Unprecedented Treatment Responses with Mitazalimab in Pancreatic Cancer

Pancreatic cancer, with its resistance to treatment and the difficulty of early diagnosis, has been a priority target for medical research. At the metastatic stage, the disease has usually spread to the liver, and available treatment options are limited and challenging. In this setting, the effects of combining mitazalimab with modified mFOLFIRINOX (mFOLFIRINOX) in metastatic pancreatic cancer may offer new hope in the fight against this difficult cancer.

Mitazalimab targets the CD40 molecule and strengthens the immune system's activity against cancer cells as a CD40 agonist (substances that activate a receptor are called "agonists"). CD40 strengthens interactions between antigen-presenting cells and T cells as an immune-cell surface receptor. This interaction is essential for the immune system to recognize and destroy cancer cells. Mitazalimab mimics this mechanism to directly strengthen the immune response, making it a type of immunotherapy treatment.

The Best Response Rates Reported to Date with Mitazalimab and mFOLFIRINOX

The confirmed response rate was 42.1%, and median response duration among responders was 12.6 months.

The combination of mitazalimab and modified folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (mFOLFIRINOX) has shown efficacy in patients with previously untreated metastatic pancreatic cancer. These findings were presented at the ESMO Gastrointestinal Cancers Congress 2024 meeting.

According to Dr. Teresa Macarulla Mercade from Spain, who presented the study, this combination treatment provided "an unprecedented duration of response" and "a prolonged survival benefit for these patients".

Dr. Macarulla Mercade and colleagues tested mitazalimab combined with mFOLFIRINOX in the phase 1b/2 OPTIMIZE-1 trial.

Details of the OPTIMIZE-1 Study

This early-stage clinical trial enrolled patients with untreated metastatic pancreatic adenocarcinoma. The efficacy population comprised 57 patients and the safety population 70 patients, most of whom were women (57.9% and 57.1%, respectively).

Efficacy and Safety Populations: These are the groups of patients followed in a clinical trial to assess a drug's efficacy and safety. The efficacy population is used to evaluate the drug's effects, while the safety population is used to evaluate its safety.

Median age in both groups was 62 years (range 43-77 years).

Most patients had not undergone previous surgery (96.5% and 95.7%) and had liver metastases (73.7% and 78.6%).

In the first part of the study, patients received mitazalimab at doses of 450 mg/kg or 900 mg/kg. In the second part, patients received the recommended phase 2 dose of 900 mg/kg. Patients received mitazalimab on days 1, 10, 24, 38 and 52, and mFOLFIRNOX on days 8, 22, 36 and 50.

The primary endpoint was the objective response rate. 

Results

• At a median follow-up of 18 months, with 30% of patients still receiving treatment, the confirmed objective response rate was 42.1%.
• Median response duration among patients who responded to treatment was 12.6 months.
• Median progression-free survival (PFS) was 7.7 months, and
• median overall survival was 14.9 months.
• The 12-month progression-free survival rate was 35.1%,
• the 12-month overall survival rate was 57.8%, and
• the 18-month overall survival rate was 36.2%.

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Subgroup Analyses

An exploratory subgroup analysis in this study showed that patients' overall survival was associated with changes in "CD4 effector T cells" after the first dose of mitazalimab.

Patients with a large increase in CD4 effector T-cell counts lived longer than those with a smaller increase; median survival in these groups was 14 months and 8.8 months, respectively (P = 0.019).

Similarly, increases in certain immune-cell types after mitazalimab treatment were associated with the depth of treatment response. In particular, increases in CD38+ natural killer (NK) T cells, CD38+ CD8+ terminal effector memory (TEMRA) cells and certain other T-cell types stood out. After adjustments, however, only an increase in CD38+ NK/T cells showed a significant association with treatment response (P = 0.04295).

In terms of safety, 78.6% of the 70 study participants experienced serious adverse events. The most common serious adverse events were neutropenia, hypokalemia, anemia, thrombocytopenia and fatigue. These data provide information about the potential risks of treatment as well as its possible benefits.

In conclusion, mitazalimab combined with modified FOLFIRINOX stands out as a promising approach to treating metastatic pancreatic cancer. The combination will continue to be developed through broader testing as first-line treatment in an upcoming phase 3 trial. This progress has the potential to provide new, effective treatment options against this difficult cancer.