Stromal Caveolin-1 Is Associated With Response and Survival in a Phase II Trial of nab-Paclitaxel With Carboplatin for Advanced NSCLC Patients

Abstract

In this phase II trial, carboplatin with nanoparticle albumin-bound (nab)-paclitaxel as first-line therapy for advanced non-small-cell lung cancer (NSCLC) was evaluated. Most patients had squamous cell histology. Tumor-associated stromal caveolin-1 (Cav-1) expression was correlated with improved response rate and survival in NSCLC patients who received nab-paclitaxel in this phase II trial. These results suggest Cav-1 might serve as a potential biomarker in this patient population.

Background: The combination of bevacizumab with platinum-based chemotherapy results in greater response rate (RR) and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). Bevacizumab is contraindicated in patients with squamous histology or hemoptysis. Nanoparticle albumin-bound (nab)-paclitaxel is a novel formulation of paclitaxel with greater dose tolerance and improved efficacy. We hypothesized that nab-paclitaxel and carboplatin would be superior to alternative doublets in advanced NSCLC patients ineligible for bevacizumab.

Patients and methods: We conducted a single-arm phase II trial (NCT00729612) with carboplatin and nab-paclitaxel on day 1 of a 21-day cycle to evaluate RR (primary end point), safety, toxicity, and OS. Eligibility included: squamous histology, hemoptysis, or ongoing anticoagulation. Correlative studies included immunohistochemistry for secreted protein acid rich in cysteine (SPARC) and caveolin-1 (Cav-1).

Results: Sixty-three patients were enrolled. Most patients had squamous cell carcinoma (n = 48); other reasons for eligibility included hemoptysis (n = 11) and anticoagulation (n = 2). Toxicity Grade ≥ 3/4 included neuropathy, cytopenias, and fatigue. RR was 38% (24 partial response/0 complete response); 20 patients had stable disease (32%). Median progression-free survival was 5 months and median OS was 9.7 months. Immunohistochemistry for SPARC and Cav-1 was performed in 38 and 37 patients respectively. Although no association was found for SPARC expression in tumor or stroma with RR or OS, we found that higher Cav-1 levels in tumor-associated stroma was associated with improved RR and OS.

Conclusion: Carboplatin and nab-paclitaxel every 21 days demonstrated promising efficacy with tolerable toxicity in NSCLC patients ineligible for bevacizumab therapy. Further analysis and validation of Cav-1 and SPARC expression in tumor and stromal compartments as prognostic and/or predictive biomarkers of NSCLC or nab-paclitaxel treatment is warranted.

Keywords: Caveolin-1; Clinical Trial; SPARC; Sensory neuropathy; nab-paclitaxel.

Conflict of interest statement

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

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1

Patient Enrollment and Responses

Figure 2

Kaplan–Meier Plots of (A) Progression-Free Survival (PFS) and (B) Overall Survival

Figure 3

(A) Kaplan–Meier Plot Demonstrating That Patients With Higher Cav-1 Expression in the Stroma (n = 18) Had Improved Overall Survival Compared With Patients With Low Cav-1 Expression in Stromal Tissue (n = 15) (Log-Rank P = .008). (B) Representative Immunohistochemistry Images for a Patient Whose Tumor Exhibited High Intensity (3) Tumor Staining for Cav-1 but Virtually Absent Stromal Staining (0) (Left Panel), and Another Patient With Low Tumor Cav-1 Staining Intensity (0), but High Stromal Staining (3) (Right Panel)