Bevacizumab: A dose review.

ONCH-1938; No. of Pages 12

ARTICLE IN PRESS

Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx

Bevacizumab: A dose review Alexander T. Falk, Jérôme Barrière, Eric Franc¸ois, Philippe Follana ∗ Centre Antoine Lacassagne, 33 avenue Valombrose, 06000 Nice, France Accepted 29 January 2015

Contents 1. 2. 3. 4.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phase I studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phase II/III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Metastatic colon cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Advanced and metastatic non-small cell lung cancer (NSCLC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Metastatic breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Advanced ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Glioblastomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Metastatic renal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5. 6. 7.

00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00

Abstract Angiogenesis is a key process in cancer development and has been described has a hallmark of cancer. Two dose-intensities were approved for cancer treatment by the Food and Drug Administration and European Medicines Agency: 2.5 mg/kg/week dose equivalent and 5 mg/kg/week dose equivalent. While bevacizumab has shown its effectiveness in clinical trials, pharmacodynamics is not fully understood and a dose-effect relationship has not been proven in vivo. Direct trials comparing high or low doses are rare with potential dose-effect toxicity. Discordant data have been reported on the efficacy of doses. This review discusses the dose of bevacizumab via the analysis of studies that led to the approval of bevacizumab in clinical practice. Optimization of doses schemes could reduce potential dose-effect toxicities, potentiate synergetic effects with chemotherapy and permit the prescription to a larger population with a better cost-effectiveness ratio. © 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Bevacizumab; Dose; In vitro; In vivo; Clinical outcomes

∗

Corresponding author. Tel.: +33 4 92 03 10 00; fax: +33 4 92 03 10 10. E-mail address: [email protected] (P. Follana).

http://dx.doi.org/10.1016/j.critrevonc.2015.01.012 1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Falk AT, et al. Bevacizumab: A dose review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.01.012


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ARTICLE IN PRESS A.T. Falk et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx

1. Introduction Angiogenesis is a key process in cancer development and has been described has a hallmark of cancer [1]. The vascular endothelial growth factor (VEGF) family of proteins and theirs receptors (VEGFR) regulate both physiological and pathological angiogenesis. VEGF expression is increased in the majority of cancers [2] and one of the major angiogenic growth factor is the vascular endothelial growth factor A (VEGF-A). Bevacizumab is a humanized monoclonal antibody that targets and inhibits the VEGF-A [3]. It was first approved by the US Food and Drug Administration (FDA) in 2004 for metastatic colon cancer. It is now approved for brain glioblastoma, lung cancer and renal cancer by the FDA. While bevacizumab has shown its effectiveness in clinical trials, pharmacodynamics is not fully understood and a doseeffect relationship has not been proven in vivo. However, two dose-intensities were approved by the FDA and European Medicines Agency (EMA): 2.5 mg/kg/week dose equivalent and 5 mg/kg/week dose equivalent. This review aims to discuss the dose of bevacizumab via the analysis of studies that led to the approval of bevacizumab in clinical practice for advanced cancers. Review of bevacizumab indications were voluntarily omitted as to only focus on posology.

2. Preclinical studies Mechanisms of action of anti-VEGF therapy are not yet fully understood. Of all the mechanisms described on preclinical data, there are three mechanisms of action that have shown clinical evidence [4]: it may prune tumoral vessels and kill a fraction of cancer cells; it can normalize tumor vasculature and micro-environment increasing the deliverance of chemotherapy [5]; it can reduce the number of bloodcirculating endothelial and progenitor cells [6,7]. Recently a more provocative concept has emerged suggesting that clinical benefits could be the result from off-tumor targets vascular normalization [8]. We can hypothesize that the action of bevacizumab is a combination of different mechanisms. Unfortunately we do not know for certain if all, few or none of these mechanisms are dose dependent. The influence of bevacizumab dose has been particularly studied on gliomablastomas tumor cells. Indeed glioblastomas are highly vascularized tumors with VEGFA upregulation compared to low grade gliomas [9]. In vitro data suggest that lower doses are sufficient to induce vascular normalization but higher dose are necessary to obtain a direct cytotoxic effect [10,11]. We do not know if we can extrapolize these results to tumor cells from another origin considering that bevacizumab has different effects depending on VEGF expression and histology [12]. Singleagent anti-angiogenic therapy in xenograft tumor models has shown some direct anti-tumoral activity in renal [13] and ovarian [14] cancer. Data is available showing that VEGF expression varies upon cancer types or even in the same

