Abraxane® (albumin-bound paclitaxel) - Injectable Treatment for Non–Small-Cell Lung Cancer

The FDA approved ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension)(albumin-bound) in October 2012 as first-line treatment for patients with locally advanced or metastatic non–small-cell lung cancer. The drug, marketed by Celgene Corporation, is an injectable used in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy.

In January 2005, the FDA approved albumin-bound paclitaxel to treat patients with metastatic breast cancer after they had failed combination chemotherapy or had relapsed within 6 months of adjuvant chemotherapy.

Patients with non–small-cell lung cancer are advised to take 100 mg/m² of albumin-bound paclitaxel administered intravenously for 30 minutes on days 1, 8, and 15 of each 21-day cycle. In addition, on day 1 of the 21-day cycle, they receive 6 mg/min/mL of carboplatin immediately after taking albumin-bound paclitaxel.

If patients have severe hematologic or neurological toxicities, they may have to reduce their dosage of albumin-based paclitaxel or stop taking the drug. Patients should also be aware of potential myelosuppression, sensory neuropathy, severe hypersensitivity reactions, and fetal harm when albumin-based paclitaxel is administered to pregnant women.

In a news release, Celgene defined non–small-cell lung cancer as any type of epithelial lung cancer other than small-cell lung carcinoma. There are 2 major types of non–small-cell lung cancer: (1) squamous cell carcinoma, which accounts for 25% to 30% of non–small-cell lung cancer cases, and (2) nonsquamous cell carcinoma, which accounts for the remaining 70% to 75% and is the most common type of lung cancer in the United States. Non–small-cell lung cancer is the leading cause of cancer death in the United States, with a 5-year survival rate of 1% for patients with stage IV disease.

The FDA approved albumin-bound paclitaxel based on the results of CA-031, a multicenter, open-label, randomized phase 3 trial. The study included 1052 patients with stage IIIB to IV non–small-cell lung cancer who had not received prior treatment. Celgene supported the study, and the authors included company employees and consultants.

This First Report Managed Care Product Spotlight provides a summary of the pivotal trial that tested albumin-bound paclitaxel safety and effectiveness.

PHASE 3 TRIAL

Below is a summary of a multicenter, open-label, randomized phase 3 trial that compared the safety and efficacy of albumin-bound paclitaxel plus carboplatin with solvent-based paclitaxel plus carboplatin.

Reference

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. doi:10.1200/JCO.2011.39.5848.

Study Objective

The trial was designed to compare the efficacy and safety of weekly albumin-bound paclitaxel plus carboplatin every 3 weeks with solvent-based paclitaxel plus carboplatin every 3 weeks in patients with advanced non–small-cell lung cancer.

Method

Patients were randomized in a 1:1 ratio to receive 100 mg/m² of albumin-bound paclitaxel administered via infusion for 30 minutes on days 1, 8, and 15 of a 21-day cycle followed by 6 mg/mL/min of carboplatin on day 1 of the 21-day cycle or 200 mg/m² of solvent-based paclitaxel administered via infusion for 3 hours every 3 weeks followed by 6 mg/mL/min of carboplatin given every 3 weeks.

The authors noted that solvent-based paclitaxel plus carboplatin is the most common taxane-platinum combination therapy used in the United States.

All patients had advanced non–small-cell lung cancer and took the treatment as first-line therapy. The authors randomized the patients by disease stage (IIIB vs IV), age (<70 years vs ≥70 years), sex, histology (squamous vs adenocarcinoma vs others), and geographic region (North America vs Russia/Ukraine vs Japan vs Australia).

The authors attempted to treat patients for at least 6 cycles, and the treatment could continue if the investigators determined there was an absence of progressive disease and unacceptable toxicity.

The primary end point of objective response rate was defined as confirmed complete response and/or partial response and was based on a blinded, centralized, independent, radiologic analysis. The authors performed spiral computed tomography scans every 6 weeks, and they were evaluated per RECIST (Response Evaluation Criteria In Solid Tumors) criteria from the screening period until the patients experienced disease progression.

