In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
Indication
On September 6, paclitaxel protein-bound particles [albumin-bound] (nab-paclitaxel, Abraxane) was approved for use in combination with gemcitabine for first-line treatment of patients with metastatic adenocarcinoma of the pancreas.1,2
Approval was based on demonstration of improved overall survival in a multicenter, international, open-label phase III trial in which 861 patients with metastatic pancreatic cancer were randomly assigned to receive the combination of nab-paclitaxel plus gemcitabine (n = 431) or gemcitabine alone (n = 430).2 Patients had a median age of 63 years (range, 27–88 years, 42% ≥ 65 years), 58% were male, 60% had Karnofsky performance score of 90 or 100, 46% had at least three sites of metastatic disease, and 84% had liver metastases. The primary lesion was located in the pancreatic head in 43% of patients, body in 31%, and tail in 25%.
Median overall survival was 8.5 months in the nab-paclitaxel/gemcitabine group vs 6.7 months in the gemcitabine group (hazard ratio [HR] = 0.72, P < .0001). Progression-free survival was also significantly prolonged n the nab-paclitaxel/gemcitabine group (5.5 vs 3.7 months, HR = 0.69, P < .0001). Objective response rates were 23% vs 7% (P < .0001).
How It Works
Nab-paclitaxel is a microtubule inhibitor composed of protein-bound paclitaxel particles, a solvent-free colloidal suspension of paclitaxel and human serum albumin that exploits the physiologic transport properties of albumin. In addition to potentially avoiding hypersensitivity reactions and adverse reactions associated with taxane solvents in conventional preparations, nab-paclitaxel may exhibit increased antitumor activity by reaching the tumor microenvironment more efficiently than solvent-based paclitaxel via caveolae-mediated transcytosis and by exhibiting preferential uptake by cancer cells.
How It Is Given
The recommended dosage of nab-paclitaxel is 125 mg/m2, administered intravenously over 30 to 40 minutes on days 1, 8, and 15 of each 28-day cycle. Gemcitabine is given on days 1, 8, and 15 of each 28-day cycle immediately after nab-paclitaxel.
There are recommendations for initial dosing and dose adjustment of nab-paclitaxel and gemcitabine in patients with neutropenia, thrombocytopenia, grade 3 or 4 febrile neutropenia, grade 3 or 4 peripheral neuropathy, grade 2 or 3 cutaneous toxicity, and gastrointestinal toxicity (grade 3 mucositis or diarrhea). No dose adjustment is necessary for patients with mild hepatic impairment, but nab-paclitaxel should be withheld for AST > 10 × upper limit of normal or bilirubin > 5 × upper limit of normal, and the starting dose should be reduced in patients with moderate to severe hepatic impairment.
Caution should be used when concomitantly administering nab-paclitaxel with inhibitors or inducers of CYP2C8 or CYP3A4 (eg, ketoconazole, gemfibrozil, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John’s wort).
Nab-paclitaxel is contraindicated in patients with absolute neutrophil count < 1,500/µL and in those with severe hypersensitivity reaction to nab-paclitaxel. Patients should undergo frequent monitoring of complete blood count.
Safety Profile
Among treated patients in the phase III trial, the median relative dose intensity for gemcitabine was 75% in the nab-paclitaxel/gemcitabine group and 85% in the gemcitabine group, and the median relative dose intensity of nab-paclitaxel was 81%.
The most common adverse events of any grade reported at a ≥ 5% higher incidence in the nab-paclitaxel/gemcitabine group included neutropenia (73% vs 58%), fatigue (59% vs 46%), peripheral neuropathy (54% vs 13%), nausea (54% vs 48%), alopecia (50% vs 5%), peripheral edema (46% vs 30%), diarrhea (44% vs 24%), and pyrexia (41% vs 28%). The most common grade 3 or higher adverse events in the nab-paclitaxel/gemcitabine group were neutropenia (38% vs 27%), peripheral neuropathy (17% vs 1%), thrombocytopenia (13% vs 9%), asthenia (7% vs 4%), and dehydration (7% vs 2%).
The most common serious adverse reactions in nab-paclitaxel/gemcitabine patients were pyrexia, dehydration, pneumonia, and vomiting. Sepsis was reported in 5% (vs 2%) and pneumonitis was reported in 4% (vs 1%) of patients who received nab-paclitaxel/gemcitabine.
Nab-paclitaxel carries boxed warnings against administration in patients with baseline neutrophil counts < 1,500/µL, for frequent monitoring of peripheral blood cell counts to detect bone marrow suppression, and against substitution of nab-paclitaxel for or with other paclitaxel formulations.
Nab-paclitaxel also carries warnings/precautions for myelosuppression, sensory neuropathy, sepsis, pneumonitis, severe hypersensitivity reactions (including fatalities), use in hepatic impairment, theoretical risk of viral transmission (due to formulation with albumin derived from human blood), and fetal harm. Women should be advised to avoid becoming pregnant and men should be advised not to father a child while receiving nab-paclitaxel. ■
References
1. U.S. Food and Drug Administration: Paclitaxel. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm367613.htm.
2. ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) prescribing information, Abraxis BioScience, LLC, September 2013. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2013/021660s037lbl.pdf.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
