Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer

Niho, Seiji; Kunitoh, Hideo; Nokihara, Hiroshi; Horai, Takeshi; Ichinose, Yukito; Hida, Toyoaki; Yamamoto, Nobuyuki; Kawahara, Mutsuto; Shinkai, Tetsu; Nakagawa, Kazuhiko; Matsui, Kunihiko; Negoro, Shunichi; Yokoyama, Akira; Kudoh, Shinzoh; Kiura, Katsuyuki; Mori, Kiyoshi; Okamoto, Hiroaki; Sakai, Hiroshi; Takeda, Koji; Yokota, Soichiro; Saijo, Nagahiro; Fukuoka, Masahiro

doi:10.1016/j.lungcan.2011.12.005

Cited by 175 publications

(187 citation statements)

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“…This study demonstrated a significant extension of the PFS time following the administration of CP plus BEV (dose, 15 mg/kg) therapy compared with CP therapy alone (HR, 0.61; 95% CI, 0.42-0.89) (20). Therefore, the BEV combined with platinum therapy is now considered to be a standard chemotherapeutic regimen for the treatment of advanced non-squamous NSCLC in Japan.…”

Section: Introductionmentioning

confidence: 79%

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Feasibility of cisplatin/pemetrexed with 15 mg/kg bevacizumab for the treatment of patients with advanced non-squamous non-small cell lung cancer

et al. 2015

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Abstract. The aim of the present study was to retrospectively evaluate the feasibility of cisplatin/pemetrexed/bevacizumab (CPB) therapy at a bevacizumab (BEV) dose of 15 mg/kg as a first-line chemotherapeutic strategy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). A total of 31 consecutive patients with non-squamous NSCLC were treated with first-line chemotherapy of CPB at a BEV dose of 15 mg/kg at the National Kyushu Cancer Center (Fukuoka, Japan) between November 2009 and December 2011. Clinical characteristics, response rate (RR), progression-free survival (PFS) time, overall survival (OS) time and adverse events were retrospectively analyzed. The 31 patients exhibited a male:female ratio of 21:10 and a median age of 60 years (range, 38-76 years). In total, 5 patients were of clinical stage III and 26 patients were of stage IV, 15 had a performance status of 0 and 16 had a performance status of 1, and 29 patients were diagnosed with adenocarcinoma and 2 were diagnosed with adenosquamous carcinoma. The EGFR mutation status was positive (exon 19 deletion), wild-type and unknown in 3, 21 and 7 patients, respectively. A total of 28 patients (90.3%) received a minimum of four courses of CPB therapy. Hematological toxicities classified as grade III or higher included neutropenia (29.0%), anemia (3.2%) and thrombocytopenia (3.2%), however, no severe non-hematological toxicities were observed. Additionally, 22 patients (71.0%) exhibited a partial response and 9 (29.0%) exhibited stable disease, resulting in a RR of 71.0% [95% confidence interval (CI), . The median PFS and OS times were 8.4 months (95% CI, 7.9-9.0) and 28.5 months (95% CI, 26.4-30.6), respectively. Therefore, CPB therapy at a BEV dose of 15 mg/kg appears to be a feasible treatment strategy for patients with advanced non-squamous NSCLC. IntroductionAt present, the standard first-line chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) is platinum doublet chemotherapy using a third-generation anticancer agent (1,2). Pemetrexed (PEM) is a novel metabolic antagonist capable of inhibiting multiple enzymes involved in folate metabolism that has been clinically introduced as an effective therapeutic agent in the treatment of NSCLC (3-5). Previously, the results of two phase III studies indicated the efficacy of PEM as a first-line therapy for advanced NSCLC (6,7). In the JMDB study, cisplatin (CDDP) plus PEM therapy was not determined to be inferior to CDDP plus gemcitabine (GEM) therapy in terms of the overall survival (OS), and the incidence of severe adverse events was significantly lower following CDDP plus PEM therapy (6). Furthermore, in a subgroup analysis according to histological type, the OS of patients with non-squamous NSCLC was significantly longer in the CDDP plus PEM therapy group compared with the CDDP plus GEM group. In addition, the effectiveness of PEM for the treatment of non-squamous NSCLC was supported by two of the phase III studies (JMEI and JMEN) (8,9). Thus, at present, CDDP plus ...