Before entering the study, patients had to provide written informed consent. Independent ethics committees of participating medical institutions in Australia, Canada, Japan, Russia, Ukraine, and the United States approved the study.

Population

The authors enrolled 1052 patients between November 2007 and August 2009: 521 were randomly assigned to receive albumin-bound paclitaxel plus carboplatin and 531 were randomly assigned to receive solvent-based paclitaxel plus carboplatin.

The groups were well balanced. Median age was 60 years, 85% of patients were <70 years of age, 75% were males, 81% were white, 73% were smokers, and 79% had stage IV disease.

Patients were eligible if they were ≥18 years of age, had histologically/cytologically confirmed nonresectable stage IIIB or IV non–small-cell lung cancer measurable by RECIST criteria, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of >12 weeks. They also had not previously received treatment for metastatic disease and did not receive radiotherapy within 4 weeks of enrollment. They could receive adjuvant chemotherapy if it was completed 12 months before entering the study.

Exclusion criteria included untreated or symptomatic brain metastasis, grade ≥1 neuropathy as determined by National Cancer Institute criteria, or a history of allergy or hypersensitivity to the study drugs.

Primary end point

• Objective overall response rate (confirmed complete response and/or partial response)

Secondary end points

• Progression-free survival
• Overall survival
• Stable disease at ≥16 weeks
• Incidence of treatment-related adverse events

Results

The authors concluded that patients with advanced non–small-cell lung cancer who took albumin-bound paclitaxel plus carboplatin as first-line therapy had a significant improvement in objective overall response rate and fewer cases of neuropathy compared with those who received solvent-based paclitaxel plus carboplatin.

The objective overall response rate based on an independent radiological assessment was 33% in the albumin-bound paclitaxel group and 25% in the solvent-based paclitaxel group (response rate ratio [RRR], 1.313; 95% confidence interval [CI], 1.082 to 1.593; P=.005). No patient in the albumin-bound paclitaxel group had a complete response, but 170 had a partial response, while 1 patient in the solvent-based paclitaxel group achieved a complete response and 131 patients had a partial response.

The objective overall response rate based on the investigator’s assessment was 38% in the albumin-bound paclitaxel group and 30% in the solvent-based paclitaxel group (RRR, 1.274; 95% CI, 1.076 to 1.509; P=.005).

The independent radiological assessment also found 20% of patients in the albumin-bound paclitaxel group and 24% of patients in the solvent-based paclitaxel group had stable disease. Meanwhile, 16% of patients in each group had progressive disease.

For patients with squamous cell histology, the independent radiology assessment found that the objective overall response rate was 41% for those in the albumin-bound paclitaxel group and 24% for the solvent-based paclitaxel group (RRR, 1.680; 95% CI, 1.271 to 2.221; P<.001).

The difference in objective overall response rate was not statistically significant for patients with nonsquamous cell histology: 26% for those taking albumin-bound paclitaxel and 25% in the solvent-based paclitaxel group (RRR, 1.034; 95% CI, 0.788 to 1.358; P=.808).

Further, patients with adenocarcinoma who took albumin-bound paclitaxel had an objective overall response rate of 26% compared with 27% in the solvent-based paclitaxel group (P=.814). Patients with large-cell carcinoma had an objective overall response rate of 33% if they took albumin-bound paclitaxel and 15% if they took solvent-based paclitaxel, while patients with undifferentiated histology had an objective overall response rate of 24% if they took albumin-bound paclitaxel and 15% if they took solvent-based paclitaxel. Neither difference was statistically significant, according to the authors.

The median progression-free survival was 6.3 months in the albumin-bound paclitaxel group compared with 5.8 months in the solvent-based paclitaxel group (hazard ratio [HR], 0.902; 95% CI, 0.767 to 1.060; P=.214).

The median overall survival was 12.1 months in the albumin-bound paclitaxel group compared with 11.2 months in the solvent-based paclitaxel group (HR, 0.922; 95% CI, 0.797 to 1.066; P=.271).

