On October 11, 2012, the U. S. Food and Drug Administration approved paclitaxel protein-bound particles for injectable suspension, albumin-bound (ABRAXANE for Injectable Suspension; Abraxis Bioscience a wholly owned subsidiary of Celgene Corporation) 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.
This approval for the first-line treatment of locally advanced or metastatic NSCLC was granted under the provisions of 505(b)(2) of the Food, Drug, and Cosmetic Act. FDA relied on the prior approval of Taxol (paclitaxel) Injection for this indication supported by an additional trial establishing that ABRAXANE was as at least as active (as determined by overall response rate) as paclitaxel when both agents are used in combination with carboplatin.
This additional trial (Protocol CA031) was a randomized, open-label, multi-national trial that enrolled 1052 patients with locally advanced or metastatic NSCLC. Patients were randomized to receive ABRAXANE at a dose of 100 mg/m2 as a weekly infusion (n=521) or paclitaxel injection at a dose of 200 mg/m2 as an intravenous infusion every three weeks (n=531). Patients in both treatment arms also received carboplatin at the same dose and schedule (AUC 6 mg•min/mL) every 3 weeks. All patients receiving paclitaxel were required to be premedicated with corticosteroids and an antihistamine, while those in the ABRAXANE arm received premedication at the investigator’s discretion.
The primary efficacy objective was to demonstrate that patients receiving ABRAXANE plus carboplatin had a significantly higher overall response rate (ORR) with no evidence of a significant impairment in overall survival compared to those receiving paclitaxel plus carboplatin. The primary endpoint of ORR, defined as percentage of patients who achieved a durable complete or partial response, was determined by a radiological review committee masked to treatment assignment.
The CA031 trial met its primary end-point demonstrating a statistically significantly higher overall response rate for patients in the ABRAXANE -containing arm of 33% (95% CI: 29, 37) compared to 25% (95% CI: 21, 28) for patients in the paclitaxel-containing arm (p = 0.005, chi square test). The absolute increase was in ORR was 8% (95% CI: 2, 8). The durability of responses was similar for responding patients in the two treatment groups, with median response durations of 6.9 and 6.0 months for the ABRAXANE and paclitaxel arms, respectively. There was no statistically significant difference in overall survival between the two treatment arms.
Safety was evaluated in 1038 patients who received at least one dose of planned treatment. The most common (≥ 10% incidence) grade 1-4 adverse drug reactions reported in the ABRAXANE -containing arm included anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, fatigue, decreased appetite, asthenia, constipation, diarrhea, arthralgia, vomiting, dyspnea, peripheral edema, rash, and myalgia. The most common (≥ 5%) grade 3-4 adverse reactions were neutropenia, anemia, and thrombocytopenia.
Serious adverse reactions occurred in 18% of patients in both treatment arms. The most common serious adverse reactions in the ABRAXANE -containing arm were anemia (4%) and thrombocytopenia (3%).
The recommended dose and schedule for initial treatment of patients with locally advanced or metastatic NSCLC is ABRAXANE,100 mg/m2 administered as an intravenous 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 of each 21-day cycle following the completion of ABRAXANE infusion.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and 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) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).