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Randomized Phase II Study of Bortezomib Alone and Bortezomib in Combination With Docetaxel in Previously Treated Advanced Non–Small-Cell Lung Cancer

Michael P. Fanucchi, Frank V. Fossella, Robert Belt, Ronald Natale, Panos Fidias, David P. Carbone, Ramaswamy Govindan, Luis E. Raez, Francisco Robert, Maria Ribeiro, Wallace Akerley, Karen Kelly, Steven A. Limentani, Jeffrey Crawford, Hans-Joachim Reimers, Rita Axelrod, Oscar Kashala, Shihong Sheng, Joan H. Schiller

From the Winship Cancer Institute, Emory University School of Medicine, Atlanta; Atlanta Veterans Affairs Medical Center, Decatur, GA; University of Texas M.D. Anderson Cancer Center, Department of Thoracic/Head and Neck Medical Oncology, Houston; University of Texas Southwestern, Dallas, TX; Kansas City Oncology Hematology Group, DBA Kansas City Cancer Centers, Kansas City; Washington University, Medical Oncology, Barnard Cancer Center; St Louis University Health Sciences Center, St Louis, MO; Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA; Massachusetts General Hospital, Boston; Millennium Pharmaceuticals Inc, Cambridge, MA; Vanderbilt University-Clinical Trials Center, Nashville, TN; Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; University of Colorado Health Sciences Center, Aurora, CO; Carolinas Hematology-Oncology Associates, Blumenthal Cancer Center, Charlotte; Duke University Medical Center, Durham, NC; and Kimmel Cancer Center at Jefferson, Philadelphia, PA

Address reprint requests to Joan H. Schiller, MD, University of Texas Southwestern, Division of Hematology/Oncology, 5323 Harry Hines Blvd, Dallas, TX 75390-8852; e-mail: joan.schiller{at}utsouthwestern.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Purpose To evaluate the efficacy and toxicity of bortezomib ± docetaxel as second-line therapy in patients with relapsed or refractory advanced non–small-cell lung cancer (NSCLC).

Patients and Methods Patients were randomly assigned to bortezomib 1.5 mg/m² (arm A) or bortezomib 1.3 mg/m² plus docetaxel 75 mg/m² (arm B). A treatment cycle of 21 days comprised four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, docetaxel on day 1. Patients could receive unlimited cycles. The primary end point was response rate.

Results A total of 155 patients were treated, 75 in arm A and 80 in arm B. Baseline characteristics were comparable. Investigator-assessed response rates were 8% in arm A and 9% in arm B. Disease control rates were 29% in arm A and 54% in arm B. Median time to progression was 1.5 months in arm A and 4.0 months in arm B. One-year survival was 39% and 33%, and median survival was 7.4 and 7.8 months in arms A and B, respectively. Adverse effect profiles were as expected in both arms, with no significant additivity. The most common grade 3 adverse events were neutropenia, fatigue, and dyspnea (4% and 53%, 19% and 26%, and 17% and 14% of patients in arms A and B, respectively).

Conclusion Bortezomib has modest single-agent activity in patients with relapsed or refractory advanced NSCLC using this schedule, with minor enhancement in combination with docetaxel. Additional investigation of bortezomib in NSCLC is warranted in combination with other drugs known to be active, or using different schedules.

