Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial

The BEBYP trial is a prospective, randomized, open-label, multicenter, phase III study evaluating the continuation or reintroduction of bevacizumab with second-line chemotherapy in mCRC patients progressed to a first-line therapy containing bevacizumab. The primary end point was PFS. Despite some limitations, mainly due to the premature interruption, the study met its primary end point.BackgroundThe combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy.Patients and methodsIn this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with anα andβ error of 0.05 and 0.20, respectively, 262 patients were required.ResultsIn consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group [adjusted HR = 0.70; 95% confidence interval (CI) 0.52–0.95; stratified log-rankP = 0.010]. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56–1.06; stratified log-rankP = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%;P = 0.573). Toxicity profile was consistent with previously reported data.ConclusionsThis study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC.Clinical Trials.gov numberNCT00720512.     

Magnitude of benefit of the addition of bevacizumab to first-line chemotherapy for metastatic colorectal cancer: meta-analysis of randomized clinical trials

Background

Although the addition of bevacizumab to 1^st line chemotherapy provides a significant survival benefit for advanced colorectal cancer, the magnitudes of both advantages and toxicities have not been extensively investigated.

Methods

A literature-based meta-analysis was conducted; Hazard Ratios were extracted from randomized trials for primary end-points (Progression Free Survival, PFS, Overall Survival OS). The log of event-based risk ratio were derived for secondary endpoints (objective/partial response rate, ORR/PR; severe hypertension, bleeding and proteinuria). Absolute differences and the number needed to treat/harm (NNT/NNH) were calculated. A meta-regression analysis with clinical predictors and a sensitivity analysis according to the trial phase-design were conducted as well.

Results

Five trials (2,728 pts) were selected. The addition of bevacizumab to 1^st line chemotherapy significantly increased both PFS (although with significant heterogeneity) and OS over exclusive chemotherapy by 17.1% and 8.6% (NNT 6 and 12), regardless of the study setting (non significant interaction between phase II and III). The chance to improve PR was significantly increased by 6.5% (NNT 15), with a trend for ORR. The risk of hypertension was significantly increased by 6.2% (NNH 16). According to the meta-regression analysis, female gender and rectal primary site were significant predictors for PFS benefit.

Conclusions

Notwithstanding all the concerns related to costs and the significant HTN risk, the significant outcome improvement provided by bevacizumab in first-line treatment for unselected advanced colorectal cancer patients, should be considered when choosing the appropriate up-front therapy.     

Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial.

PURPOSE: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with irinotecan-based chemotherapy in first-line treatment of metastatic colorectal cancer (CRC). This randomized, phase II trial compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan. PATIENTS AND METHODS: Patients had metastatic CRC and one of the following characteristics: age > or = 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin < or = 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed. RESULTS: Median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (hazard ratio, 0.79; P = .16). Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo); hazard ratio was 0.42; P = .088. Grade 3 hypertension was more common with bevacizumab treatment (16% v 3%) but was controlled with oral medication and did not cause study drug discontinuation. CONCLUSION: Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.     

Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)-leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m(2)/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m(2), as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU-LV occurred in 相似文献   

FOLFOXIRI or FOLFOXIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: a propensity score-adjusted analysis from two randomized clinical trials

BackgroundFOLFOXIRI plus bevacizumab is a valid option as upfront treatment for metastatic colorectal cancer (mCRC) patients. While several trials investigated the effect of combining bevacizumab with different chemotherapy regimens, including fluoropyrimidines monotherapy and oxaliplatin- or irinotecan-containing doublets, no randomized comparison assessing the impact of the addition of bevacizumab to FOLFOXIRI is available.Patients and methodsA total of 122 mCRC patients received first-line FOLFOXIRI in the phase III trial by the GONO (FOLFOXIRI group) and 252 patients received first-line FOLFOXIRI plus bevacizumab in the TRIBE trial (FOLFOXIRI plus bevacizumab group). A propensity score-adjusted method was adopted to provide an estimation of the benefit from the addition of bevacizumab to FOLFOXIRI in terms of survival and activity parameters.ResultsPatients in the FOLFOXIRI group had more frequently Eastern Cooperative Oncology Group performance status of one or two, high Köhne score, metachronous and liver-limited disease, had previously received adjuvant treatments and had their primary tumors resected. The median progression-free survival (PFS) was 12.3 months in the FOLFOXIRI plus bevacizumab group compared with 10.0 months in the FOLFOXIRI group {propensity score-adjusted hazard ratio (HR) 0.74 [95% confidence interval (CI) 0.59–0.94], P = 0.013}. This association was significant also in the multivariable model (P = 0.024). The median OS was 29.8 months in the FOLFOXIRI plus bevacizumab group compared with 23.6 months in the FOLFOXIRI group [propensity score-adjusted HR: 0.72 (95% CI 0.56–0.93), P = 0.014]. At the multivariable model, the addition of bevacizumab was still associated with significantly longer OS (P = 0.030). No significant differences in RECIST response rate (RR) [65.1% versus 55.7%; propensity score-adjusted odds ratio (OR): 1.29 (95% CI 0.81–2.05), P = 0.280], early RR [62.7% versus 57.8%; OR: 1.14 (95% CI 0.68–1.93), P = 0.619] and median depth of response (42.2% versus 53.8%, P = 0.259) were reported.ConclusionsThough in the absence of a randomized comparison, the addition of bevacizumab to FOLFOXIRI provides significant benefit in PFS and OS, thus supporting the use of FOLFOXIRI plus bevacizumab as upfront treatment for mCRC patients.Trials&rsquo; numbersNCT01219920 and NCT00719797     

FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer

BackgroundBRAF V600E mutation plays a negative prognostic role in metastatic colorectal cancer (mCRC), leading to a median Progression Free Survival (PFS) of 4–6 months with first-line conventional treatments. Our group recently reported in a retrospective exploratory analysis of a phase II trial that FOLFOXIRI (5-FU/LV+Oxaliplatin+Irinotecan) plus bevacizumab might allow to achieve remarkable results in terms of PFS and Overall Survival (OS) also in this poor-prognosis subgroup. The aim of this work was to prospectively validate our retrospective finding.Patients and methodsThis phase II trial was designed to detect an increase in 6 month-Progression Free Rate (6 m-PFR) from 45% to 80% in a population of BRAF mutant mCRC patients treated with first-line FOLFOXIRI plus bevacizumab. Secondary end-points were PFS, OS, response rate (RR) and the analysis of outcome parameters in the pooled population consisting of both retrospectively and prospectively included patients. This trial is registered with ClinicalTrials.gov, number NCT01437618.ResultsTwo-hundred-fourteen potentially eligible mCRC patients were screened for BRAF mutational status. Fifteen BRAF mutant patients (7%) were included in the validation cohort. At a median follow up of 25.7 months, 6 m-PFR was 73%. Median PFS and OS were 9.2 and 24.1 months, respectively. In the pooled population, at a median follow up of 40.4 months, 6 m-PFR was 84%. Median PFS and OS were 11.8 and 24.1 months, respectively. Overall RR and disease control rate were 72% and 88%, respectively.ConclusionLacking randomised trials in this specific molecular subgroup, FOLFOXIRI plus bevacizumab might be a reasonable option for the first-line treatment of BRAF mutant mCRC patients.     

A randomized, phase II trial of standard triweekly compared with dose-dense biweekly capecitabine plus oxaliplatin plus bevacizumab as first-line treatment for metastatic colorectal cancer: XELOX-A-DVS (dense versus standard)

Background.

Capecitabine administered for 7 days biweekly with oxaliplatin (XELOX) biweekly has been reported to have activity and safety profiles similar to those of standard capecitabine given for 14 days triweekly. Multiple studies have shown that the addition of bevacizumab to 5-fluorouracil–based chemotherapy is active and well tolerated.

Methods.

Patients with metastatic colorectal cancer (mCRC) were randomized to XELOX plus bevacizumab using a standard triweekly cycle (Q3W) or a dose-dense biweekly cycle (Q2W) schedule. The primary endpoint was the progression-free survival (PFS) interval. This trial is registered on ClinicalTrials.gov (identifier, {"type":"clinical-trial","attrs":{"text":"NCT00159432","term_id":"NCT00159432"}}NCT00159432).

Results.

In total, 435 U.S. patients were randomized. The median PFS intervals were 9.6 months in the Q3W group and 9.1 months in the Q2W group. The median overall survival times were 28.4 months and 22.1 months and the median times to treatment failure were 5.5 months and 3.4 months, respectively. Overall, gastrointestinal disorders were the most common (93%) adverse event (AE). Grade 3 or 4 AEs occurred in 75% and 81% of patients in the Q3W and Q2W groups, respectively. Treatment discontinuation as a result of diarrhea (5% versus 10%) and hand–foot syndrome (2% versus 9%) was less common in the Q3W group than in the Q2W group, respectively.

Conclusions.

Based on these results, the first-line treatment of U.S. patients with mCRC using a biweekly combination of XELOX and bevacizumab at the doses studied cannot be recommended. XELOX Q3W remains the preferred schedule for the management of mCRC.     