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Section: Introductionmentioning

confidence: 79%

“…This differs from the dose of 15 mg/kg used in the E4599 study (13), which identified an extension in the OS period following the addition of BEV to platinum doublet chemotherapy. Furthermore, in the United States and Japan, 15 mg/kg is the approved and most frequently used BEV dose (13,20).…”

Section: Introductionmentioning

confidence: 99%

Feasibility of cisplatin/pemetrexed with 15 mg/kg bevacizumab for the treatment of patients with advanced non-squamous non-small cell lung cancer

et al. 2015

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“…Concerning the OS, the higher frequency of EGFR mutations in the Japanese population may favorably affect patient outcomes compared with previous reports (SAiL and ARIES). In a Japanese phase II study (10), OS was 22.8 months and PFS was 6.9 months for first-line treatment with CBDCA + PTX + Bev. In that trial, the EGFR mutation data were not available, but 41% of patients received EGFR-TKIs as post-protocol therapy.…”

Section: Discussionmentioning

confidence: 99%

A prospective cohort study of patients with non-squamous non-small cell lung cancer treated with bevacizumab

Naoki

Takeda²,

Soejima

et al. 2017

Oncology Letters

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Abstract. First-line chemotherapy regimens that include bevacizumab (Bev) have been hypothesized to improve outcomes in patients with advanced non-squamous non-small cell lung cancer (non-sq NSCLC). Although approved to treat NSCLC in 2009, insufficient data exist on the clinical uses of Bev in Japan. The present study prospectively evaluated the efficacy and safety of Bev-containing combination chemotherapy. Eligible patients exhibited histologically or cytologically documented advanced or recurrent non-sq NSCLC. Patients were administered 15 mg/kg Bev with standard chemotherapy followed by maintenance Bev. The primary endpoints were progression-free survival (PFS) and safety. A total of 102 patients with non-sq NSCLC were enrolled, 44.1% of whose tumor carried epidermal growth factor receptor (EGFR) mutations. The overall response rate to the intervention was 44.1%, and the median PFS was 8.3 months [95% confidence interval (CI)=6.4-10.2 months]. The median overall survival was 26.3 months (95% CI=22.2-30.4 months). The incidence of Bev-associated severe adverse events was similar to those in previous trials, excluding a grade 3-4 hypertension rate of 30.4% in the present study. Multivariate analysis revealed that a higher TNM classification of malignant tumor staging-T factor, adjusted hazard ratio (HR)=1.33 (95% CI=1.10-1.61), and poor performance status [adjusted HR=1.63 (1.02-2.60)] were associated with significantly shorter PFS, whilst the EGFR exon 19 deletion was significantly associated with prolonged PFS [adjusted HR=0.47 (0.25-0.87)]. Bev-containing chemotherapy was safe and effective for patients with non-sq NSCLC in clinical settings in Japan. The EGFR exon 19 deletion was suggested as a positive predictive factor for the efficacy of Bev-containing chemotherapy. IntroductionIn several clinical trials, first-line combination chemotherapies containing bevacizumab (Bev) were revealed to improve clinical outcomes in patients with advanced non-squamous non-small cell lung cancer (non-sq NSCLC) (1-3). Sandler et al (3) reported significant survival benefits, such as overall survival (OS) of >1 year (12.3 months), with addition of Bev to paclitaxel plus carboplatin in the treatment of non-sq NSCLC. Although Bev was approved for NSCLC in 2009 in Japan, there are insufficient data regarding the efficacy, toxicity and predictive markers for Bev treatment. The present study evaluated the efficacy and safety of Bev-containing combination chemotherapy in patients with non-sq NSCLC in clinical settings in Japan. Landmark survival analysis, or disease control at 8 weeks, was reported to be a more powerful predictor of subsequent survival compared with the traditional tumor response rate in advanced NSCLC (4). This may provide an early assessment of subsequent outcome. Since treatment with bevacizumab occasionally results in cavitary lesion without tumor shrinkage (5), stable disease may also be important for understanding drug efficacy. Therefore, landmark analysis was utilized in the present study. In addition, ...

