UCLA

Background

Matrix metalloproteinase 9 (MMP9) expression in the tumor microenvironment is implicated in multiple protumorigenic processes. Andecaliximab (GS-5745), a monoclonal antibody targeting MMP9 with high affinity and selectivity, was evaluated in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma.

Patients and methods

This phase I study was completed in two parts: part A was a dose-finding, monotherapy phase that enrolled patients with advanced solid tumors, and part B examined andecaliximab in combination with chemotherapy in specific patient cohorts. In the cohort of patients with pancreatic adenocarcinoma (n = 36), andecaliximab 800 mg every 2 weeks was administered in combination with gemcitabine and nab-paclitaxel. Patients were treated until unacceptable toxicity, withdrawal of consent, disease progression, or death. Efficacy, safety, and biomarker assessments were performed.

Results

Andecaliximab combined with gemcitabine and nab-paclitaxel appeared to be well tolerated and did not demonstrate any unusual toxicities in patients with pancreatic adenocarcinoma. The most common treatment-emergent adverse events were fatigue (75.0%), alopecia (55.6%), peripheral edema (55.6%), and nausea (50.0%). Median progression-free survival was 7.8 months (90% confidence interval, 6.9-11.0) with an objective response rate of 44.4% and median duration of response of 7.6 months. Maximal andecaliximab target binding, defined as undetectable, andecaliximab-free MMP9 in plasma, was observed.

Conclusion

Andecaliximab in combination with gemcitabine and nab-paclitaxel demonstrates a favorable safety profile and clinical activity in patients with advanced pancreatic adenocarcinoma.

Implications for practice

The combination of andecaliximab, a novel, first-in-class inhibitor of matrix metalloproteinase 9, with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma provided a median progression-free survival of 7.8 months and objective response rate of 44.4%. The majority of systemic biomarkers related to matrix metalloproteinase 9 activity and immune suppression increased at 2 months, whereas biomarkers related to tumor burden decreased. Although this study demonstrates promising results with andecaliximab plus chemotherapy in patients with advanced pancreatic adenocarcinoma, andecaliximab was not associated with a survival benefit in a phase III study in patients with advanced gastric/gastroesophageal junction carcinoma.