Neoadjuvant BMS-813160, nivolumab, gemcitabine and nab-paclitaxel for patients with pancreatic cancer

Background: Targeting tumor-associated macrophages through C-C chemokine receptor type 2 (CCRs) in pancreatic ductal adenocarcinoma (PDAC) improves the efficacy of chemotherapy and restores T cell immunity in preclinical models. Methods: We conducted a phase I/II single institution study (NCT03496662) combining chemotherapy gemcitabine and nab-paclitaxel (GnP), CCR2/5 inhibitor BMS-813160 and nivolumab for four 28-day cycles for patients with borderline resectable (BR) or locally advanced (LA) PDAC. The recommended phase 2 dose (RP2D) of BMS-813160 was established in the 3+3 design. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included resection rate, median progression-free survival (mPFS) and overall survival (mOS). Results: 8 patients were treated with GnP alone (control arm) and 31 patients (29 response evaluable) were treated at RP2D. No grade 3/4 toxicities attributed to nivolumab or BMS-813160 were identified. After 4 cycles of study treatment (N=26), ORR was 35.7% and 16.7% among BR- and LA-PDAC patients respectively, compared to 0% of control patients. 78.6% BR- and 16.7% of LA-PDAC patients who completed study treatment underwent surgical resection. For intent-to-treat analyses, BR-PDAC patients had a mPFS and mOS of 14.6 and 20.4 months respectively; and for LA-PDAC patients, were 14.7 and 17 months, respectively. Biomarker analyses showed decreased intratumoral monocytes, macrophages, enhanced T cell proliferation and effector gene expression. Conclusions: Neoadjuvant BMS-813160/nivolumab/GnP was well tolerated and appears to achieve comparable ORR and resectability to historical data, however with prolonged PFS and OS in LA-PDAC patients, warranting a larger phase II study with a more efficacious CCR2-targeted therapeutic.