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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000079
Brief Reports

Phase II Study of Bendamustine in Relapsed Chemotherapy Sensitive or Resistant Small-Cell Lung Cancer

Lammers, Philip E. MD*; Shyr, Yu PhD; Li, Chung-I PhD; Hutchison, Anne Smith MD; Sandler, Alan MD§; Carbone, David Paul MD, PhD; Johnson, David H. MD; Keedy, Vicki Leigh MD#; Horn, Leora MD, Msc#

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Author Information

*Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee; Department of Biostatistics, Center for Quantitative Science, Vanderbilt University Medical Center, Nashville, Tennessee; South Carolina Oncology Associates, Columbia, South Carolina; §Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, OHSU Knight Cancer Institute, Portland, Oregon; Department of Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Arthur G. James Cancer Hospital, Columbus, Ohio; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas; and #Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

Disclosure: Dr. Lammers received funding support from NIH K12CA90625. The other authors declare no conflict of interest.

Address for correspondence:Leora Horn, MD, Msc, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, 777 Preston-Research Building, Nashville, TN 37232-6307. E-mail: leora.horn@vanderbilt.edu

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Abstract

Introduction: To determine the time to progression (TTP), response rate (RR), and toxicity for North American patients with relapsed small-cell lung cancer (SCLC) treated with bendamustine in the second- or third-line setting.

Methods: Patients with relapsed, histologically confirmed SCLC were eligible for enrollment on study. The study population included patients with both chemotherapy-sensitive and chemotherapy-resistant disease treated with up to two prior lines of chemotherapy. Patients were treated with 120 mg/m2 of bendamustine on days 1 and 2 of a 21-day cycle for up to six cycles. Primary end point was TTP; secondary end points included toxicity, RR, and overall survival.

Results: Fifty-nine patients were accrued, 50 patients met eligibility for enrollment. The median age of patients was 62, and 56% were men. Twenty-nine patients (58%) had chemotherapy-sensitive disease. Median TTP was 4.0 months (95% confidence interval [CI], 3.3–5.4), median overall survival was 4.8 months (95% CI, 3.8–6.3), and the RR was 26% (95% CI, 13.3%–39.5%). Patients with chemosensitive disease had a median TTP of 4.2 months (95% CI, 3.3–6.0) compared with 3.4 months (95% CI, 2.7–∞) for chemotherapy-resistant disease. The RR was 33% (95% CI, 14.2%–51.8%) in patients with chemosensitive disease and 17% (95% CI, 0%–34.4%) in those with chemoresistant disease. The most common grade 3/4 adverse events were fatigue (20%), dyspnea (12%), and anemia (12%).

Conclusion: Bendamustine has modest activity in relapsed SCLC similar to other agents evaluated in this patient population.

An estimated 246,210 new cases of lung cancer were diagnosed in the United States in 2013.1 Small-cell lung cancer (SCLC) will account for 12% to 15% of these cases. Approximately 60% to 70% of patients are diagnosed with extensive-stage disease at presentation. Despite response rates (RRs) of up to 80% to first-line therapy, the majority of patients eventually relapse with a median survival of 18 to 24 months for patients with limited-stage disease and 6 to 12 months for patients with extensive-stage disease.2 The prognosis is especially poor for patients who relapse or progress after first-line therapy within the first 3 months. Currently, topotecan is the only U.S. Food and Drug Administration–approved agent for use in patients with relapsed SCLC.3,4 A multitude of trials have investigated other chemotherapy agents in patients with relapsed SCLC, but none have proven efficacy over topotecan’s limited benefit.

It is readily understood that there is a considerable need for improved therapies for patients with SCLC. Bendamustine is a bifunctional alkylating agent which is approved by Food and Drug Administration for use as first-line therapy for chronic lymphocytic lymphoma5 and for rituximab-refractory indolent non-Hodgkin’s lymphoma.6,7 A European phase II study of single-agent bendamustine in patients with relapsed chemosensitive SCLC reported an RR of 29%, a median overall survival (OS) of 7 months, and the toxicity profile seemed to be superior when compared with toxicities compiled from studies of topotecan.8

Bendamustine has not been evaluated in a North American patient population with relapsed SCLC. To further evaluate the efficacy and toxicity of this promising agent, we conducted a single-arm, phase II study of bendamustine as a single-agent in relapsed SCLC, in patients with both chemosensitive and chemoresistant disease. The primary end point was time to progression (TTP). Secondary end points included RR, OS, and toxicity.

