Original study
Paclitaxel-Loaded Polymeric Micelle (230 mg/m2) and Cisplatin (60 mg/m2) vs. Paclitaxel (175 mg/m2) and Cisplatin (60 mg/m2) in Advanced Non–Small-Cell Lung Cancer: A Multicenter Randomized Phase IIB Trial

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Abstract

Introduction

The development of paclitaxel-loaded polymeric micelle (PPM) has circumvented many of the infusion-related difficulties associated with standard solvent-based paclitaxel. PPM plus cisplatin combination chemotherapy showed significant antitumor activity in phase I and II studies. This prospective randomized controlled phase IIB study assessed the noninferiority of the efficacy and tolerability of high-dose PPM plus cisplatin to a standard dose of paclitaxel plus cisplatin.

Patients and Methods

Patients with stage IIIB/IV or recurrent non–small-cell lung cancer (NSCLC) who were chemonaive were eligible for participation. The patients were randomly assigned to receive PPM 230 mg/m2 plus cisplatin 60 mg/m2 or paclitaxel 175 mg/m2 plus cisplatin 60 mg/m2 once every 3-week cycle. The primary endpoint was to compare the response rate (RR) between the groups with coprimary analyses to assess noninferiority. Secondary endpoints included progression-free survival, overall survival, and safety.

Results

A total of 276 patients were randomized to PPM plus cisplatin (n = 140) or paclitaxel plus cisplatin (n = 136). RR was 43.6% in the PPM plus cisplatin group and 41.9% in the paclitaxel plus cisplatin group. Noninferiority of PPM plus cisplatin compared with paclitaxel plus cisplatin was confirmed for RR. There were no differences in progression-free survival and overall survival between the groups. Although there was a higher rate of grade 3 neutropenia in the PPM plus cisplatin group, the overall rate of adverse events was comparable between the 2 groups.

Conclusion

PPM in combination with cisplatin was well tolerated, and its response rate was noninferior to that of paclitaxel plus cisplatin in patients with advanced NSCLC and who were chemonaive.

Introduction

Non–small-cell lung cancer (NSCLC) is a major cause of death due to cancer.1 The use of cytotoxic chemotherapy is associated with a response rate (RR) of 20% to 35% and a median survival time of 10 to 12 months among patients with advanced NSCLC.2 Given the safety and efficacy limitations of current therapeutic options, however, new chemotherapeutic agents and combination regimens are needed to further ameliorate symptoms and increase antitumor activity in a manner that is both convenient and safe in patients with advanced NSCLC. Paclitaxel is one of the most commonly used agents in combination with platinum for the treatment of advanced NSCLC. However, paclitaxel is highly hydrophobic, and the lipid-based solvent (Cremophor EL [CrEL]) is used as a vehicle. Given that CrEL causes leaching of the plasticizers from standard intravenous tubing and that it is also associated with hypersensitivity reactions, administration of solvent-based paclitaxel requires a long infusion period, the use of special nonpolyvinyl chloride infusion systems, and premedication with corticosteroids, diphenhydramine, and an H2 histamine receptor antagonist.3, 4 Novel formulations have been developed to improve the efficacy and to decrease the toxicity associated with CrEL-paclitaxel formulation.5, 6, 7

Paclitaxel-loaded polymeric micelle (PPM) (Genexol-PM; Samyang Co, Seoul, Korea) is a novel formulation of paclitaxel, a sterile lyophilized polymeric micellar formulation without CrEL. A phase I study of PPM, administered intravenously for 3 hours every 3 weeks, established a maximum tolerated dose of 390 mg/m2, which is higher than the maximum tolerated dose for paclitaxel with the 3-week regimen.8 In the phase II study, PPM (230 mg/m2) plus cisplatin in patients with advanced NSCLC revealed significant antitumor activity.9 In brief, 69 patients were enrolled. The overall RR was 37.7%, and the median time to progression was 5.8 months. However, there were unexpected grade 3/4 hypersensitivity reactions in 2 of the initial 15 patients.9 After those events, premedication to prevent hypersensitivity was recommended. We then conducted a phase IIB study that compared PPM (230 mg/m2) plus cisplatin with paclitaxel (175 mg/m2) plus cisplatin in patients who had advanced NSCLC and who were chemonaive.

Section snippets

Patients

Eligible patients were ages 18 years or older, had histologically or cytologically confirmed advanced (stage IIIB with malignant pleural or pericardial effusion or stage IV) or recurrent NSCLC after surgical treatment, had an Eastern Cooperative Oncology Group performance status 0 to 2, had measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors),10 had no previous chemotherapy, had an absolute neutrophil count higher than 1.5 × 103/μL,3 and had adequate hepatic function.

Patient Characteristics

Patient characteristics are listed in Table 1. Between June 2008 and December 2009, 294 patients were screened for eligibility and entry into this trial at 18 investigative sites, and 276 patients were randomly assigned to 1 of 2 treatments: PPM plus cisplatin or paclitaxel plus cisplatin (Figure 1). Within the overall patient population, 139 (50.4%) patients had adenocarcinoma, 111 (40.2%) had squamous cell carcinoma, 5 (1.8%) had large cell carcinoma, and 21 (7.6%) had another histologic

Toxicities

All the patients who were randomly assigned and had received at least 1 dose of trial treatment (safety population) were included in the safety analysis. The majority of AEs reported during the study were graded 1 or 2. Grade 3 or 4 toxicity by treatment group for the safety population is summarized in Table 5. The overall incidence of AEs of grade ≥3 was similar for both groups. Although the rate of grade ≥3 neutropenia was higher in the PPM plus cisplatin group than in the paclitaxel plus

Discussion

We compared the efficacy of a new paclitaxel formulation to that of CrEL-paclitaxel and evaluated the toxicity profiles under increased paclitaxel dose (230 mg/m2) in patients with advanced NSCLC who were chemonaive. This trial demonstrated that the PPM plus cisplatin regimen had a noninferior overall RR to the paclitaxel plus cisplatin regimen in advanced NSCLS and a similar PFS and OS. The toxicity profiles of the treatment combinations were similar between the 2 groups and chemotherapy dose

Conclusion

PPM administered at 230 mg/m2 in combination with cisplatin in a 3-week cycle was found to be well tolerated, and this regimen had a noninferior efficacy to that of conventional paclitaxel plus cisplatin in advanced NSCLC. In particular, patients with squamous cell lung cancer had better RRs than those with other cell types. Therefore, PPM should be further studied in combination with platinum agents as first-line treatments for patients with squamous cell histology.

Disclosure

The authors have stated that they have no conflicts of interest.

Acknowledgments

We thank the patients, investigators, and institutions involved in this study. This study was sponsored by CJ Pharmaceuticals, South Korea. The following institutions participated in this study: Chungnam National University Hospital and Cancer Institute (Sun Yong Kim, MD, Hee Sun Park, MD), Konkuk University Medical Center (Kye Young Lee, MD, Hee Joung Kim, MD), Keimyung University Dongsan Medical Center (Young June Jeon, MD, Chi Young Jung, MD), Korea University Medical Center (Ki Hwan Jung,

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