Both drugs are given as 30-min infusions. The standard treatment schedule of nabP+gemcitabine is to administer gemcitabine to the patient immediately after nabP on days 1, 8 and 15 of a 28-day cycle. Rapid inactivation of gemcitabine could explain limited antitumour efficacy of gemcitabine in patients with PDAC. 6, 7 In the KPC model, nabP induced reactive oxygen species (ROS) that led to decreases in cytidine deaminase (CDA), a key intracellular enzyme that inactivates gemcitabine. 4, 5 However, studies in the KPC genetically engineered mouse model reported that genetic ablation of SPARC did not change intra-tumoural nabP concentrations. Initial exploration in mice xenografts and PDAC patients treated with nabP indicated drug-induced stromal depletion, which may facilitate gemcitabine delivery to the tumour. SPARC may act as an albumin-binding protein capable of sequestering nabP to concentrate the drug intra-tumourally. PDAC is a stromal-rich tumour expressing high amounts of secreted protein acidic and rich in cysteine (SPARC). The mechanism by which nabP enhances gemcitabine efficacy is uncertain.
The registration MPACT trial established nab-Paclitaxel (nabP) combined with gemcitabine as a standard first-line treatment for patients with metastatic PDAC, reporting improved median OS of 8.7 months for the combination compared with 6.6 months for gemcitabine alone ( p = 0.001). The median overall survival (OS) of patients with metastatic PDAC is under 1 year, even with optimal chemotherapy. 1 Without surgery, PDAC is almost uniformly lethal however, most patients present with unresectable disease. Pancreatic ductal adenocarcinoma (PDAC) is the leading cause of cancer mortality. SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS. Strongly positive tumour epithelial cytidine deaminase (CDA) expression favoured benefit from SEQ therapy (PFS HR 0.31, 95% CI 0.13–0.70). CTCAE Grade ≥3 neutropaenia incidence doubled with SEQ therapy but was not detrimental to QoL. Six-month PFS was 46% with SEQ and 32% with CON scheduling.
In total, 71 patients received sequential (SEQ) and 75 concomitant (CON) treatment. Secondary outcome measures were objective response rate (ORR), overall survival (OS), safety, quality of life (QoL) and predictive biomarkers. The primary outcome measure was progression-free survival (PFS). Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP. Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy this hypothesis was tested in a clinical trial.
Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC).