Randomized phase II trial of concurrent versus sequential bortezomib plus docetaxel in advanced non-small-cell lung cancer

A california cancer consortium trial

Primo N. Lara, Jeff Longmate, Karen Reckamp, Barbara Gitlitz, Athanassios Argiris, Suresh Ramalingam, Chandra Belani, Philip C. Mack, Derick H.M. Lau, Mariana Koczywas, John J. Wright, Frances A. Shepherd, Natasha Leighl, David R. Gandara

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)33-37
Number of pages5
JournalClinical Lung Cancer
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2011

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docetaxel
Non-Small Cell Lung Carcinoma
Neoplasms
Proteasome Inhibitors
Survival
Apoptosis
Poly(ADP-ribose) Polymerases
Bortezomib
Hyponatremia
Syncope
Caspase 3

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Lara, Primo N. ; Longmate, Jeff ; Reckamp, Karen ; Gitlitz, Barbara ; Argiris, Athanassios ; Ramalingam, Suresh ; Belani, Chandra ; Mack, Philip C. ; Lau, Derick H.M. ; Koczywas, Mariana ; Wright, John J. ; Shepherd, Frances A. ; Leighl, Natasha ; Gandara, David R. / Randomized phase II trial of concurrent versus sequential bortezomib plus docetaxel in advanced non-small-cell lung cancer : A california cancer consortium trial. In: Clinical Lung Cancer. 2011 ; Vol. 12, No. 1. pp. 33-37.
@article{50614312f654423596d37f16a9cda95c,
title = "Randomized phase II trial of concurrent versus sequential bortezomib plus docetaxel in advanced non-small-cell lung cancer: A california cancer consortium trial",
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.",
author = "Lara, {Primo N.} and Jeff Longmate and Karen Reckamp and Barbara Gitlitz and Athanassios Argiris and Suresh Ramalingam and Chandra Belani and Mack, {Philip C.} and Lau, {Derick H.M.} and Mariana Koczywas and Wright, {John J.} and Shepherd, {Frances A.} and Natasha Leighl and Gandara, {David R.}",
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Lara, PN, Longmate, J, Reckamp, K, Gitlitz, B, Argiris, A, Ramalingam, S, Belani, C, Mack, PC, Lau, DHM, Koczywas, M, Wright, JJ, Shepherd, FA, Leighl, N & Gandara, DR 2011, 'Randomized phase II trial of concurrent versus sequential bortezomib plus docetaxel in advanced non-small-cell lung cancer: A california cancer consortium trial', Clinical Lung Cancer, vol. 12, no. 1, pp. 33-37. https://doi.org/10.3816/CLC.2011.n.004

Randomized phase II trial of concurrent versus sequential bortezomib plus docetaxel in advanced non-small-cell lung cancer : A california cancer consortium trial. / Lara, Primo N.; Longmate, Jeff; Reckamp, Karen; Gitlitz, Barbara; Argiris, Athanassios; Ramalingam, Suresh; Belani, Chandra; Mack, Philip C.; Lau, Derick H.M.; Koczywas, Mariana; Wright, John J.; Shepherd, Frances A.; Leighl, Natasha; Gandara, David R.

In: Clinical Lung Cancer, Vol. 12, No. 1, 01.01.2011, p. 33-37.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Randomized phase II trial of concurrent versus sequential bortezomib plus docetaxel in advanced non-small-cell lung cancer

T2 - A california cancer consortium trial

AU - Lara, Primo N.

AU - Longmate, Jeff

AU - Reckamp, Karen

AU - Gitlitz, Barbara

AU - Argiris, Athanassios

AU - Ramalingam, Suresh

AU - Belani, Chandra

AU - Mack, Philip C.

AU - Lau, Derick H.M.

AU - Koczywas, Mariana

AU - Wright, John J.

AU - Shepherd, Frances A.

AU - Leighl, Natasha

AU - Gandara, David R.

PY - 2011/1/1

Y1 - 2011/1/1

N2 - 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.

AB - 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.

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