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CHICAGO -- The investigational CD40 agonist mitazalimab and modified FOLFIRINOX demonstrated encouraging activity in patients with previously untreated metastatic pancreatic ductal adenocarcinoma, according to the .

The primary endpoint of the study was met with a confirmed overall response rate (ORR) of 40.4% that was higher than historical controls, reported Jean-Luc Van Laethem, MD, of the Erasme Hospital, Hopital Universitaire de Bruxelles, Université Libre de Bruxelles in Brussels, in a poster presentation at the American Society of Clinical Oncology annual meeting. The study was published simultaneously in .

Van Laethem and colleagues also noted that use of the combination "resulted in deep responses with an unprecedented duration of response and prolonged overall survival," although they cautioned these were secondary outcomes and "must be interpreted as preliminary."

"These findings provide evidence on the potential utility of a novel treatment regimen for metastatic pancreatic ductal adenocarcinoma, a cancer with very low survival rates," they said.

In an , Jennifer Y. Wo, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues, noted that the response rate reported in this study was higher than that seen with FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and gemcitabine plus nab-paclitaxel, which have been standard first-line regimens for a decade.

While the response rate, along with the promising secondary endpoint results, "appear superior compared with outcomes seen with FOLFIRINOX, a larger randomized study is needed to confirm the benefit of addition of mitazalimab compared with FOLFIRINOX alone," they suggested. "Nevertheless, the results are encouraging and warrant further exploration."

They added that evaluating biomarkers such as cytokines and immune cells in response to mitazalimab "provides crucial insights into mechanisms of action and could be considered in future trials involving similar CD40 agonist molecules."

Van Laethem and colleagues noted that the sequence and timing of mitazalimab "is an important, differentiating aspect of OPTIMIZE-1" as it introduced a priming dose of mitazalimab a week before the first dose of chemotherapy was administered.

In a video presentation accompanying the poster, Van Laethem said the priming dose of mitazalimab at day 1 "activates macrophages and stromal degradation," while the administration of FOLFIRINOX at day 8, induces tumor cell death and releases antigens that are presented to the immune system.

Finally, with the objective of promoting long-term antitumor responses, mitazalimab is again administered at day 10, "priming tumor-specific T cells via activation of dendritic cells," he explained.

OPTIMIZE-1 was a single-arm multicenter study that enrolled adults with histologically-confirmed metastatic pancreatic ductal adenocarcinoma and ECOG performance status 0 or 1 at 14 university hospitals in Belgium, France, and Spain.

70 patients were enrolled in the study (median age 62, 57% female), and all were included in the safety analysis, while 57 were evaluated for activity.

At data cutoff median follow-up was 12.7 months, with 29 patients (51%) still on study and 18 (32%) on treatment. One patient (2%) achieved a complete response, while partial responses and stable disease were observed in 22 patients (39%).

"Responses were durable and deep," Van Laethem said, with 30 patients under therapy for more than 6 months, and 10 patients for more than 12 months.

Regarding the study's secondary outcomes:

• Median duration of response: 12.5 months (95% CI 7.5-not evaluable)
• Median progression-free survival: 7.7 months (95% CI 5.8-11.3)
• Median overall survival (OS): 14.3 months (95% CI 10.0-21.6)
• 12-month OS: 59.3% (95% CI 44.2-71.7)

As for safety, Van Laethem reported that the safety profile of the combination "was consistent with mFOLFIRINOX, with no signs of additive toxicity related to the addition of mitazalimab."

Grade 3 or worse treatment-emergent adverse events AEs were reported in 55 (79%) of the 70 patients in the safety set. The most common grade ≥3 AEs were neutropenia (26%), hypokalemia (16%), and anemia, and thrombocytopenia (11%).

Serious AEs were reported in 41% of patients, the most common being vomiting (7%), decreased appetite (6%), and diarrhea and cholangitis (4% each), with none considered related to mitazalimab.

No treatment-related deaths were reported.

"The combination will be developed as frontline therapy for metastatic pancreatic ductal adenocarcinoma in a randomized phase III trial, and this encouraging data in pancreatic cancer warrant evaluation of mitazalimab in other tumor types," Van Laethem said.