Weekly nab-Paclitaxel in Combination With Carboplatin Versus Solvent-Based Paclitaxel Plus Carboplatin as First-Line Therapy in Patients With Advanced Non-Small-Cell Lung Cancer: Final Results of a Phase III Trial
This phase III trial compared the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) plus carboplatin with solvent-based paclitaxel (sb-paclitaxel) plus carboplatin in advanced non-small-cell lung cancer (NSCLC).
In all, 1,052 untreated patients with stage IIIB to IV NSCLC were randomly assigned 1:1 to receive 100 mg/m(2) nab-paclitaxel weekly and carboplatin at area under the concentration-time curve (AUC) 6 once every 3 weeks (nab-PC) or 200 mg/m(2) sb-paclitaxel plus carboplatin AUC 6 once every 3 weeks (sb-PC). The primary end point was objective overall response rate (ORR).
On the basis of independent assessment, nab-PC demonstrated a significantly higher ORR than sb-PC (33% v 25%; response rate ratio, 1.313; 95% CI, 1.082 to 1.593; P = .005) and in patients with squamous histology (41% v 24%; response rate ratio, 1.680; 95% CI, 1.271 to 2.221; P < .001). nab-PC was as effective as sb-PC in patients with nonsquamous histology (ORR, 26% v 25%; P = .808). There was an approximately 10% improvement in progression-free survival (median, 6.3 v 5.8 months; hazard ratio [HR], 0.902; 95% CI, 0.767 to 1.060; P = .214) and overall survival (OS; median, 12.1 v 11.2 months; HR, 0.922; 95% CI, 0.797 to 1.066; P = .271) in the nab-PC arm versus the sb-PC arm, respectively. Patients ≥ 70 years old and those enrolled in North America showed a significantly increased OS with nab-PC versus sb-PC. Significantly less grade ≥ 3 neuropathy, neutropenia, arthralgia, and myalgia occurred in the nab-PC arm, and less thrombocytopenia and anemia occurred in the sb-PC arm.
The administration of nab-PC as first-line therapy in patients with advanced NSCLC was efficacious and resulted in a significantly improved ORR versus sb-PC, achieving the primary end point. nab-PC produced less neuropathy than sb-PC.
"With the natural affinity of albumin to tumor cells, it enables
paclitaxel to be concentrated in cancer lesion to exert bigger anti-neoplastic
effect. In a phase III trial of Abraxane plus carboplatin versus solvent-based
paclitaxel , Abraxane arm shows
significantly higher ORR than the solvent-based paclitaxel arm (33% vs 25%,
p = 0.005) and equivalent progression free survival (PFS) and OS. The ORR benefit is
especially bigger in squamous subtype (41% vs 24%, p < 0.001) and the OS
beneficial trend is bigger in this group too. "
[Show abstract][Hide abstract] ABSTRACT: Recent advances have shown that histology and genetic biomarkers are important in patient selection, which have led to significantly better outcomes for lung cancer patients. However, most new treatments only apply to adenocarcinoma or non-squamous, and in squamous carcinoma there is little breakthrough. In a phase III trial nab-paclitaxel plus carboplatin showed superior response rate over paclitaxel and carboplatin. In subgroup analysis the squamous histology appeared to be a predictive factor to nab-paclitaxel treatment.
This is an open-label, randomized, active controlled phase II trial. A total of 120 untreated advanced squamous lung cancer patients are randomized at a 1:1 ratio to receive nab-paclitaxel (135 mg/m2, d1, 8, q3w) plus carboplatin (AUC 5, d1, q3w) or gemcitabine (1,250 mg/m2, d1, 8, q3w) and carboplatin (AUC 5, d1, q3w). The primary endpoint is objective response rate and the second endpoints are progression free survival, overall survival, safety and biomarkers associated with nab-paclitaxel. The treatment will continue up to six cycles or intolerable toxicity.
