Abraxane Receives New Indication for Locally Advanced or Metastatic Non–Small-Cell Lung Cancer When Curative Surgery or Radiation Therapy Is Not an Option

April 2013 Vol 6 No 3 Payers’ Guide to New FDA Approvals - Select Drug Profiles, Payers' Guide
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For the purposes of treatment, lung cancer is classified as non–small cell, which accounts for approximately 85% of cases, or as small cell, representing 14% of cases.1 Non–small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide.2 The greatest risk factor for lung cancer is cigarette smoking. Other risk factors include smoking pipes or cigars and exposure to agents such as radon gas, secondhand smoke, asbes­tos, chromium, cadmium, arsenic, some organic chemicals, radiation, and air pollution. The rate of lung cancer may be increased in individuals with a history of tuberculosis or a genetic susceptibility to the disease.1,3

The Burden and Impact of Lung Cancer
In 2012, the American Cancer Society estimated there would be 226,160 individuals with new cases of lung cancer, representing approximately 14% of all cancer diagnoses, and 160,340 deaths from lung cancer in the United States, which is approximately 28% of all cancer deaths.1

Lung cancer is the second leading cause of new cases of cancer (other than nonmelanoma skin cancer or noninvasive cancers other than bladder cancer) in both men and women in the United States, and the leading cause of death for both sexes.1

The likelihood of developing lung cancer increases with age.1 Although the rate of lung cancer has been decreasing in men over the past 20 years, it has only recently started decreasing in women. Sex differences in the incidence of lung cancer and in death rates are a result of historic rates of smoking and smoking cessation in men and women over the past 50 years.4

Lung cancer is usually diagnosed at later stages and is rarely cured.4 Symptoms can include persistent cough, blood-tinged sputum, chest pain, change in the voice, and recurrent pneumonia or bronchitis.1 Median age at diagnosis is age 70 years for men and age 71 years for women.5
Annual chest x-rays do not decrease mortality from lung cancer. Although a screening trial using low-dose spiral computed tomography reduced the death rate by 20% for high-risk individuals (ie, current and former heavy smokers), it is not known if this technology is applicable for screening of those with less cigarette exposure. The risks of screening include cumulative radiation exposure and unnecessary biopsies and surgery.1

The 1-year relative survival for patients with lung cancer—which has been increasing over the past several decades as a result of better surgical techniques and combination therapies—was 43% in the period between 2003 and 2006.1 The 5-year survival rate for all stages of lung cancer combined is only 16%. Early detection at the localized stage results in a 5-year survival rate of 52%, but localized lung cancer represents only 15% of all cases. The overall 5-year survival for NSCLC is 17%,1 but the 5-year survival rate for stage IV NSCLC is only 1%.6

Current Treatments for Lung Cancer
The current treatments for lung cancer are based on the type and stage of the tumor, and include surgery, radiation therapy, chemotherapy, and targeted therapies, such as bevacizumab, erlotinib, or crizotinib.1,3 Surgery is the most common treatment choice for localized NSCLC (stage I or stage II).3

Chemotherapy after surgery usually improves survival. However, NSCLC is usually diagnosed at a more ad­vanced stage, and treatment often in­cludes radiation therapy and chemo­therapy, which can be combined with sur­gery. Patients with advanced NSCLC usually receive chemotherapy, targeted therapy, or both.1 Platinum-based regimens are recommended for patients with stage IV NSCLC.3 Al­though many combinations of new agents have been tested in patients with advanced, inoperable NSCLC, their prognosis is still poor, suggesting a need for new therapeutic options.3

Abraxane Receives a New Indication for NSCLC
On October 11, 2012, paclitaxel protein-bound particles for injectable suspension (Abraxane for Injectable Suspension), an albumin-bound form of paclitaxel, was approved for the first-line treatment of locally advanced or metastatic NSCLC in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy.7

Abraxane is a nanoparticle protein-bound paclitaxel, which may therefore also be referred to as nab-paclitaxel.6
Abraxane is already indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or for relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.8

The new indication for NSCLC was based on a clinical trial comparing weekly infusions of Abraxane at a dose of 100 mg/m2 (ITT [intention to treat],  n = 521) to infusions of paclitaxel every 3 weeks at a dose of 200 mg/m2 (ITT, n = 531). All patients also received carboplatin (AUC [area under the curve], 6 mg•min/mL) every 3 weeks.6,7 The study design and results are described in detail below.