	INTRODUCTION

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Lung cancer is a major public health problem worldwide. It is the leading cause of cancer-related death in the United States and Europe,^1,2 and 172,570 people in the United States were estimated to develop cancer of the lung and bronchus in 2005.¹ The 5-year survival rate remains low at 15%.¹ Non–small-cell lung cancer (NSCLC) accounts for 75% to 85% of lung cancers.^3-5 The majority of NSCLC patients present with advanced, unresectable disease (stage IIIB/IV), which remains incurable.⁶ First-line treatment of advanced NSCLC has improved substantially during the last 10 years with the approval of vinorelbine, gemcitabine, paclitaxel, and docetaxel; doublet chemotherapy with one of these agents plus cisplatin or carboplatin is now the standard of care.^7-10 Recently, data from a phase III trial have shown that addition of the anti–vascular endothelial growth factor monoclonal antibody bevacizumab to paclitaxel plus carboplatin extended survival in patients with advanced nonsquamous NSCLC.¹¹ In second-line treatment, docetaxel is one of the standards of care,^12,13 and has shown superiority to best supportive care in terms of survival and quality of life^14,15 and better time to progression (TTP) and progression-free survival (PFS) than vinorelbine or ifosfamide.³ The antifolate pemetrexed was approved recently by the US Food and Drug Administration for second-line treatment of advanced NSCLC, after a phase III trial demonstrating overall survival comparable to docetaxel.^16,17 The epidermal growth factor receptor–tyrosine kinase inhibitor, erlotinib, also recently gained US Food and Drug Administration approval after it was shown to produce superior survival compared with placebo in the salvage setting.¹⁸

Bortezomib (VELCADE; Millennium Pharmaceuticals Inc, Cambridge, MA, and Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ) is the first proteasome inhibitor to be approved and investigated in clinical trials. It is approved in the United States and Europe for treating multiple myeloma patients who have received at least one prior therapy, after phase II and III studies,^19-21 and is being investigated in other hematologic malignancies^22,23 and solid tumors.^24-28 Proteasome inhibition affects the ubiquitin-proteasome pathway, disrupting protein homeostasis and resulting in cell-cycle disruption, inhibition of transcription factors such as nuclear factor kappa-B, and antiangiogenic effects, which ultimately affect tumor growth and proliferation, and result in apoptosis.^6,29,30

Bortezomib has a novel cytotoxicity profile in National Cancer Institute (NCI) in vitro and in vivo assays,³¹ and has demonstrated preclinical activity in NSCLC tumor cell lines as a single agent^32-35 and in combination with other chemotherapy agents.^34,36-38 Bortezomib plus docetaxel has demonstrated enhanced cytotoxic activity in preclinical studies in NSCLC^30,39,40 and other solid tumors.^41,42 Phase I and II studies of bortezomib alone^24,27,43 and bortezomib plus docetaxel^44,45 have indicated antitumor activity in solid tumors, and the regimens generally were well tolerated. These observations provided the rationale for this phase II study, which was carried out to determine the efficacy and safety of bortezomib alone and bortezomib plus standard-dose docetaxel as second-line therapy in locally advanced and metastatic NSCLC patients.

	PATIENTS AND METHODS

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Patients
Institutional review boards at each study center approved the study; all patients provided written informed consent before undergoing any study-related procedures. Patients with histologically/cytologically confirmed inoperable, locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, who had received one prior chemotherapy regimen for locally advanced or metastatic disease, were enrolled subject to these main inclusion criteria: age 18 years, measurable disease, Karnofsky performance status 70%, and life expectancy more than 3 months. Patients were excluded if they had previously received bortezomib or docetaxel; had grade 2 peripheral neuropathy, as defined by NCI Common Toxicity Criteria Version 2.0; received chemotherapy, radiation therapy, or major surgery within 4 weeks before enrollment; received monoclonal antibodies within 6 weeks before enrollment; had inadequate hematologic, renal, or hepatic end-organ function; or had uncontrolled brain metastases or CNS disease.

Study Design
This randomized, open-label, phase II study was conducted at 20 centers in the United States. A two-stage study design was chosen to allow an interim analysis after 40% of the estimated total number of patients in each arm had had the opportunity to complete four treatment cycles. This allowed the option of stopping either arm or the entire study early if treatments showed insufficient efficacy. In the first stage, patients were randomly assigned in a 15:16 ratio to arm A (bortezomib alone) or arm B (bortezomib plus docetaxel). After criteria were met for continuing both arms at the interim analysis, enrollment continued using this randomization scheme.

In both treatment arms, a treatment cycle was 21 days long and comprised four bortezomib injections (3- to 5-second intravenous push) on days 1, 4, 8, and 11, followed by a 10-day rest period. Bortezomib dosing was 1.5 mg/m² in arm A and 1.3 mg/m² in arm B, selected based on the findings of phase I studies of bortezomib or bortezomib plus docetaxel in solid tumors.^24,44,45 Arm B patients also received docetaxel 75 mg/m² (1-hour infusion) on day 1 of each cycle, completed 1 hour before bortezomib administration, plus dexamethasone prophylaxis (six 8-mg doses administered orally during 3 days, commencing the night before planned docetaxel infusion). This dose of docetaxel has been shown to produce response rates of 5.5% to 8.8% in NSCLC.^3,14,17 In both treatment arms, toxicities were managed using dose modifications and delays when necessary. Provided that treatment was well tolerated, patients could undergo an unlimited number of cycles until disease progression, complete response (CR), occurrence of an unacceptable adverse event (AE), death, or the meeting of any criterion for withdrawal from treatment. Following confirmation of a CR, patients were to remain on treatment for two additional cycles.

Efficacy, Safety, and Other Measurements
The primary objective was to assess tumor response rates according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. The secondary objectives were to establish TTP, determine overall and 1-year survival, and assess safety and tolerability in both treatment arms; evaluate pharmacokinetic and pharmacodynamic profiles of bortezomib and docetaxel in combination therapy; and conduct pharmacogenomic hypothesis-generating analyses. However, insufficient data were collected for planned pharmacokinetic and pharmacodynamic evaluations (84 samples for five patients and 40 samples for five patients, respectively). Similarly, insufficient samples were collected for pharmacogenomic analyses.

Patients were evaluated at scheduled visits during screening, treatment, and long-term follow-up. At screening, a complete medical history, including chest x-ray and ECG, was obtained; a physical examination was conducted; laboratory samples were collected for hematology, clinical chemistry, and urinalysis; and target and nontarget lesions were identified and measured by computed tomography scan or magnetic resonance imaging. During treatment, assessments were conducted at twice-weekly visits (days 1, 4, 8, and 11) during the first 6 weeks, then weekly (days 1 and 8) until the end of treatment. Safety and efficacy evaluations conducted during treatment included symptom-directed physical examinations, Karnofsky performance status determination, and laboratory analyses. All AEs were documented; toxicities were graded according to NCI Common Toxicity Criteria Version 2.0. Every 6 weeks, patients’ target and nontarget lesions were assessed radiographically at the study site and objective overall tumor response was assessed using RECIST guidelines. In addition, scans from patients identified by investigators as having a response were reviewed at a central contract research organization. It was not intended for an independent radiologist to review all scans. After withdrawal from treatment, patients were observed for disease and survival assessment every 3 months until death. Patients who withdrew before disease progression were observed every 6 weeks, when possible, until disease progression, and then every 3 months until death.

Statistical Methods
Efficacy analyses were performed based on all patients who were randomly assigned and received at least one dose of study drug. This study was not powered to demonstrate efficacy differences between treatment groups but rather to estimate response rates within treatment groups. The study was noncomparative; statistical analysis of differences between arms was not performed. The primary end point was response rate, with responders defined as any patients with at least partial response (PR) according to RECIST guidelines. Secondary end points included time to response, TTP, survival, and safety. Time-to-event variables were analyzed based on Kaplan-Meier estimates. Safety analyses were performed based on all patients who received at least one dose of any study drug. A two-stage design for each treatment arm was chosen to derive the sample size, to allow for interim analyses to assess efficacy for early termination. To detect at least a 5% response rate in arm A and at least a 10% response rate in arm B, a null hypothesis of a response rate of 5%, and an alternative hypothesis of a response rate of 12% for arm A, and a null hypothesis of a response rate of 10% and an alternative hypothesis of a response rate of 20% for arm B were tested under the two-stage design. Sample size of a total of 155 patients, 75 in arm A and 80 in arm B, was determined. At the interim analysis, each treatment arm was concluded ineffective and stopped if no more than one investigator-assessed response was observed among the first 30 enrolled patients in arm A or no more than two responses were observed among the first 32 enrolled patients in arm B. The safety profile was also taken into consideration regarding continuation of each arm. The interim analysis met predetermined efficacy and safety criteria; therefore, patient accrual continued in both arms.⁴⁶

