Randomized Phase II Trial of Concurrent Versus Sequential Bortezomib Plus Docetaxel in Advanced Non-Small-Cell Lung Cancer: A California Cancer Consortium Trial

• Authors: Primo N. Lara, University of California, Davis; Jeff Longmate, City of Hope National Medical Center; Karen Reckamp, City of Hope National Medical Center; Barbara Gitlitz, University of Southern California; Athanassios Argiris, University of Pittsburgh; Suresh Ramalingam, Emory University; Chandra P. Belani, Penn State Hershey Cancer Institute; Phillip C. Mack, University of California, Davis; Derick H. M. Lau, University of California, Davis; Mariana Koczywas, City of Hope National Medical Center; John J. Wright, National Cancer Institute; Frances A. Shepherd, University of Toronto; Natasha Leighl, University of Toronto; David R. Gandara, University of California, Davis
• Journal Title: Clinical Lung Cancer
• Volume: Volume 12, Number 1
• Publisher: Elsevier: 12 months | 2011-01-01, Pages 33-37
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.3816/CLC.2011.n.004
• Subjects: Health Sciences, Oncology; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Bortezomib; Docetaxel; Proteasome inhibition; PROTEASOME INHIBITOR BORTEZOMIB; SOLID TUMORS; PS-341; CHEMOTHERAPY; COMBINATION; APOPTOSIS; XENOGRAFTS; ARREST; MECHANISMS; THERAPY

Abstract

Background: The proteasome inhibitor bortezomib sensitizes tumor cells to chemotherapy-induced apoptosis. In preclinical non-small-cell lung cancer (NSCLC) models, p53-dependent growth arrest after bortezomib treatment resulted in reduced cytotoxicity if bortezomib preceded docetaxel. The reverse sequence of docetaxel before bortezomib was associated with increased apoptosis, cleavage of caspase-3 and PARP (poly [ADP-ribose] polymerase), and reduction in Bcl-2. A prospective randomized phase II trial of concurrent versus sequential docetaxel and bortezomib was conducted to assess whether administration sequence resulted in measurable clinical differences. Patients and Methods: Previously treated patients with advanced NSCLC were randomized to concurrent (CON) or sequential (SEQ) docetaxel (75 mg/m2 intravenous [I.V.]) followed by bortezomib, every 3 weeks. In the CON arm, bortezomib (1.6 mg/m2 I.V.) was given on days 1 and 8, and in the SEQ arm, it was given on days 2 and 8. Previous erlotinib as well as treated or controlled brain metastases were allowed. The primary endpoint was objective response rate (RR); progression-free (PFS) and overall survival (OS) were secondary endpoints. Results: Eighty-one patients were randomized (40 CON and 41 SEQ). Grade 3+ toxicities were mostly due to myelosuppression. One patient each had grade 4 hyponatremia and syncope. Toxicities were similar between the arms. There was 1 treatment-related death in the SEQ arm. There were 8 partial responders, 4 in each arm, for an overall RR of 10%. Disease control rate was similar in both arms (50% vs. 49%). Median PFS was 12 weeks in the CON arm and 11 weeks in the SEQ arm. Median OS times in the CON and SEQ arms were 13.3 and 10.5 months, respectively. Conclusion: Docetaxel plus bortezomib given sequentially or concurrently has similar RR and PFS. Median survival in the SEQ arm exceeds published survival estimates for either agent alone or in combination. Any further studies in this population would require molecular characterization of a phenotype most likely to benefit from proteasome inhibitor therapy.