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“…6 A Japanese phase 2 study also indicated that bevacizumab in combination with paclitaxel and carboplatin improved the ORR and PFS compared with paclitaxel and carboplatin alone. 7 In a confirmatory phase 3 study (the Avastin in Lung [AVAiL] trial), the addition of bevacizumab to cisplatin and gemcitabine resulted in a significant improvements in the ORR and PFS. 8,9 These observations provide a rationale for combining bevacizumab with platinum-doublet chemotherapy in individuals with advanced nonsquamous NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Phase 2 study of S‐1 and carboplatin plus bevacizumab followed by maintenance S‐1 and bevacizumab for chemotherapy‐naive patients with advanced nonsquamous non–small cell lung cancer

Urata

Okamoto

Takeda

et al. 2013

Cancer

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BACKGROUND:A previous phase 3 trial demonstrated noninferiority in terms of overall survival for combined S-1 (an oral fluoropyrimidine) and carboplatin compared with combined paclitaxel and carboplatin as first-line treatment for advanced non-small cell lung cancer (NSCLC). In the current study, the authors evaluated the efficacy and safety of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab in chemotherapy-naive patients with advanced nonsquamous NSCLC. METHODS: Patients received carboplatin (area under the concentration-time curve, 5 mg mL 21 per minute) and bevacizumab (15 mg/kg) on day 1 plus oral S-1 (80 mg/m 2 per day) on days 1 through 14 every 21 days for up to 6 cycles. For patients without disease progression, S-1 and bevacizumab were continued until disease progression or unacceptable toxicity developed. RESULTS: Forty-eight patients were enrolled in the phase 2 study; of these, 35 patients (72.9%) completed at least 4 cycles. Most toxicities of grade 3 were hematologic, and no increase in relative incidence associated with maintenance with S-1 and bevacizumab was observed. The objective response rate was 54.2% (95% confidence interval, 39.2%-68.6%), and the median progression-free survival was 6.8 months (95% confidence interval, 4.3-8.2 months). CONCLUSIONS: The regimen of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab was active and feasible as first-line treatment for advanced nonsquamous NSCLC. Cancer 2013;119:2275-81. INTRODUCTIONLung cancer is the leading cause of death related to cancer worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of lung cancer cases. 1 For individuals with advanced or metastatic NSCLC, platinum-based chemotherapy is the mainstay of first-line treatment 2,3 on the basis of the moderate improvement in survival and quality of life it affords compared with best supportive care alone. 4 A phase 3 study, the Eastern Cooperative Oncology Group (ECOG) E4599 trial, demonstrated that bevacizumab, a humanized monoclonal antibody specific for vascular endothelial growth factor, 5 given with paclitaxel and carboplatin resulted in significant improvements in the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with paclitaxel and carboplatin alone in individuals with advanced nonsquamous NSCLC. 6 A Japanese phase 2 study also indicated that bevacizumab in combination with paclitaxel and carboplatin improved the ORR and PFS compared with paclitaxel and carboplatin alone. 7 In a confirmatory phase 3 study (the Avastin in Lung [AVAiL] trial), the addition of bevacizumab to cisplatin and gemcitabine resulted in a significant improvements in the ORR and PFS. 8,9 These observations provide a rationale for combining bevacizumab with platinum-doublet chemotherapy in individuals with advanced nonsquamous NSCLC.

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Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer

Cited by 175 publications

References 13 publications

Feasibility of cisplatin/pemetrexed with 15 mg/kg bevacizumab for the treatment of patients with advanced non-squamous non-small cell lung cancer

Feasibility of cisplatin/pemetrexed with 15 mg/kg bevacizumab for the treatment of patients with advanced non-squamous non-small cell lung cancer

A prospective cohort study of patients with non-squamous non-small cell lung cancer treated with bevacizumab

Phase 2 study of S‐1 and carboplatin plus bevacizumab followed by maintenance S‐1 and bevacizumab for chemotherapy‐naive patients with advanced nonsquamous non–small cell lung cancer

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