	RESULTS

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Patient Demographics and Disposition
Of 158 randomly assigned patients, 155 received at least one dose of study drug; 75 in arm A and 80 in arm B. The two treatment arms were comparable with respect to patient and disease characteristics, number and type of prior therapies, and best response to last prior chemotherapy (Table 1). All patients had received one prior line of chemotherapy for locally advanced or metastatic disease except one patient in arm A, who had received only gefitinib before study entry. This patient was not among those responding to treatment. Exposure to bortezomib and reasons for study termination were comparable between treatment arms (Table 2). Figure 1 shows exposure to treatment in both arms. Bortezomib dose reductions and interruptions were more common in arm B (31% and 70%, respectively) than arm A (9% and 51%, respectively).

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Patient disposition by number of treatment cycles completed.

Median TTP, duration of response, duration of disease control, survival, and PFS are listed in Table 3. Kaplan-Meier TTP and survival curves are shown in Figure 2. In an analysis in which subsequent treatment was censored, no changes in survival were seen. At last available follow-up, 80% of patients in arm A and 68% of patients in arm B had PD.

View larger version (26K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier (A) time to progression (TTP) and (B) survival curves, by treatment arm (intent-to-treat population, n = 155).

View this table: [in this window] [in a new window]   Table 4. Most Commonly Reported Drug-Related Adverse Events in 20% of Total Patients, by Treatment Arm

View this table: [in this window] [in a new window]   Table 5. Most Commonly Reported Grade 3/4 Adverse Events in 5% of All Patients, by Grade and by Treatment Arm

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The results of this randomized, multicenter clinical trial indicate that bortezomib monotherapy has modest activity in relapsed or refractory advanced NSCLC, with an overall investigator-assessed response rate of 8%. Despite limited patient exposure (median, two cycles), this is comparable with single-agent response rates reported for other agents in second-line advanced NSCLC. Fossella et al³ and Shepherd et al^14,40 reported response rates of 6.7% and 5.5%, respectively, in phase III studies of docetaxel 75 mg/m², and in another phase III study, Hanna et al¹⁷ reported response rates of 9.1% and 8.8% for pemetrexed 500 mg/m² and docetaxel 75 mg/m², respectively. Our results are also comparable with the 8.9% response rate reported by Shepherd et al¹⁸ for erlotinib 150 mg in a phase III study in second- and third-line advanced NSCLC. Median overall survival of 7.4 months and 1-year survival probability of 38.7% with bortezomib monotherapy are also comparable to results from these studies. Median overall survival was 5.7,³ 7.5,¹⁴ and 7.9 months¹⁷ for docetaxel, 8.3 months for pemetrexed,¹⁷ and 6.7 months for erlotinib¹⁸; 1-year survival probability was 32%,³ 37%,¹⁴ and 29.7%¹⁷ for docetaxel, and 29.7% for pemetrexed.¹⁷

This study was noncomparative and not powered to demonstrate differences between treatment arms; however, bortezomib plus docetaxel seemed to demonstrate modest benefit compared with bortezomib monotherapy in terms of higher disease control rate, lower rate of PD, longer TTP, and longer PFS. Nevertheless, the combination of bortezomib plus docetaxel was not as active as might have been expected based on preclinical results; indeed, investigator-assessed response rate, disease control rate, median TTP, PFS, overall survival, and 1-year survival probability in arm B are consistent with data for single-agent docetaxel.^3,14,17 This may be due to a number of factors. For example, the dose, schedule, or sequence of administration of the agents might not have been optimal, or there may have been negative interaction between the agents. The potential importance of sequence of administration has been indicated in preclinical studies. Gumerlock et al³⁹ showed that, in vitro, docetaxel followed by bortezomib is more cytotoxic in the Calu-1 cell line than the alternative sequence; however, in vivo in the Calu-1 xenograft model, both sequences cause approximately 40% tumor growth inhibition, whereas simultaneous administration results in no tumor growth inhibition, potentially indicating antagonistic effects.⁴⁰ In contrast, preliminary data from in vivo tumor model studies conducted at Millennium Pharmaceuticals show that coadministration in general provides optimal efficacy and does not reveal sequence dependency (Millennium Pharmaceuticals Inc, data on file). It should be noted that the significance of sequence of administration has yet to be verified in the clinical setting.