Clinical Pharmacology: Development and Mechanism of Action
Abraxane is an albumin-bound form of paclitaxel, the active component. Abraxane has a mean particle size of approximately 130 nm.8,10 Abraxane does not contain any solvents or ethanol. The 130-nm particle size will not obstruct capillaries when the agent is delivered by intravenous (IV) infusion.10 Abraxane was developed to avoid toxicities associated with the vehicle polyoxyethylated castor oil (Cremophor EL), which is used to deliver paclitaxel because of its poor solubility.10,11

Paclitaxel is contraindicated in pa­tients with a history of hypersensitivity reactions to the drug itself or to other drugs formulated in polyoxy­ethylated castor oil. Patients receiving paclitaxel require pretreatment with cor­ticosteroids, diphenhydramine, and H2 antagonists to avoid hypersensitivity reactions.12 Severe hypersensitivity reactions that re­quired treatment occurred in 2% to 4% of patients receiving paclitaxel in clinical trials, and some of these reactions were fatal, despite premedication.12

Unlike paclitaxel, Abraxane does not require premedication and can be infused over a shorter period of time.8,12 Abraxane was also designed to increase intratumor concentrations of the active drug using endogenous albumin pathways.11

The mechanism of action of Abrax­ane is microtubule inhibition, the same as that of paclitaxel. Abraxane promotes the assembly of microtubules from tubulin dimers and stabilizes these microtubules, by preventing de­polymerization. This stabilization prevents microtubules from reorganizing properly and from maintaining their normal structure during mitosis, thereby inhibiting cancer-cell division, motility, and intracellular transport.8,10

Phase 3 Clinical Trial in Locally Advanced or Metastatic NSCLC
The new indication for Abraxane as first-line treatment of locally advanced or metastatic NSCLC, in combination with carboplatin in patients who are not candidates for curative surgery or for radiation therapy, was approved on the basis of one phase 3 clinical trial, showing significantly improved overall response rates (ORRs) in all patients receiving Abraxane, regardless of histology results.6,7,9

Trial Design
This randomized, multicenter, open-label phase 3 trial compared the efficacy and safety of Abraxane plus carboplatin with that of solvent-based paclitaxel (paclitaxel injection) plus carboplatin as first-line systemic treatment in patients with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC. A total of 1052 patients were randomly assigned in a 1:1 ratio to receive weekly 30-minute infusions of Abraxane 100 mg/m2 or 3-hour infusions of paclitaxel 200 mg/m2 after premedication every 3 weeks.

All patients also received IV carboplatin (AUC, 6 mg•min/mL) every 3 weeks after infusion with Abraxane or paclitaxel. The primary objective was ORR.6,8

Table 1
Table 1: Baseline Demographics and Disease Characteristics in the Phase 3 NSCLC Trial, ITT Population.

Patient Population
Key baseline demographic and disease characteristics of the enrolled patients are listed in Table 1. The 2 treatment groups were well-balanced.6

Table 2
Table 2: Common (≥10% Incidence) Adverse Reactions in Patients Receiving Abraxane plus Carboplatin.

Safety Profile
Adverse reactions (ie, safety) were assessed in the 514 patients who received Abraxane plus carboplatin, and in the 524 patients who received paclitaxel injection plus carboplatin.6,8 The median number of treatment cycles was 6 for each treatment group. The doses and schedules for the 2 treatment groups were different; therefore, direct dose-dependent and schedule-dependent comparisons concerning safety cannot be made.8 The ad­verse reactions seen most frequently (≥10% incidence) for the patients re­ceiving Abraxane plus carboplatin are listed in Table 2.8 These common adverse reactions occurred at a similar incidence in the paclitaxel injection plus carboplatin–treated patients.

Table 3
Table 3: Selected Hematologic Toxicities between Treatment Groups.

The frequency and severity of hematologic abnormalities occurring with a difference of ≥5% for all grades (grades 1-4) or ≥2% for grade 3 and 4 toxicities for the 2 treatment groups are listed in Table 3.8 Only 1% of patients in each arm developed febrile neutropenia, and 1 treatment-related death was reported in each arm.6 Thrombo­cytopenia and anemia associated with Abraxane plus carboplatin were readily manageable.6

Table 4
Table 4: Selected Nonhematologic Toxicities between Treatment Groups.

The frequency and severity of nonhematologic adverse reactions occurring with a difference of ≥5% for all grades (grades 1-4) or ≥2% for grade 3 and 4 toxicities between the 2 treatment groups are listed in Table 4.8 The incidences of severe neuropathy, myalgia, and arthralgia were lower in the Abraxane plus carboplatin group.6

In the Abraxane plus carboplatin–treated group, 17 of 514 (3%) patients developed grade 3 peripheral neuropathy (PN), and none developed grade 4 PN. In 10 (59%) of these patients, the grade 3 neuropathy resolved or improved to grade 1 after interruption or discontinuation of Abraxane.8 Median time to improvement of grades 3 or 4 sensory neuropathy was shorter (38 days) for patients in the Abraxane plus carboplatin group than the median time (104 days) for those in the paclitaxel injection plus carboplatin group.6

Table 5
Table 5: Efficacy Results from the Phase 3 NSCLC Trial, ITT Population.

The trial met its primary end point.7 The ORR was significantly higher in the Abraxane plus carboplatin group than in the paclitaxel injection plus carboplatin group (33% vs 25%, re­spectively; P = .005). No significant difference was found in overall survival between the 2 treatment groups.8 The efficacy results are summarized in Table 5.

