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The Role of Combination Maintenance with Pemetrexed and Bevacizumab for Advanced Stage Nonsquamous Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

ABSTRACT: To evaluate the effect of combination maintenance therapy of pemetrexed plus bevacizumab for patients with advanced non-small cell lung cancer.We identified relevant studies by electronic search (Embase, PubMed, Cochrane, and Web of Science from 1 January 1960 to 29 October 2016) and manual search. The primary outcome of interest was progression-free survival (PFS) and secondary end point included overall survival (OS) and toxicities. The data was pooled for quantitative analysis and the final effect size was reported as hazard ratio (HR) for survival outcomes and relative risk (RR) for safety outcomes, both with a random-effects model.Three randomized controlled trials enrolling 1302 patients with advanced non-small cell lung cancer were included in this meta-analysis. An evident PFS improvement (HR = 0.73, 95% CI = 0.63-0.83, P < 0.01) was observed in patients with pemetrexed and bevacizumab combination maintenance therapy compared with single-agent maintenance therapy, yet it did not subsequently lead to a significant improvement in OS (HR = 0.97, 95% CI = 0.84-1.10, P = 0.66). Our analysis also showed statistically increased risks for provoking grade 3-4 adverse events in patients managed using pemetrexed plus bevacizumab combination (RR = 1.59, 95% CI = 1.07-2.36, P = 0.022).Pemetrexed plus bevacizumab combination maintenance therapy leads to significant improvement in PFS but not in OS for patients with advanced non-small cell lung cancer, which also increases the risks of grade 3-4 adverse events. Yet, in view of the limitation of existing studies and this meta-analysis, current evidence is not adequate to support routine use of pemetrexed-bevacizumab maintenance.

SUBMITTER: Shan F

PROVIDER: S-EPMC5994575 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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The Role of Combination Maintenance with Pemetrexed and Bevacizumab for Advanced Stage Nonsquamous Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Shan Feiyu F Zhang Bo B Sun Leitao L Xie Lufan L Shen Minhe M Ruan Shanming S

BioMed research international 20180528

<h4>Purpose</h4>To evaluate the effect of combination maintenance therapy of pemetrexed plus bevacizumab for patients with advanced non-small cell lung cancer.<h4>Methods</h4>We identified relevant studies by electronic search (Embase, PubMed, Cochrane, and Web of Science from 1 January 1960 to 29 October 2016) and manual search. The primary outcome of interest was progression-free survival (PFS) and secondary end point included overall survival (OS) and toxicities. The data was pooled for quant ...[more]

PMID: 29998136

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Project description:IntroductionPRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed (Pem+Cb) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab (Pac+Cb+Bev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC).MethodsPatients ≥18 years of age with stage IV nonsquamous NSCLC (American Joint Committee on Cancer v7.0), and Eastern Cooperative Oncology Group performance status 0/1 were randomized (1:1) to four cycles of induction Pem+Cb (pemetrexed, 500 mg/m, carboplatin, area under the curve = 6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m, carboplatin, area under the curve = 6, and bevacizumab, 15 mg/kg) followed by Bev maintenance in the absence of progressive disease or discontinuation. The primary objective was progression-free survival (PFS) without grade 4 toxicity (G4PFS). Secondary end points were PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Resource utilization was also assessed.ResultsBaseline characteristics of the patients randomized to Pem+Cb (N = 182) and Pac+Cb+Bev (N = 179) were well balanced between the arms. Median (months) G4PFS was 3.91 for Pem+Cb and 2.86 for Pac+Cb+Bev (hazard ratio = 0.85, 90% confidence interval, 0.7-1.04; p = 0.176); PFS, OS, ORR, or DCR did not differ significantly between the arms. Significantly more drug-related grade 3/4 anemia (18.7% versus 5.4%) and thrombocytopenia (24.0% versus 9.6%) were reported for Pem+Cb. Significantly more grade 3/4 neutropenia (48.8% versus 24.6%), grade 1/2 alopecia (28.3% versus 8.2%), and grade 1/2 sensory neuropathy were reported for Pac+Cb+Bev. Number of hospitalizations and overall length of stay did not differ significantly between the arms.ConclusionsPem+Cb did not produce significantly better G4PFS compared with Pac+Cb+Bev. Pem+Cb was not superior in PFS, OS, ORR, or DCR compared with Pac+Cb+Bev. Both regimens were well tolerated, although, toxicity profiles differed.

Project description:ObjectiveTo evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance therapy with pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS) protein and mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).MethodsA cohort of 144 patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance PB was administered until disease progression or unacceptable toxicity.ResultsOne hundred forty-four Colombian patients with a median follow-up of 13.8 months and a median number of 6 maintenance cycles (range, 1-32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median PFS and (OS) rates were 7.9 months (95% CI, 5.9-10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. We documented grade 3/4 hematologic toxicities, including anemia (14%), neutropenia (8%), and thrombocytopenia (16%). The identified grade 3/4 non-hematologic toxicities were proteinuria (2%), venous thrombosis (4%), fatigue (11%), infection (6%), nephrotoxicity (2%), and sensory neuropathy (4%). No grade >3 hemorrhagic events or hypertension cases were reported. OS was significantly higher in patients with the lowest TS mRNA levels [median, 29.6 months (95% CI, 26.2-32.9)] compared with those in patients with higher levels [median, 9.3 months (95% CI, 6.6-12.0); p = 0.0001]. TS expression (mRNA levels or protein expression) did not influence the treatment response.ConclusionOverall, PCB followed by maintenance pemetrexed and bevacizumab was effective and tolerable in Hispanic patients with non-squamous NSCLC. This regimen was associated with acceptable toxicity and prolonged OS, particularly in patients with low TS expression. We found a role for Ki67 and TS expression as prognostic factors.