An additional factor contributing to the lower-than-expected activity of the combination regimen may be that exposure to docetaxel was lower than in comparable studies; the median number of treatment cycles was just two, compared with three, four, and four in phase III studies of docetaxel 75 mg/m².^3,14,17 Similarly, initial bortezomib dose and mean dose density were lower in arm B than in arm A. Furthermore, a greater proportion of patients in this study had received prior paclitaxel (arm A, 67%; arm B, 70%) compared with the studies by Fossella et al (31% to 42%),³ Shepherd et al (0%),¹⁴ and Hanna et al (27.8%).¹⁷ In the study by Fossella et al,³ prior paclitaxel did not appear to affect efficacy, but in the study by Hanna et al,¹⁷ response rates to docetaxel in patients with CR/PR, SD, and PD to prior paclitaxel were 3.9%, 6.9%, and 4.0%, respectively, compared with the overall response rate of 8.8%.

The safety of the combination regimen was similar to that expected, based on the known toxicities associated with bortezomib and docetaxel at the doses used in this study, and with routine use of dexamethasone.^3,14 However, there was no evidence of additive toxicity, particularly neurotoxicity. The GI side effects of bortezomib were prominent in arm A and rate of dehydration was higher in arm A than arm B, perhaps owing to the lack of routinely prescribed prophylactic antiemetics; in contrast, patients in arm B received dexamethasone. As expected, myelosuppression, notably severe neutropenia, was more common in arm B than in arm A; four patients (5%) in arm B required hospitalization for febrile neutropenia compared with none in arm A. Peripheral neuropathy and thrombocytopenia, which are associated particularly with bortezomib, were more common in arm A, possibly owing to the higher initial bortezomib dose or higher mean bortezomib dose density.

The confirmation of only two investigator-assessed responses by central radiology review is not easily understandable; however, differences between investigator-assessed responses and central radiology review have been observed in other clinical trials.^47-49 It is important to note that response rate is not a good predictor for time-to-event parameters in lung cancer, and these data for bortezomib monotherapy are comparable with those for other approved single agents in this setting.

In conclusion, bortezomib has single-agent activity in relapsed or refractory advanced NSCLC comparable to other approved second-line agents. Additional studies will be needed to determine the most efficacious way to combine this drug with other cytotoxic agents.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The following members of the 048 Study Group participated in this study: Wallace Akerley, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Rita Axelrod, Thomas Jefferson University, Philadelphia, PA; Robert Belt, Kansas City Oncology Hematology Group, DBA Kansas City Cancer Center, Kansas City; Ramaswamy Govindan, Washington University; Hans-Joachim Reimers, St Louis University Health Sciences Center, St Louis, MO; David Carbone, Vanderbilt-Ingram Cancer Center, Nashville, TN; Jeffrey Crawford, Duke Comprehensive Cancer Center, Durham, NC; Michael Fanucchi, Winship Cancer Institute, Emory University School of Medicine, Atlanta; Maria Ribeiro, Atlanta VA Medical Center, Decatur, GA; Panos Fidias, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, MA; Robert Figlin, University of California at Los Angeles, Los Angeles; Ronald Natale, Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA; Frank Fossella, University of Texas M.D. Anderson Cancer Center, Houston, TX; Karen Kelly, University of Colorado Health Sciences Center, Aurora, CO; Steven Limentani, Carolinas Hematology-Oncology Associates, Charlotte, NC; John Murren, Yale University School of Medicine, New Haven, CT; Martin Oken, Hubert H. Humphrey Cancer Center, North Memorial Medical Center, Robbinsdale, MN; Luis Raez, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL; Francisco Robert, University of Alabama Comprehensive Cancer Center, Birmingham, AL; Joan Schiller, University of Wisconsin Comprehensive Cancer Center, Madison, WI.

