressed on the surface of B cells, monocytes, macrophages, and dendritic cells. CD40 agonist–mediated stimulation redirects tumor-infiltrating macrophages from M2 to M1 phenotype, promotes fibrotic stromal degradation, and enhances tumor sensitivity to chemotherapy.”
Jean-Luc Van Laethem, MD
Study Details
In the trial, 70 patients from 14 sites in Belgium, France, and Spain enrolled between September 2021 and March 2023 received mitazalimab at 450 μg/kg (n = 5) or 900 μg/kg (n = 65) combined with mFOLFIRINOX (oxaliplatin at 85 mg/m2, leucovorin at 400 mg/m2, irinotecan at 150 mg/m2, and fluorouracil at 2,400 mg/m2). In the first 21-day cycle, mitazalimab was administered on days 1 and 10 and mFOLFIRINOX was given on day 8; in subsequent 14-day cycles, mitazalimab was administered 2 days after mFOLFIRINOX.
The phase II primary endpoint of the study was objective response rate, with the endpoint being met if the response rate was ≥ 30%.
Key Findings
No dose-limiting toxicities were observed with mitazalimab dosed at 450 μg/kg; one dose-limiting toxicity was observed when it was given at 900 μg/kg. The recommended phase II dose was established as 900 μg/kg.
Median follow-up was 12.7 months (95% confidence interval [CI] = 11.1–15.7 months).
Among 57 evaluable patients who received the 900 μg/kg dose in phase II of the trial, objective response was observed in 23 (40%, one-sided 90% CI = ≥ 32%), with complete response in 1 patient. Stable disease was observed in an additional 22 patients (39%), yielding a disease control rate of 79%. Median response duration was 12.5 months (95% CI = 7.5 months to not evaluable). Among the 57 evaluable patients, 29 (51%) remained on study and 18 (32%) remained on treatment at data cutoff in November 2023.
Median progression-free survival was 7.7 months (95% CI = 5.8–11.3 months), with rates at 6 and 12 months of 62% and 34%, respectively. Median overall survival was 14.3 months (95% CI = 10.0–21.6 months), with rates at 6 and 12 months of 90% and 59%, respectively.
Among all 70 patients who received study treatment, the most common grade ≥ 3 adverse events were neutropenia (26%), hypokalemia (16%), anemia (11%), and thrombocytopenia (11%). Serious adverse events occurred in 41% of patients, most commonly vomiting (7%) and decreased appetite (6%). No treatment-related deaths were reported.
The investigators concluded, “Mitazalimab with mFOLFIRINOX demonstrated manageable safety and encouraging activity, warranting continued development in a phase III, randomized, controlled trial. The results from OPTIMIZE-1 pave the way for further exploration and confirmation of a novel immunotherapy treatment regimen for metastatic pancreatic ductal adenocarcinoma, which is a complex and aggressive cancer with very low survival rates and restricted treatment options.”
Dr. Van Laethem, of Hôpital Universitaire de Bruxelles, Universite Libre de Bruxelles, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Alligator Bioscience. For full disclosures of the study authors, visit thelancet.com.
