AACR 2019: CD40 Antibody Combined With Chemotherapy in Advanced Pancreatic Cancer


Key Points

  • As of the data cutoff for the interim analysis, 20 of 24 patients (83%) experienced tumor reduction.
  • A randomized phase II study evaluating chemotherapy, APX005M, and/or nivolumab—in which the primary endpoint is 1-year overall survival—is underway.

An interim analysis of a small phase Ib study by O’Hara et al evaluating the CD40 agonistic monoclonal antibody APX005M in combination with gemcitabine and nab-paclitaxel with or without the programmed cell death protein 1 (PD-1) inhibitor nivolumab in untreated patients with metastatic pancreatic ductal adenocarcinoma has found that the therapy caused tumors to shrink in 20 of 24 evaluable patients. The early findings provide a potential effective combination strategy in the treatment of pancreatic cancer. The study was presented at the American Association for Cancer Research (AACR) Annual Meeting (Abstract CT004).

Pancreatic ductal adenocarcinoma is estimated to become the second leading cause of cancer-related deaths by 2030. Although previous studies have shown that PD-1 inhibitors alone are ineffective in the treatment of pancreatic ductal adenocarcinoma, preclinical data suggest that chemotherapy with agonistic CD40 antibodies can be combined with anti–PD-1 therapy to trigger effective T-cell immunity.

Study Methodology

Patients with previously untreated pancreatic ductal adenocarcinoma were enrolled in four cohorts:

  • Gemcitabine/nab-paclitaxel/APX005M at 0.1 mg/kg (cohort B1)
  • Gemcitabine/nab-paclitaxel/APX005M at 0.3 mg/kg (cohort B2)
  • Gem/nab-paclitaxel/nivolumab/APX005M at 0.1 mg/kg (cohort C1)
  • Gem/nab-paclitaxel/nivolumab/APX005M at 0.3 mg/kg (cohort C2).

The primary study objectives were to evaluate safety and determine the recommended phase II dose of APX005M. Secondary objectives included tumor response and immune pharmacodynamics. Analyses were performed on dose-limiting toxicity–evaluable subjects, defined as receiving 1 dose of APX005M and ≥ 2 doses of gemcitabine/nab-paclitaxel during cycle 1 and remaining on study through cycle 2, day 1.

Study Results

A total of 30 patients received therapy, and 24 were dose-limiting toxicity–evaluable (6 per cohort). Median follow-up was 32.2 weeks. Thirteen (54%) of the patients experienced an adverse event leading to discontinuation of therapy, and 10 (42%) experienced a treatment-related serious adverse event. Two dose-limiting toxicities were observed, one each in cohorts B2 and C1 (grade 3 and 4 febrile neutropenia, respectively).

Adverse event rates were similar across cohorts. Four (17%) subjects died (2 each in cohorts B1 and C1) due to disease progression (n = 2) and adverse events (n = 2, sepsis and septic shock in the setting of neutropenia). Within the dose-limiting toxicity–evaluable population, best overall responses included 14 (58%) partial responses (11 confirmed, 3 unconfirmed) and 8 (33%) patients with stable disease. One patient (4%) had progressive disease, and 1 (4%) had no treatment evaluation.

Postbaseline tumor assessments were available for two of the six dose-limiting toxicity–inevaluable patients (best overall responses of stable disease and confirmed partial response). Multiplexed immunohistochemical analysis of baseline tumors revealed a low CD8 T-cell concentration and high macrophage infiltrate level.

Analysis of circulating mutant KRAS DNA showed marked and rapid decrease with therapy in some patients. Immune profiling of peripheral blood mononuclear cells at baseline and on-treatment by mass cytometry revealed remodeling of the myeloid compartment in response to treatment, with rapid activation of dendritic cells in most patients. A randomized phase II study evaluating chemotherapy, APX005M, and/or nivolumab—in which the primary endpoint is 1-year overall survival—is underway.

Clinical Significance

“These findings give us clues that this new and innovative combination therapy can be effective against pancreatic cancer,” said Mark H. O’Hara, MD, Assistant Professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania, and the study’s co–lead author. “Although only time and further research will truly tell, our data are a reason for optimism.”

Disclosure: Funding was provided by the Cancer Research Institute. Apexigen, manufacturer of APX005M, and Bristol-Myers Squibb, manufacturer of nivolumab, supplied treatment for this study. The study authors’ full disclosures can be found at

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