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PATIENTS AND METHODS

Patient Population

Eligible patients were recruited from Vanderbilt-Ingram Cancer Center Affiliated Network sites. Patients were aged 18 years or older, had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2, and had received up to two prior lines of chemotherapy, one of which must have been a platinum-containing regimen. Patients with symptomatic or untreated brain metastases were excluded. All patients signed informed consent. Chemoresistant disease was defined as no response to platinum-containing regimen and/or progression of disease within 90 days of treatment with a platinum-containing chemotherapy regimen; chemosensitive disease was defined as stable disease (SD) or response to platinum-containing chemotherapy that lasted at least 90 days. The Vanderbilt Medical Center Institutional Review Board approved this study.

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Treatment Strategy

Patients were treated with 120 mg/m2 of bendamustine intravenously on days 1 and 2 of a 21-day schedule. Erythropoesis-stimulating agents and granulocyte colony–stimulating factors were allowed at the discretion of the investigator, consistent with American Society of Clinical Oncology guidelines. Disease assessment with computed tomography scans was repeated every two cycles. Toxicities were tabulated using National Cancer Institute Common Toxicity Criteria version 2.0. Response was evaluated using Response Evaluation Criteria in Solid Tumors 1.0. Patients with evidence of a response to treatment or SD in the absence of unacceptable toxicity were treated up to a maximum of six cycles.

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Statistical Methods
Sample Size Estimation and Power Calculation

The primary objective of this phase II trial was to evaluate the median TTP. Secondary objectives included RR, OS, and toxicity. The sample size estimation was completed a priori using the one sample test on the basis of exponential distribution. A sample size of 42 provided at least 80% power to detect a 50% improvement of the median TTP from previous studies of topotecan with two-sided type I error of 5%. The null hypothesis was that treatment with bendamustine would not result in a TTP of 4.5 months. The power analysis was on the basis of assumptions of an accrual time of 18 months and an additional 12 months of follow-up.

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Statistical Analysis Plan

TTP and OS were estimated using the Kaplan–Meier method with the 95% confidence interval (CI). Survival for the chemosensitive population and the chemoresistant population was compared with the log-rank test. Adverse medical events, including National Cancer Institute toxicity grade 3 and grade 4 laboratory abnormalities were tabulated.

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RESULTS

From September 2009 to February 2012, a total of 59 patients were consented and 50 patients underwent treatment on study. Of the nine patients who did not begin treatment, four were excluded because of laboratory abnormalities, three required urgent radiation therapy, and two had a decline in PS after signing consent and before starting on therapy. Patient characteristics are included in Table 1. The median age was 62 years, 56% were men, and 84% of patients had ECOG PS 0 to 1. Twenty-one patients (42%) had received two prior lines of chemotherapy. The median TTP from first-line chemotherapy was 6 months. Twenty-nine patients (58%) had chemosensitive disease and 21 (42%) had chemoresistant disease.

Table 1
Table 1
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Median TTP was 4.0 months (95% CI, 3.3–5.4 months) (Fig. 1A); patients with chemosensitive disease had a median TTP of 4.2 months (95% CI, 3.3–6.0 months) and those with chemoresistant disease had a median TTP of 3.4 months (95% CI, 2.7–∞ months) (Fig. 1B). Median OS was 4.8 months (95% CI, 3.8–6.3 months) (Fig. 2A). Patients with chemosensitive disease had a median OS of 5.7 months (95% CI, 4.1–7.4 months) and patients with chemoresistant disease had a median OS of 4.1 months (95% CI, 2.5–7.9 months) (Fig. 2B). Forty-two patients were evaluable for response, one patient had a complete response, 10 had partial response, and 17 patients had SD as the best response. Therefore, the RR was 26% (95% CI, 13.3%–39.5%) and the overall clinical benefit (complete response + partial response + SD) was 67%. Fourteen patients had progressive disease at the first evaluation. Thirty-three percent of patients (95% CI, 14.2%–51.8%) with chemosensitive disease had a response to therapy and 17% of patients (95% CI, 0%–34.4%) with chemoresistant disease had a response to therapy.