	Authors’ Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Michael P. Fanucchi Millennium Pharmaceuticals Millennium Pharmaceuticals; Sanofi-Aventis Frank V. Fossella Millennium Pharmaceuticals Robert Belt Millennium Pharmaceuticals Ronald Natale Millennium Pharmaceuticals Millennium Pharmaceuticals Millennium Pharmaceuticals Ramaswamy Govindan Aventis; Lilly; Genentech Lilly; Pfizer; Ligand; AstraZeneca; Merck; Millennium Pharmaceuticals; Taiho Luis E. Raez Millennium Pharmaceuticals; Sanofi-Aventis Sanofi-Aventis Sanofi-Aventis; Millennium Pharmaceuticals Karen Kelly Millennium Pharmaceuticals; Sanofi-Aventis Steven A. Limentani Millennium Pharmaceuticals Millennium Pharmaceuticals Jeffrey Crawford Millennium Pharmaceuticals Oscar Kashala Millennium Pharmaceuticals Millennium Pharmaceuticals Shihong Sheng Millennium Pharmaceuticals Millennium Pharmaceuticals Joan H. Schiller Millennium Pharmaceuticals Millennium Pharmaceuticals Millenium Pharmaceuticals

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Frank V. Fossella, Ronald Natale, Jeffrey Crawford, Oscar Kashala, Shihong Sheng, Joan H. Schiller Provision of study materials or patients: Michael P. Fanucchi, Frank V. Fossella, Robert Belt, Ronald Natale, Panos Fidias, David P. Carbone, Ramaswamy Govindan, Luis E. Raez, Francisco Robert, Maria Ribeiro, Wallace Akerley, Karen Kelly, Steven A. Limentani, Jeffrey Crawford, Hans-Joachim Reimers, Rita Axelrod, Joan H. Schiller Collection and assembly of data: Frank V. Fossella, Robert Belt, Ronald Natale, David P. Carbone, Maria Ribeiro, Wallace Akerley, Steven A. Limentani, Hans-Joachim Reimers Data analysis and interpretation: Michael P. Fanucchi, Frank V. Fossella, Ronald Natale, Wallace Akerley, Jeffrey Crawford, Oscar Kashala, Shihong Sheng, Joan H. Schiller Manuscript writing: Michael P. Fanucchi, Steven A. Limentani, Oscar Kashala Final approval of manuscript: Michael P. Fanucchi, Frank V. Fossella, Ronald Natale, Panos Fidias, Ramaswamy Govindan, Luis E. Raez, Francisco Robert, Wallace Akerley, Karen Kelly, Jeffrey Crawford, Rita Axelrod, Oscar Kashala, Shihong Sheng, Joan H. Schiller

 

	ACKNOWLEDGMENTS

 
We thank John R. Murren for his contribution to the 048 study; we regret to report that he passed away last year. We also thank Steve Hill and Rosemary Washbrook (Gardiner-Caldwell London) for their assistance in drafting the manuscript, and Robert Figlin and Martin M. Oken, members of the 048 Study Group, for their contribution to patient enrollment.

	NOTES

 
Supported by Millennium Pharmaceuticals Inc and Johnson & Johnson Pharmaceutical Research & Development LLC.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL, and the 11th World Conference on Lung Cancer (IASLC), July 3-7, 2005, Barcelona, Spain.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Published by the American Society of Clinical Oncology

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
1. American Cancer Society: Cancer Facts and Figures 2005. American Cancer Society, Atlanta, GA, 2005

2. Boyle P, Ferlay J: Cancer incidence and mortality in Europe, 2004. Ann Oncol 16:481-488, 2005[Abstract/Free Full Text]

3. Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non–small-cell lung cancer previously treated with platinum-containing chemotherapy regimens: The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18:2354-2362, 2000[Abstract/Free Full Text]