Cost-effectiveness of capecitabine and bevacizumab maintenance treatment after first-line induction treatment in metastatic colorectal cancer

AimCapecitabine and bevacizumab (CAP-B) maintenance therapy has shown to be more effective compared with observation in metastatic colorectal cancer patients achieving stable disease or better after six cycles of first-line capecitabine, oxaliplatin, bevacizumab treatment in terms of progression-free survival. We evaluated the cost-effectiveness of CAP-B maintenance treatment.MethodsDecision analysis with Markov modelling to evaluate the cost-effectiveness of CAP-B maintenance compared with observation was performed based on CAIRO3 study results (n = 558). An additional analysis was performed in patients with complete or partial response. The primary outcomes were the incremental cost-effectiveness ratio (ICER) defined as the additional cost per life year (LY) and quality-adjusted life years (QALY) gained, calculated from EQ-5D questionnaires and literature and LYs gained. Univariable sensitivity analysis was performed to assess the influence of input parameters on the ICER, and a probabilistic sensitivity analysis represents uncertainty in model parameters.ResultsCAP-B maintenance compared with observation resulted in 0.21 QALYs (0.18LYs) gained at a mean cost increase of €36,845, yielding an ICER of €175,452 per QALY (€204,694 per LY). Varying the difference in health-related quality of life between CAP-B maintenance and observation influenced the ICER most. For patients achieving complete or partial response on capecitabine, oxaliplatin, bevacizumab induction treatment, an ICER of €149,300 per QALY was calculated.ConclusionCAP-B maintenance results in improved health outcomes measured in QALYs and LYs compared with observation, but also in a relevant increase in costs. Despite the fact that there is no consensus on cost-effectiveness thresholds in cancer treatment, CAP-B maintenance may not be considered cost-effective.     

贝伐珠单抗联合FOLFIRl方案一线治疗转移性结直肠癌的临床研究

目的评价贝伐珠单抗联合FOLFIRI方案一线治疗转移性结直肠癌的疗效和安全性。方法将42例转移性结直肠癌患者随机分为FOLFIRI组和FOLFIRI＋贝伐珠单抗组。FOLFIRI组（n=21）采用伊立替康（CPT一11,180mg／m2,d1）＋甲酰四氢叶酸钙（CF,400mg／m2,d1）＋氟尿嘧啶（5-FU,400mg／m2,静脉推注,d1;然后5-FU,2400mg／m2,以微量泵进行持续静脉滴注46小时）。FOLFIRI＋贝伐珠单抗组（n=21）采用贝伐珠单抗（每2周5mg／kg,d1）＋FOLFIRI方案。2周为1个周期,3个周期后评价疗效。两组患者均持续治疗至病情进展或毒性不能耐受。结果42例患者均可评价疗效和不良反应。FOLFIRI组和FOLFIRI＋贝伐珠单抗组的治疗有效率分别为28．6％和61．9％,FOLFIRI＋贝伐珠单抗组的有效率显著高于FOLFIRI组（P=0．03）。FOLFIRI＋贝伐珠单抗组的临床获益率明显高于FOLFIRI组（90．5％US61．9％,P：0．03）。FOLFIRI组和FOLFIRI＋贝伐珠单抗组中位无疾病进展时间（progression—freesurvival,PFS）分别为6．6个月和10．0个月（P=0．000）。两组的主要不良反应为迟发性腹泻和中性粒细胞减少,贝伐珠单抗组增加的不良反应主要有高血压（P=0．002）、出血（P=0．001）和蛋白尿（P=0．035）。结论FOLFIRI方案化疗联用贝伐珠单抗提高了晚期结直肠癌患者治疗的有效率和临床获益率,并延长了PFS,不良反应患者可以耐受。     

Commentary on a phase III trial of bevacizumab plus XELOX or FOLFOX4 for first-line treatment of metastatic colorectal cancer: the NO16966 trial

Replacing infusional 5-fluorouracil (5-FU) leucovorin (LV) with oral capecitabine would be more convenient to patients, because it would lead to reduced hospital chair time and infusion-related toxicities. Previous trials with oral capecitabine-based regimens (other than XELOX [capecitabine/oxaliplatin]) have failed to demonstrate the equivalent efficacy of capecitabine based regimens to various 5-FU/oxaliplatin regimens (nonstandard FOLFOX [5-FU/LV/oxaliplatin] combinations); of note, these trials did not use the XELOX and standard FOLFOX regimens. An international phase III trial (NO16966) was initiated to demonstrate the noninferiority of XELOX to FOLFOX4 for the first-line treatment of metastatic colorectal cancer. The protocol was later amended to compare bevacizumab and chemotherapy versus placebo and chemotherapy. The efficacy data showed that XELOX was as effective as FOLFOX4 (progression-free survival [PPS; intent-to-treat population]: hazard ratio [HR], 1.04; 97.5% confidence interval, 0.93-1.16). Also, bevacizumab/chemotherapy(pooled with XELOX or FOLFOX) significantly prolonged PPS (HR 0.83; p=0.0023) compared with placebo and chemotherapy (XELOX/FOLFOX). In subgroup analysis, the addition of bevacizumab to XELOX (9.3 months vs. 7.4 months. HR.0.77; P=0.0026) and FOLFOX4(9.4 months vs. 8.6 months; HR, 0.89; P = 0.1871) prolonged PFS compared with respective placebo arms; however, it did not show statistical significance with the FOLFOX4 regimen. The adverse events were manageable and comparable between treatment arms.