CCR2 Inhibition Combined With FOLFIRINOX Safe for Pancreatic Cancer

CCR2-targeted therapy with investigational PF-04136309 in combination with FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) chemotherapy is safe and tolerable in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma.¹

Preclinical models have demonstrated that blockade of CCR2, which plays a role in the recruitment of tumor-associated macrophages for construction of an immunosuppressive tumor microenvironment, restores anti-tumor immunity in pancreatic cancer.

Therefore, researchers sought to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX.

For the single-center, open-label, dose-finding, phase 1b study, researchers enrolled 47 treatment-naïve patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma.

Patients were assigned to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and bolus fluorouracil 400 mg/m², followed by 2400 mg/m² 46-hour continuous infusion), administered every 2 weeks for 6 cycles, or in combination with oral PF-04136309, given at a starting dose of 500 mg twice daily, both for 12 weeks.

Researchers determined that the 500 mg twice daily dose would be the recommended phase 2 dose for PF-04136309.

Results showed that the most common grade 3 or worse adverse events in the CCR2 inhibitor group were neutropenia, febrile neutropenia, lymphopenia, diarrhea, and hypokalemia.

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Two patients discontinued combination therapy due to treatment-related toxicities compared with 1 patient in the FOLFIRINOX alone group. Of note, no treatment-related death occurred.

In regard to activity, 49% of the 33 receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective response, with 97% of the 33 patients achieving local tumor control. No patients in the chemotherapy alone group achieved an objective response, but 80% had stable disease.

Reference

1. Nywening TM, Wang-Gillam A, Sanford DE, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial [published online ahead of print April 4, 2016]. Lancet Oncol. doi: 10.1016/S1470-2045(16)00078-4.