Project description:BackgroundIn the era of immunotherapy, it is still unclear which is the best first-line therapy for patients with oncogenic driver negative advanced non-squamous non-small cell lung cancer (NS-NSCLC) who cannot tolerate immunotherapy, or subsequent therapy for patients with oncogenic driver positive NS-NSCLC whose disease progressed on prior targeted therapy. To assess the optimal choice of first-line and maintenance treatment regimens, we performed a meta-analysis of prospective randomized controlled clinical trials (RCTs) of patients with NS-NSCLC on bevacizumab combined with chemotherapy.MethodsAll eligible RCTs comparing pemetrexed-platinum with or without bevacizumab (PP ± B) and paclitaxel-carboplatin with bevacizumab (PC + B) as a first-line therapy, or comparing bevacizumab plus pemetrexed (Pem + B) and bevacizumab alone (B) as a maintenance treatment for advanced NS-NSCLC, were included after systematically searching web databases and meeting abstracts. The main research endpoints were comparisons of overall survival (OS) and progression-free survival (PFS). The other endpoints were objective response rate (ORR), 1-year PFS rate (PFSR1y) and major grade 3/4 treatment-related adverse events.ResultsData of 3139 patients from six RCTs were incorporated into analyses. Three RCTs were included in an analysis that compared PP ± B and PC + B as a first-line therapy for advanced NS-NSCLC. Patients treated with first-line PP ± B showed similar OS and ORR, but significantly improved PFS (hazard ratio [HR], 0.88) and PFSR1y (risk ratio [RR], 0.83), as compared to patients treated with PC + B (all P < 0.05). PP ± B resulted in higher rates of grade 3/4 anemia and thrombocytopenia, but lower rates of neutropenia, febrile neutropenia, and sensory neuropathy than PC + B (all P < 0.001). The other three RCTs were included in an analysis that compared Pem + B and B as a maintenance treatment. Compared with B, Pem + B maintenance treatment resulted in significant improvements in OS (HR, 0.88), PFS (HR, 0.64), and PFSR1y (RR, 0.70), but higher rates of anemia, thrombocytopenia, and neutropenia (all P < 0.001).ConclusionAlthough the first-line PP + B regimen had longer PFS and PFSR1y than the PC + B regimen, no OS difference was observed. Addition of pemetrexed to bevacizumab as maintenance therapy significantly improved OS compared with bevacizumab maintenance alone, but led to more toxicity.

Project description:Progress in the treatment options for small cell lung cancer (SCLC) remains poor. Concerns exist regarding the efficacy of bevacizumab in SCLC. The present study aimed to evaluate the efficacy of bevacizumab in extensive stage (ES)-SCLC. A meta-analysis on studies conducted and listed on the Medline, Cochrane Trials, ASCO, ESMO and ClinicalTrial databases, and Chinese databases prior to April 2015 was performed. All clinical trials in which patients with ES-SCLC were treated with bevacizumab were considered. Survival rates at specific time points were extracted from the reported survival curves. Hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS), rates for PFS, OS, overall response rate (ORR), and side-effects were synthesized using random-effects or fixed-effects model. Two randomized control trials (RCT) (176 patients) and six single-arm trials (292 patients) were identified. In RCTs, no statistically significant differences were observed in PFS [HR, 0.70; 95% confidence interval (CI), 0.41-1.19; P=0.19] or OS (HR, 1.21; 95% CI, 0.84-1.75; P=0.31). In the first-line trials, pooled 6-month and 1-year PFS rates were 57% (95% CI, 39-76%) and 10% (95% CI, 4-16%), respectively. Synthesized 1-year and 2-year OS rates were 45% (95% CI, 36-54%) and 10% (95% CI, 6-14%), respectively. Reported median PFS and OS times for pretreated patients were 2.7-4.0 months and 6.3-7.4 months, respectively. Pooled ORRs were 71% (95% CI, 59-82%) in the first-line trials and 18% (95% CI, 11-25%) in the second-line trials. The most common types of reported toxicities were chemotherapy-associated, including neutropenia, leukopenia, fatigue and thrombocytopenia. According to the RCTs, bevacizumab did not appear to improve the PFS or OS for patients with ES-SCLC, with low quality of evidence. Due to the disappointing pooled efficacy in the single-arm trials, more clinical studies on bevacizumab in SCLC may not be valuable, although the evidence was with low quality.

Dataset Information

The Role of Combination Maintenance with Pemetrexed and Bevacizumab for Advanced Stage Nonsquamous Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Publications

The Role of Combination Maintenance with Pemetrexed and Bevacizumab for Advanced Stage Nonsquamous Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

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