4. Fossella F, Pereira JR, von Pawel J, et al: Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non–small-cell lung cancer: The TAX 326 study group. J Clin Oncol 21:3016-3024, 2003[Abstract/Free Full Text]

5. Lilenbaum RC, Herndon JE II, List MA, et al: Single-agent versus combination chemotherapy in advanced non–small-cell lung cancer: The cancer and leukemia group B (study 9730). J Clin Oncol 23:190-196, 2005[Abstract/Free Full Text]

6. Schenkein DP: Use of proteasome inhibition in the treatment of lung cancer. Clin Lung Cancer 6:S89-S96, 2004 (suppl 2)[Medline]

7. Bunn PA Jr: Chemotherapy for advanced non–small-cell lung cancer: Who, what, when, why? J Clin Oncol 20:23S-33S, 2002[Medline]

8. Bunn PA Jr: Treatment of advanced non–small-cell lung cancer with two-drug combinations. J Clin Oncol 20:3565-3567, 2002[Free Full Text]

9. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002[Abstract/Free Full Text]

10. Waechter F, Passweg J, Tamm M, et al: Significant progress in palliative treatment of non-small cell lung cancer in the past decade. Chest 127:738-747, 2005[CrossRef][Medline]

11. Sandler AB, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial-E4599. J Clin Oncol 23:2s, 2005 (suppl; abstr LBA4)

12. Belani CP, Eckardt J: Development of docetaxel in advanced non-small-cell lung cancer. Lung Cancer 46:S3-S11, 2004 (suppl 2)[CrossRef][Medline]

13. Wakelee H, Ramalingam S, Belani CP: Docetaxel in advanced non-small cell lung cancer. Expert Rev Anticancer Ther 5:13-24, 2005[CrossRef][Medline]

14. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non–small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103, 2000[Abstract/Free Full Text]

15. Dancey J, Shepherd FA, Gralla RJ, et al: Quality of life assessment of second-line docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: Results of a prospective, randomized phase III trial. Lung Cancer 43:183-194, 2004[CrossRef][Medline]

16. Cohen MH, Johnson JR, Wang YC, et al: FDA drug approval summary: Pemetrexed for injection (Alimta) for the treatment of non-small cell lung cancer. Oncologist 10:363-368, 2005[Abstract/Free Full Text]

17. Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589-1597, 2004[Abstract/Free Full Text]

18. Shepherd FA, Rodrigues Pereira J, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005[Abstract/Free Full Text]

19. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003[Abstract/Free Full Text]

20. Richardson PG, Sonneveld P, Schuster MW, et al: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-2498, 2005[Abstract/Free Full Text]

21. Jagannath S, Barlogie B, Berenson J, et al: A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165-172, 2004[CrossRef][Medline]

22. Goy A, Younes A, McLaughlin P, et al: Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol 23:667-675, 2005[Abstract/Free Full Text]

23. O’Connor OA, Wright J, Moskowitz C, et al: Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 23:676-684, 2005[Abstract/Free Full Text]

24. Aghajanian C, Soignet S, Dizon DS, et al: A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8:2505-2511, 2002[Abstract/Free Full Text]

25. Cusack JC: Rationale for the treatment of solid tumors with the proteasome inhibitor bortezomib. Cancer Treat Rev 29:21-31, 2003 (suppl 1)[Medline]

26. Lara PN Jr, Davies AM, Mack PC, et al: Proteasome inhibition with PS-341 (bortezomib) in lung cancer therapy. Semin Oncol 31:40-46, 2004[CrossRef][Medline]

27. Papandreou CN, Daliani DD, Nix D, et al: Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 22:2108-2121, 2004[Abstract/Free Full Text]

28. Park DJ, Lenz HJ: The role of proteasome inhibitors in solid tumors. Ann Med 36:296-303, 2004[CrossRef][Medline]

29. Adams J: The proteasome: A suitable antineoplastic target. Nat Rev Cancer 4:349-360, 2004[CrossRef][Medline]

30. Mack PC, Davies AM, Lara PN, et al: Integration of the proteasome inhibitor PS-341 (Velcade) into the therapeutic approach to lung cancer. Lung Cancer 41:S89-S96, 2003 (suppl 1)[Medline]