The subgroup analyses found that for patients in North America, the median progression-free survival for patients in the albumin-bound paclitaxel group was 7.0 months compared with 5.4 months for patients in the solvent-based paclitaxel group, although the difference was not statistically significant (HR, 0.694). Also, among patients ≥70 years of age, the median progression-free survival in the albumin-bound paclitaxel group was 8.0 months compared with 6.8 months in the solvent-based paclitaxel group, although the difference was not statistically significant (HR, 0.687).

The overall survival for patients enrolled in North America was 12.7 months for those taking albumin-bound paclitaxel and 9.8 months for those taking solvent-based paclitaxel (HR, 0.622; P=.008).

Patients in the albumin-bound paclitaxel group had significantly fewer cases of sensory neuropathy, neutropenia, arthralgia, and myalgia compared with the solvent-based paclitaxel group (P<.05 in all comparisons). There were significantly fewer cases of thrombocytopenia and anemia in the solvent-based paclitaxel group (P<.05 in both comparisons).

The most common nonhematologic grade ≥3 treatment-related adverse events were fatigue, sensory neuropathy, anorexia, nausea, myalgia, and arthralgia. The most common hematologic grade ≥3 treatment-related adverse events were neutropenia, leucopenia, thrombocytopenia, and anemia.

The nonhematologic and hematologic treatment-related adverse events were similar during the first 6 cycles compared with the entire treatment period. There were 2 treatment-related deaths during the study, 1 in each group.

Of the patients taking albumin-bound paclitaxel, 53% received second-line therapy compared with 54% of patients in the solvent-based paclitaxel group. Among patients taking second-line therapy, the most common treatments were docetaxel (7%), pemetrexed (5%), erlotinib (4%), and gefitinib (3%). The median time from the end of study therapy to the start of second-line therapy was 31 days in the albumin-bound paclitaxel group and 33 days in the solvent-based paclitaxel group.

At the time of the data cutoff for the final analysis, all but 3 patients had discontinued treatment. The median number of cycles was 6.0 for both groups. The most common reasons for stopping treatment were progressive disease (52%), investigator discretion (18%), patient discretion (13%), and unacceptable toxicity without progressive disease (12%).

SAFETY NOTES

The product’s Prescribing Information warns that patients with baseline neutrophil counts <1500 cells/mm³ or platelet counts <100,000 cells/m³ should not take albumin-bound paclitaxel. All patients should have frequent peripheral blood cell counts to monitor the occurrence of bone marrow suppression.

Patients with moderate and severe hepatic impairment who receive albumin-bound paclitaxel may be at an increased risk of toxicities related to paclitaxel. Thus, patients with severe hepatic impairment should have their dose reduced to 50 mg/m², however, the dose can be increased to 75 mg/m² in subsequent cycles if patients tolerate the drug.

When handling albumin-bound paclitaxel, people are advised to use gloves because it is a cytoxic drug and potentially toxic. If the skin is exposed to albumin-bound paclitaxel, it could lead to tingling, burning, and redness. People are advised to immediately wash the affected area with soap and water.

The product’s labeling warns that patients taking albumin-bound paclitaxel may experience fetal harm, be at a risk of low blood cell counts, and experience persistent vomiting, diarrhea, dehydration, allergic reaction, cough, or breathing difficulties. The following adverse events occur frequently in patients taking the drug: sensory neuropathy, alopecia, fatigue/asthenia, and myalgia/arthralgia.

Before using albumin-bound paclitaxel, patients should tell their physician if they have liver or kidney problems, plan on fathering a child, are pregnant or plan on becoming pregnant, or are breastfeeding or planning on breastfeeding. They should also share information about the medicines they are taking, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Common side effects of albumin-bound paclitaxel include hair loss, numbness or tingling in the hands or feet, abnormal heart beat, tiredness, joint and muscle pain, changes in liver function tests, anemia, nausea, infections, and diarrhea.

Abraxane Facts

• Abraxane was approved by the FDA on October 12, 2012, to treat locally advanced or metastatic non–small-cell lung cancer in combination with carboplatin
• Abraxane is marketed by Celgene Corporation