This ongoing trial will be the first prospective randomized trial to explore the efficacy of nab-paclitaxel as the first-line treatment specifically in squamous carcinoma of lung.
Clinicaltrials.gov reference: NCT01236716
BMC Cancer 09/2014; 14(1):684. DOI:10.1186/1471-2407-14-684 · 3.36 Impact Factor
"More recently, Abraxane® has also been described for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine, and patients with locally advanced or metastatic non-small cell lung carcinoma, in combination with carboplatin (Kudlowitz and Muggia, 2014). Abraxane® has a greater therapeutic index than paclitaxel alone, being administered at higher doses with less toxicity and more efficacy than traditional paclitaxel therapy (Gradishar et al., 2005; Socinski et al., 2012; Iwamoto, 2013). Abraxane® is currently still being further evaluated in clinical trials for other tumors, such as cancer of the bladder (NCT00583349) and multiple myeloma (NCT02075021). "
[Show abstract][Hide abstract] ABSTRACT: Serum albumin is a multi-functional protein that is able to bind and transport numerous endogenous and exogenous compounds. The development of albumin drug carriers is gaining increasing importance in the targeted delivery of cancer therapy, particularly as a result of the market approval of the paclitaxel-loaded albumin nanoparticle, Abraxane®. Considering this, there is renewed interest in isolating and characterizing albumin-binding proteins or receptors on the plasma membrane that are responsible for albumin uptake. Initially, the cellular uptake and intracellular localization of albumin was unknown due to the large confinement of the protein within the vascular and interstitial compartment of the body. Studies have since assessed the intracellular localization of albumin in order to understand the mechanisms and pathways responsible for its uptake, distribution and catabolism in multiple tissues, and this is reviewed herein.
Frontiers in Physiology 08/2014; 5:299. DOI:10.3389/fphys.2014.00299 · 3.53 Impact Factor
"Abraxane, an albumin-bound PX nanoparticle (mean diameter 130 nm), was approved by the FDA in October 2012 for the first-line treatment of NSCLC in combination with carboplatin. In the phase III trial CA-031, weekly albumin-bound paclitaxel (nab-PX) exhibited decreased neuropathy and neutropenia compared to solvent-based paclitaxel (sb-PX), likely due to the absence of toxic excipients.3 However, the 10% improvement of progression-free survival (P=0.21) and overall survival (P=0.27) was not statistically significant. "
[Show abstract][Hide abstract] ABSTRACT: A nanoparticle (NP) formulation with 2'-(2-bromohexadecanoyl)-paclitaxel (Br-16-PX) conjugate was developed in these studies for the treatment of non-small cell lung cancer (NSCLC). The lipophilic paclitaxel conjugate Br-C16-PX was synthesized and incorporated into lipid NPs where the 16-carbon chain enhanced drug entrapment in the drug delivery system and improved in vivo pharmacokinetics. The electron-withdrawing bromine group was used to facilitate the conversion of Br-C16-PX to paclitaxel at the tumor site. The developed system was evaluated in luciferase-expressing A549 cells in vitro and in an orthotopic NSCLC mouse model. The results demonstrated that the Br-C16-PX NPs had a higher maximum tolerated dose (75 mg/kg) than Taxol(®) (19 mg/kg) and provided significantly longer median survival (88 days versus 70 days, P<0.05) in the orthotopic NSCLC model. An improved pharmacokinetic profile was observed for the Br-C16-PX NPs at 75 mg/kg compared to Taxol at 19 mg/kg. The area under the concentration versus time curve (AUC)0-96 h of Br-C16-PX from the NPs was 91.7-fold and 49.6-fold greater than Taxol in plasma and tumor-bearing lungs, respectively, which provided sustained drug exposure and higher antitumor efficacy in the NP-treated group.
International Journal of Nanomedicine 07/2014; 9(1):3601-10. DOI:10.2147/IJN.S66040 · 4.38 Impact Factor
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