Original StudyPhase II Trial of Dose-dense Pemetrexed, Gemcitabine, and Bevacizumab in Patients With Advanced, Non–Small-cell Lung Cancer
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.
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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)
- et al.
Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer
Ann Oncol
(2013) - et al.
Phase II randomized study of dose-dense docetaxel and cisplatin every 2 weeks with pegfilgrastim and darbepoetin alfa with and without chemo-protector BNP7787 in patients with advanced non-small cell lung cancer (CALGB 30303)
J Thorac Oncol
(2008) - et al.
A randomized phase II trial of pemetrexed/gemcitabine/bevacizumab or pemetrexed/carboplatin/bevacizumab in the first-line treatment of elderly patients with advanced non-small cell lung cancer
J Thorac Oncol
(2012) - et al.
Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741
J Clin Oncol
(2003) Gemcitabine and pemetrexed disodium combinations in vitro and in vivo
Lung Cancer
(2001)- et al.
Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors
J Clin Oncol
(2000)
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