Original Study
Phase II Trial of Dose-dense Pemetrexed, Gemcitabine, and Bevacizumab in Patients With Advanced, Non–Small-cell Lung Cancer

Presented in part at the 45th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2009.
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Abstract

Introduction

Platinum-based chemotherapy is standard for untreated, advanced non-small-cell lung cancer (NSCLC). We investigated the activity and tolerability of the novel combination of dose-dense pemetrexed, gemcitabine, and bevacizumab in patients with advanced NSCLC.

Methods

This multicenter phase II trial evaluated the safety and efficacy of the combination of pemetrexed (400 mg/m2), gemcitabine (1200 mg/m2), and bevacizumab (10 mg/kg), given every 14 days in patients with untreated, advanced NSCLC. The primary endpoint was progression-free survival with secondary endpoints of response rate and overall survival.

Results

Thirty-nine patients were enrolled. Treatment was well tolerated; the most common grade 3-4 toxicities were neutropenia and fatigue. Of the 38 patients evaluable for tumor response, 1 (3%) had complete response, 15 (39%) had partial response, 12 (31%) had stable disease, and 10 (26%) had progressive disease. Median progression-free survival was 6.1 months (95% confidence interval [CI], 4.2-7.9) and median overall survival was 18.4 months (95% CI, 13.1-29.5). The 1-year overall survival rate was 64% (95% CI, 51%-81%) and the 2-year overall survival rate was 41% (95% CI, 28%-60%).

Conclusions

Treatment with dose-dense pemetrexed, gemcitabine, and bevacizumab met the primary endpoint with promising efficacy and a manageable safety profile in patients with untreated advanced NSCLC. This regimen represents a reasonable therapeutic option.

Introduction

Platinum-based chemotherapy remains the standard of care for patients with advanced NSCLC; however, no chemotherapy doublet has emerged as superior. Gemcitabine and pemetrexed have significant efficacy in nonsquamous NSCLC and a superior toxicity profile compared with other agents (ie, cisplatin, taxanes). The favorable tolerability allows a “dose-dense” approach that may improve efficacy without intolerable side effects. Although dose-dense regimens have shown clinical benefit in other tumors, such as breast cancer, the benefit in NSCLC remains unproven.1 In vitro models have demonstrated synergy between gemcitabine and pemetrexed, and a phase I study in patients with advanced cancer recommended pemetrexed 500 mg/m2 and gemcitabine 1500 mg/m2 every 2 weeks for further study.2, 3

Previous studies have demonstrated safety and clinical benefit when bevacizumab was added to both pemetrexed- and gemcitabine-containing regimens.4, 5 In a meta-analysis that included 2194 patients, chemotherapy plus bevacizumab significantly increased both overall survival and progression-free survival compared with chemotherapy alone.6 We conducted a phase II trial of gemcitabine, pemetrexed, and bevacizumab on an every 2 weeks schedule in chemo-naïve patients with advanced NSCLC.

Section snippets

Eligibility

Patients with untreated stage IIIB (pleural/pericardial effusion) or IV NSCLC were eligible. Squamous cell was initially allowed if the primary tumor had been removed before the pemetrexed restriction for use in patients with nonsquamous histology. Other requirements included age ≥ 18, Zubrod performance status (PS) 0 to 1, absolute neutrophil count (ANC) ≥ 1500/mm3, platelet count ≥ 100,000/mm3, creatinine clearance ≥ 45 mL/min, total bilirubin ≤ 1.5 times the institutional upper limit of

Results

Thirty-nine patients were enrolled at 2 sites between September 2006 and August 2010. Patient characteristics are summarized in Table 1. The median number of cycles of pemetrexed/gemcitabine/bevacizumab received was 7 (range, 1-12). Nine patients continued bevacizumab as maintenance therapy for a median of 4 cycles (range, 1-52).

Discussion

The combination of pemetrexed, gemcitabine, and bevacizumab given on an every 2 weeks schedule was well tolerated with manageable toxicity in this single-arm, phase II study. The regimen increased median PFS beyond 6 months and the response rate of 42% was encouraging. The median OS of 18.4 months compared favorably with that achieved with other first-line regimens. Three patients remain alive with disease control.

Dose-dense chemotherapy (decreasing the interval between treatment cycles) has

Disclosure

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

Acknowledgments

Eli Lilly and Company and Genentech, Inc. provided funding/drugs.

References (13)

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