A Dose Finding Study of Weekly and Every-3-Week nab-Paclitaxel Followed by Carboplatin as First-Line Therapy in Patients with Advanced Non-small Cell Lung Cancer

Abstract

Introduction: This nonrandomized study aimed to identify the optimal dose of every-3-week (q3w) and weekly nab-paclitaxel plus q3w carboplatin as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) for a phase 3 trial. Methods: Previously untreated patients with advanced NSCLC enrolled sequentially into seven cohorts (25 patients/cohort, N ϭ 175). Cohorts 1 to 4 and 5 to 7 received nab-paclitaxel q3w and weekly, respectively. Patients were evaluated for efficacy and safety. Results:The most common treatment-related Ն grade 3 adverse events were neutropenia (60%), neuropathy (19%), fatigue (9%), and thrombocytopenia (29%) (no grade 4 neuropathy or fatigue). A 100 mg/m 2 weekly nab-paclitaxel produced less serious adverse events than other doses/schedules. Response rate (RR) was greater in the weekly versus q3w cohorts (47% vs. 30%). Median progression-free survival (PFS) ranged from 4.8 to 6.9 months, and overall survival (OS) ranged from 8.3 to 15.0 months (all cohorts). Patients receiving 100 mg/m 2 weekly nab-paclitaxel achieved 48% RR with 6.2 and 11.3 months of PFS and OS, respectively. In a retrospective analysis, patients with nonsquamous cell carcinoma receiving weekly nab-paclitaxel had significantly improved RR (59.4% vs. 23.5%, respectively, p ϭ 0.003), and Ͼ2 months longer PFS and OS compared with q3w schedule. In patients with squamous cell carcinoma, the q3w schedule significantly increased PFS by 3 months (p ϭ 0.014) and OS by Ͼ2 months (no difference in RR) compared with the weekly schedule. Conclusion:nab-Paclitaxel plus carboplatin is an effective therapy for advanced NSCLC. Based on favorable efficacy and safety profiles, a phase 3, randomized, multicenter study comparing 100 mg/m 2 weekly nab-paclitaxel plus q3w carboplatin to solvent-based paclitaxel plus carboplatin has enrolled patients.

First line treatment of advanced non-small-cell lung cancer – specific focus on albumin bound paclitaxel

“…60 No substantial pharmacokinetic interactions were noticed in the study with the combination. Among the 18 evaluable patients, ORR of 38.9% was reported with toxicity profile similar to the ones reported by Socinski et al 59 A combination of nab-paclitaxel 300 mg/m 2 , carboplatin AUC 6, and bevacizumab 15 mg/kg every 21 days was investigated in a Phase II setting by Reynolds et al as front line treatment of advanced (stage IIIB, IV) non-squamous NSCLC. 61 This study enrolled a total of 50 patients and a response rate of 31% and stable disease rate of 54%.…”

“…Febrile neutropenia rate of 10% was also higher than the 5% reported in carboplatin/sb-paclitaxel/ bevacizumab group in Eastern Cooperative Oncology Group 4599 (ECOG 4599) study, 62 and 0% in carboplatin/nab-paclitaxel in Socinski's Phase I study. Somewhat counterintuitively, the incidence of grade 3 or 4 peripheral neuropathy or thrombocytopenia was only 4% and 10%, respectively, much lower in comparison to the corresponding non-bevacizumab cohort reported by Socinski et al 59 treated with otherwise the same dose schedule (see Table 2). Specific outcomes in the elderly population were not reported in this study wherein median age of participants was 67 years.…”

“…Socinski et al also conducted a dose-finding study of the combination of nab-paclitaxel with carboplatin prior to evaluation in the Phase III trial setting. 59 The Phase I study enrolled 175 patients in the study sequentially into seven cohorts, each cohort consisting of seven patients. Cohorts one to four received q3-weekly (administered once every 3 weeks) nab-paclitaxel whereas cohorts five to seven received once weekly nab-paclitaxel.…”

Update on Taxanes in the First-Line Treatment of Advanced Non-Small-Cell Lung Cancer

“…In several trials, nab-paclitaxel-carboplatin demonstrated antitumour activity 12,50,51 . A phase i/ii study of nab-paclitaxel-carboplatin identified the maximum tolerated dose of single-agent nab-paclitaxel as 125 mg/m 2 administered in the first 3 weeks of a 4-week cycle 51 .…”

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“…More recently, a phase III clinical trial on MBC patients was conducted where 260 mg/ m 2 nap-paclitaxel was applied every week compared to 175 mg/ m 2 of paclitaxel every 3 week, and was found to show significant improvement in outcomes including overall response rate (ORR), time of tumor progression (TTP) and progression free survival (PFS) [11,53]. According to this data, nab-paclitaxel dose of 260 mg/ m 2 every 3 week has obtained an approval for use in MBC in more than 40 countries [54,55]. Furthermore, nab-paclitaxel has been shown to reduce drug exposure to healthy tissue [43].…”