31. Adams J, Palombella VJ, Sausville EA, et al: Proteasome inhibitors: A novel class of potent and effective antitumor agents. Cancer Res 59:2615-2622, 1999[Abstract/Free Full Text]

32. Ling YH, Liebes L, Jiang JD, et al: Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines. Clin Cancer Res 9:1145-1154, 2003[Abstract/Free Full Text]

33. Ling YH, Liebes L, Ng B, et al: PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther 1:841-849, 2002[Abstract/Free Full Text]

34. Mortenson MM, Schlieman MG, Virudachalam S, et al: Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapy in the A549 non-small-cell lung cancer cell line. Cancer Chemother Pharmacol 54:343-353, 2004[Medline]

35. Yang Y, Ikezoe T, Saito T, et al: Proteasome inhibitor PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/ c-Jun/AP-1 signaling. Cancer Sci 95:176-180, 2004[CrossRef][Medline]

36. Denlinger CE, Rundall BK, Keller MD, et al: Proteasome inhibition sensitizes non-small-cell lung cancer to gemcitabine-induced apoptosis. Ann Thorac Surg 78:1207-1214, 2004[Abstract/Free Full Text]

37. Denlinger CE, Rundall BK, Jones DR: Proteasome inhibition sensitizes non-small cell lung cancer to histone deacetylase inhibitor-induced apoptosis through the generation of reactive oxygen species. J Thorac Cardiovasc Surg 128:740-748, 2004[Abstract/Free Full Text]

38. Denlinger CE, Keller MD, Mayo MW, et al: Combined proteasome and histone deacetylase inhibition in non-small cell lung cancer. J Thorac Cardiovasc Surg 127:1078-1086, 2004[Abstract/Free Full Text]

39. Gumerlock P, Kawaguchi T, Moisan L, et al: Mechanisms of enhanced cytotoxicity from docetaxel/PS-341 combination in non-small cell lung carcinoma (NSCLC). Proc Am Soc Clin Oncol 21:1214, 2002 (abstr 304)

40. Gumerlock PH, Kimura T, Holland WS, et al: Differential in vivo activity of docetaxel plus PS-341 combination therapy in non-small cell lung carcinoma (NSCLC) xenografts. J Clin Oncol 22:652s, 2004 (suppl; abstr 7144)

41. Nawrocki ST, Sweeney-Gotsch B, Takamori R, et al: The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther 3:59-70, 2004[Abstract/Free Full Text]

42. Pink M, Pien C, Ona V, et al: PS-341 enhances chemotherapeutic effect in human xenograft models. Proc AACR 43:158, 2002 (abstr 787)

43. Stevenson JP, Nho CW, Johnson SW, et al: Phase II/ pharmacodynamic trial of PS-341 (bortezomib, Velcade) in advanced non-small cell lung cancer. Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004

44. Albanell J, Baselga J, Guix M, et al: Phase I study of bortezomib in combination with docetaxel in anthracycline-pretreated advanced breast cancer. Proc Am Soc Clin Oncol 22:16, 2003 (abstr 63)

45. Dreicer R, Roth B, Petrylak D, et al: Phase I/II trial of velcade plus docetaxel in patients with advanced androgen-independent prostate cancer. Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004

46. Fanucchi M, Belt R, Fossella F, et al: Phase 2 study of bortezomib ± docetaxel in previously treated advanced non-small cell lung cancer: Interim analysis. Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004

47. Johnson DH, Fehrenbacher L, Novotny WF, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184-2191, 2004[Abstract/Free Full Text]

48. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 21:2237-2246, 2003 [Erratum: J Clin Oncol 22:4811, 2004][Abstract/Free Full Text]

49. Smit EF, Mattson K, von Pawel J, et al: ALIMTA (pemetrexed disodium) as second-line treatment of non-small-cell lung cancer: A phase II study. Ann Oncol 14:455-460, 2003[Abstract/Free Full Text]

Submitted March 4, 2006; accepted August 28, 2006.

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