Pancreatic ductal adenocarcinomas (PDAC) exhibit a high degree of desmoplasia, with extensive connective tissue growth factor (CTGF) expression and extracellular matrix production1, 2. Pamrevlumab (FG-3019), anti-CTGF antibody, is evaluated in fibrotic disease and cancer. Studies in the LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) transgenic mouse model of PDAC demonstrated that pamrevlumab, in combination with gemcitabine, prolonged survival and increased tumor cell apoptosis associated with the down-regulation of the anti-apoptotic protein XIAP3.
In Phase 2 randomized study, gemcitabine/Nab-paclitaxel (G/N) +/- pamrevlumab was given to treatment-naïve locally advanced pancreatic cancer (LAPC) patients to improve resection outcomes and overall survival (OS). 33 LAPC patients were randomized 2:1 to G/N with (Arm A) (n = 22) or without (Arm B) (n = 11) pamrevlumab. Patients who completed 6 cycles of chemotherapy underwent resectability assessment by NCCN and other (CA 19-9, PET, RECIST) criteria, and, if eligible, resection with no further treatment. Patients who progressed received second-line treatment as per physician choice.
No increases in SAEs or surgical complications were observed in Arm A vs Arm B. No significant difference was seen in RECIST, PET or CA 19-9 between the arms. More patients in Arm B (45%, n = 5) than in Arm A (25%, n = 3) discontinued treatment early, mainly due to progression of disease, SAE or physician choice. Of all of the patients who completed 6 cycles of treatment, 78% of patients in Arm A, and 17% of patients in Arm B were deemed resectable; and 44% in Arm A vs 17% in Arm B underwent resection. The primary reasons in patients, who scored as eligible but resected were: metastatic disease, SAE, and physician decision. An improved resection rate was associated with a trend towards improved OS in Arm A.
Improved resection rate combined with increased median OS in Arm A suggests that pamrevlumab is a valuable addition to neoadjuvant therapy in LAPC patients without added toxicity, and that this combination therapy may have a positive impact on OS in LAPC patients.
Clinical trial identification
Legal entity responsible for the study
E. Carrier: Consultant to Targazyme Full time employee of Fibrogen. V. Picozzi: Research funding from Celgene. K. Mody: Research Support: Ipsen, Senwha, Medimmune, Tracon. J. Winter: Research grant from American Cancer Society. J. Glaspy: Consultant for Fibrogen. Research grant from Fibrogen. K. Lipson, S. Porter, E. Kouchakji: Full time employee of Fibrogen. All other authors have declared no conflicts of interest.