Dosing and Administration
Unlike paclitaxel, Abraxane does not require premedication.8 The recommended dose of Abraxane for patients with NSCLC is 100 mg/m2, which is administered as an IV infusion over 30 minutes 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 only of each 21-day cycle, beginning immediately after administration of Abraxane is completed.8

Dose Modifications
Dose modifications are not required for patients with mild hepatic impairment (AST [aspartate aminotransferase] <10 times the upper limit of normal [ULN], or bilirubin up to 1.25 times ULN). Abraxane should not be administered to patients with AST >10 times ULN or bilirubin >5 times ULN. The starting doses for patients with NSCLC who have moderate hepatic impairment (AST <10 times ULN and bilirubin 1.26-2 times ULN) or severe hepatic impairment (AST <10 times ULN and bilirubin 2.01-5 times ULN) should be reduced to 75 mg/m2 or to 50 mg/m2, respectively. Subsequent dose increases or adjustments should be based on individual tolerance.8

Patients with NSCLC should not receive Abraxane on day 1 of a cycle if they do not have an absolute neutro­phil count (ANC) of ≥1500 cells/mm3 and platelet counts of ≥100,000 cells/ mm3. Treatment should be withheld until counts reach these levels on day 1 or until ANC is ≥500 cells/mm3 and platelet counts are ≥50,000 cells/mm3 on days 8 and 15 of a cycle. Abraxane should be withheld for grades 3 or 4 PN.

Table 6
Table 6: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC.

Permanent modifications to Abrax­ane and to carboplatin doses are required when treatment is resumed after neutropenia, neutropenic fever, thrombocytopenia, or PN.8 These dose reductions are summarized in Table 6.

Warnings and Precautions
The prescribing information for Abraxane contains a Boxed Warning concerning neutropenia. The Boxed Warning states the following8:

  • Do not administer Abraxane therapy to patients with baseline neutrophil counts of <1500 cells/mm3; to monitor bone marrow suppression, primarily neutropenia, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Abraxane
  • An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. Do not substitute pac­litaxel formulations.
  • Other warnings, precautions, and contraindications for Abraxane in­clude8:
  • Abraxane is contraindicated in patients with neutrophil counts of <1500 cells/mm3
  • Patients who experience a severe reaction to Abrax­ane should not be rechallenged with the drug
  • Abraxane causes myelosuppression; complete blood counts should be mon­itored and doses reduced as needed
  • Sensory neuropathy is a frequent adverse event and may require dose reduction or treatment interruption
  • Severe, fatal hypersensitivity reactions have been reported; do not rechallenge patients with Abraxane
  • Hepatic impairment can increase exposure and toxicity of paclitaxel; Abraxane should be administered with caution in patients with hepatic impairment
  • Abraxane contains albumin derived from human blood, which has a theoretical risk of viral transmission
  • Abraxane may cause fetal harm when administered to pregnant women; women of childbearing age should avoid becoming pregnant while receiving Abraxane
  • Men should be advised not to father a child while receiving Abraxane.

NSCLC is the most common type of lung cancer, which is the leading cause of cancer-related mortality in the United States. There have not been many new treatment options ap­proved for NSCLC. The approval of Abraxane for the treatment of NSCLC offers a new treatment option for all patients with this type of malignancy whose treatment options are limited, especially those who are not candidates for curative surgery or for radiation therapy.


  1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf. Accessed October 29, 2012.
  2. Chien C-R, Shih Y-C T. Economic evaluation of beva­cizumab in the treatment of non-small cell lung cancer (NSCLC). Clinicoecon Outcomes Res. 2012;24:201-208.
  3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non–small-cell lung cancer. Version 2.2012. www.nccn.org. Accessed October 29, 2012.
  4. Vera-Llonch M, Weycker D, Glass A, et al. Health care costs in patients with metastatic lung cancer re­ceiving chemotherapy. BMC Health Serv Res. 2011;11:305-312.
  5. American Cancer Society. Cancer Treatment and Sur­vivorship Facts & Figures 2012-2013. Atlanta, GA: American Cancer Society; 2012.
  6. Socinski MA, Bonderenko 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. 2012;30:2055-2062.
  7. US Food and Drug Administration. Drugs. Pac­litaxel (Abraxane). October 11, 2012. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm323668.htm. Accessed October 29, 2012.
  8. Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) [package insert]. Summit, NJ: Celgene Corporation; October 2012.
  9. Celgene Corporation. FDA approves ABRAXANE for the first-line treatment of advanced non-small cell lung cancer. October 12, 2012. http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=1744792&highlight=. Accessed October 29, 2012.
  10. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound pac­litaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12: 1317-1324.
  11. Green MR, Manikhas GM, Orlov S, et al. Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol. 2006;17:1263-1268.
  12. Taxol (paclitaxel) injection [package insert]. Prince­ton, NJ: Bristol-Myers Squibb Corporation; April 2011.
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