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 October 11, 2012, paclitaxel protein-bound particles for injectable suspension, albumin-bound (nab-paclitaxel, Abraxane) was approved for use in combination with carboplatin for the initial treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) who are not candidates for curative surgery or radiation therapy. Nab-paclitaxel has a prior indication in metastatic breast cancer.
Approval in NSCLC was based on the prior approval of conventional paclitaxel injection for this indication and support from a randomized, open-label, multinational trial showing that nab-paclitaxel was at least as active as solvent-based paclitaxel injection when each was used in combination with carboplatin.2,3 For further discussion of this pivotal trial, see sidebar.
How It Works
Conventional paclitaxel preparations are formulated with solvents to overcome poor aqueous solubility. Solvent-based paclitaxel is associated with risk of hypersensitivity reactions requiring premedication with steroids and antihistamines, as well as increased risk of other toxicities. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel, is a solvent-free colloidal suspension of paclitaxel and human serum albumin that exploits the physiologic transport properties of albumin. In addition to avoiding hypersensitivity reactions and adverse reactions associated with taxane solvents, 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 dose of nab-paclitaxel is 100 mg/m2 via 30-minute infusion on days 1, 8, and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC 6 mg • min/mL on day 1 of each 21-day cycle, beginning immediately after the completion of nab-paclitaxel administration. Premedication to prevent hypersensitivity reactions is generally not needed prior to nab-paclitaxel administration. Premedication may be needed in patients with prior hypersensitivity reactions to nab-paclitaxel, and patients with a severe hypersensitivity reaction should not be rechallenged with the agent.
The nab-paclitaxel dose must be reduced for patients with moderate and severe hepatic impairment. The drug should not be administered on day 1 of a treatment cycle until the absolute neutrophil count is ≥ 1,500/µL and platelet count is ≥ 100,000/µL. In patients developing severe neutropenia or thrombocytopenia, treatment should be withheld until recovery (to ≥ 500/µL or ≥ 50,000 µL on days 8 or 15) and then resumed at a permanently reduced dose. Nab-paclitaxel should also be withheld for grade 3 or 4 peripheral neuropathy and resumed at a permanently reduced dose upon recovery to grade 1 or resolution.
Metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. Therefore, nab-paclitaxel should be used with caution in patients receiving inhibitors (eg, ketoconazole, gemfibrozil) or inducers (eg, rifampin, carbamazepine) of either isoenzyme.
Safety Profile
The following (≥ 10% incidence) adverse events occurred with a similar incidence in the nab-paclitaxel (incidence shown) and paclitaxel injection groups: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%). Select adverse events of any grade that were more common (≥ 5% difference) with nab-paclitaxel were peripheral edema (10% vs 4%) and epistaxis (7% vs 2%), and those that were more common with paclitaxel injection were peripheral neuropathy (64% vs 48%), arthralgia (25% vs 13%), and myalgia (19% vs 10%).
Grade 3 or 4 peripheral neuropathy occurred in 3% of nab-paclitaxel recipients (grade 3 only) and in 12% of paclitaxel injection recipients; grade 3 neuropathy improved to grade 1 or resolved in 10 (59%) of 17 nab-paclitaxel patients following interruption or discontinuation of the drug. Grade 3 or 4 hematologic toxicity included anemia in 28% of nab-paclitaxel patients vs 7% of paclitaxel injection patients, neutropenia in 47% vs 58%, and thrombocytopenia in 18% vs 9%. Serious adverse events occurred in 18% of both treatment groups, with the most common events in nab-paclitaxel patients being anemia (4%) and thrombocytopenia (3%).
Nab-paclitaxel carries a boxed warning for neutropenia; it is recommended that peripheral blood counts be monitored frequently for the occurrence of bone marrow suppression. In addition, there is a boxed warning against substitution of nab-paclitaxel for or with other paclitaxel formulations.
Nab-paclitaxel has additional warnings/precautions for myelosuppression, sensory neuropathy, severe hypersensitivity reactions (including fatality), use in patients with hepatic impairment, theoretical risk of viral transmission (since the formulation contains albumin derived from human blood), and fetal harm. Women should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving nab-paclitaxel. ■
References
1. U.S. Food and Drug Administration: Hematology/oncology approvals & safety notifications: Paclitaxel (Abraxane). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm323668.htm. Accessed October 22, 2012.
2. ABRAXANE® for injectable suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) prescribing information, Abraxis BioScience, LLC, October 2012. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/021660s031lbl.pdf. Accessed October 22, 2012.
3. Socinski MA, Bondarenko I, Karaseva NA, et al: 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. J Clin Oncol 30:2055-2062, 2012.