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Toxicity
Figure 1
Figure 1
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Figure 2
Figure 2
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The most common adverse events (AEs) from this study are listed in Table 2. There were no grade 5 AEs related to bendamustine. The most common grade 3/4 AEs were fatigue, dyspnea, and anemia experienced by 20%, 12%, and 12%, respectively. Twelve patients experienced a serious AE that required 15 separate hospitalizations while on the study. The reasons for hospitalization included dyspnea (3 episodes), anemia (2), bronchitis (2), diarrhea (2), neutropenic fever (2), pneumonia (1), nausea/vomiting (1), pain (1), and hip fracture (1). The rate of grade 3/4 febrile neutropenia was 4%, sensory neuropathy was 2%, and 4% of patients experienced any grade alopecia.

Table 2
Table 2
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DISCUSSION

In this single-arm, phase II study, bendamustine had modest activity and was well tolerated in patients with relapsed chemotherapy-sensitive and chemotherapy-resistant SCLC. Treatment with bendamustine resulted in a median TTP of 4.0 months (95% CI, 3.3–5.4 months) and did not meet the prespecified primary end point of a median TTP of 4.5 months. Although crosscomparison studies are difficult, the RR and survival in patients with relapsed chemosensitive disease seem similar to results from a previous study of bendamustine conducted in Europe.8 This study, however, provides the first evidence that bendamustine has activity in patients with chemotherapy-resistant disease. This study was conducted in patients who are likely to be representative of the majority of patients with relapsed SCLC as the study included those with ECOG PS of 2 and patients with up to two prior lines or therapy.

In the last 20 years, median survival for patients with chemotherapy-resistant SCLC has not appreciably changed.9 Multidrug regimens studied in relapsed SCLC have generally shown improved RRs compared with single agents, but this has not translated into a survival benefit. In addition, a multitude of chemotherapy drugs and targeted agents tested as single agents in phase II studies in patients with relapsed SCLC have also not shown superiority to topotecan.

In the current study, bendamustine was generally well tolerated. Fatigue, anemia, and thrombocytopenia were the most common side effects and were found in similar numbers of patients compared with previous studies of bendamustine.5–8 The rate of grade 3/4 drug-related hematological toxicity and febrile neutropenia was lower than the rate reported in clinical trials of topotecan used for this disease.10 Importantly, bendamustine does not commonly cause alopecia which can be a concern for many lung cancer patients receiving chemotherapy.11,12 It also does not routinely cause either neuropathy or infusion reactions, and as such, does not require corticosteroids for premedication.

Bendamustine has shown efficacy in this population in two separate studies, and because of attractive side effect profile, it may be an option for use in patients with relapsed and/or resistant SCLC. A larger phase III study will be required to prove improved efficacy and quality of life of bendamustine compared with topotecan.

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ACKNOWLEDGMENTS

The authors thank all the patients and families who participated in this study. The authors also thank the members of the thoracic team at Vanderbilt-Ingram Cancer Center and members of the Vanderbilt-Ingram Cancer Center Affiliate Network who participated in this study.

This study was supported by a grant from Teva pharmaceuticals. Study was supported by a grant from Cephalon.

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REFERENCES

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30

2. Tiseo M, Ardizzoni A. Current status of second-line treatment and novel therapies for small cell lung cancer. J Thorac Oncol. 2007;2:764–772

3. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17:658–667

4. O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006;24:5441–5447

5. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27:4378–4384

6. Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study. Cancer. 2010;116:106–114

7. Friedberg JW, Cohen P, Chen L, et al. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin’s lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008;26:204–210

8. Schmittel A, Knödler M, Hortig P, Schulze K, Thiel E, Keilholz U. Phase II trial of second-line bendamustine chemotherapy in relapsed small cell lung cancer patients. Lung Cancer. 2007;55:109–113

9. Ebi N, Kubota K, Nishiwaki Y, et al. Second-line chemotherapy for relapsed small cell lung cancer. Jpn J Clin Oncol. 1997;27:166–169

10. von Pawel J, Gatzemeier U, Pujol JL, et al. Phase ii comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol. 2001;19:1743–1749

11. Bernard M, Brignone M, Adehossi A, et al. Perception of alopecia by patients requiring chemotherapy for non-small-cell lung cancer: a willingness to pay study. Lung Cancer. 2011;72:114–118

12. Carelle N, Piotto E, Bellanger A, Germanaud J, Thuillier A, Khayat D. Changing patient perceptions of the side effects of cancer chemotherapy. Cancer. 2002;95:155–163

Bendamustine; Small-cell lung cancer; Relapsed; Refractory; Phase II

Copyright © 2014 by the International Association for the Study of Lung Cancer

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