histology groups [15]. On the contrary, higher doses can also have its drawbacks. It could lead to a vasculature that is inefficient for drug delivery and the loss of synergistic antitumor activity [16,17]. It could also lead to hypoxia, a known pathway of tumor invasiveness activation [18].

3. Phase I studies Gordon et al. [3] investigated the safety of bevacizumab using doses from 0.1 to 10 mg/kg on day 0, 28, 35 and 42. No dose limiting toxicity was found even with the highest dose at 10 mg/kg. Free serum VEGF concentrations were undetectable at bevacizumab administration for doses ≥0.3 mg/kg. In a phase I/II trial escalating doses of bevacizumab, ranging from 3 mg/kg to 20 mg/kg, 75 patients previously treated with metastatic breast cancer were administered bevacizumab intravenously every other week [19]. The authors concluded for an optimal dose of 10 mg/kg every 2 weeks (E2W) because patients had a greater number of partial response at this dose with too much adverse events at 20 mg/kg, this deduction with the power of a phase I/II study is subject to discussion. A third study was designed to test the safety of bevacizumab combined with chemotherapy [20] with bevacizumab administered at a unique dose of 3 mg/kg every week with either doxorubicin, carboplatine–paclitaxel or 5-fluorouracile and no synergistic toxicities were found. Unfortunately, phase I dose findings for bevacizumab are scarce with testing of a high variability of doses ranging from 0.1 to 20 mg/kg with different schedules from every week to every 3 weeks (E3W). The absence of dose limiting toxicity which is common with antibodies makes it difficult to choose an optimal dose for further phase II studies. Of note, a biological effect was seen starting at 0.3 mg/kg which could mean that low dose can be sufficient to trigger some mechanisms of action. It seems that the choice of Cobleigh et al. has influenced later studies, many have used the 10 mg/kg E2W based on this paper.

4. Phase II/III For easier reading and fast referencing, Tables 1 and 2 resume data on phase II/III clinical trials and Table 3 the doses approved by the EMA and FDA. 4.1. Metastatic colon cancer Bevacizumab in metastatic colon cancer was first studied by Kabbinavar et al. [35] in a randomized phase II study. Patients received fluorouracil (FU)/leucovorin (LV) as first line therapy with either no, 5 mg/kg E2W or 10 mg/kg E2W bevacizumab administration. The primary objective of PFS was only significant for the 5 mg/kg arm [HR 0.46 (CI 95% 5.8–10.9, p = 0.005), when the data for bevacizumab-treated



Line

Phase Number of patients

Regimen

BEV schedule

BEV dose equivalent testeda

Primary objective

Primary results (medians)

Secondary results (medians)

Hurwitz et al. (2004) [21]

Metastatic colon

First-line

III

402

IFL/placebo vs IFL/BEV (5 mg/kg)

E2W

Low

OS

OS: 15.6 vs 20.3 mos

Giantonio et al. (2007) [22]

Metastatic colon

Previously treated

III

829

FOLFOX4 vs FOLFOX4/bevacizumab (10 mg/kg) vs bevacizumab (10 mg/kg)

E2W

High

OS

Bennouna et al. (2013) [23]

Metastatic colon

Second-line

III

820

E2W or E3W

Low

OS

Sandler et al. (2006) [24] Miller et al. (2005) [25]

Advanced/metastaticFirst-line NSCLC Metastatic Second or breast cancer third line

III

878

E3W

High

OS

III

462

Fluouropyrimidine-based chemotherapy vs Fluouropyrimidine-based chemotherapy/BEV (2.5 mg/kg week-equivalent) Carboplatin/paclitaxel vs carboplatin/paclitaxel/BEV (15 mg/kg) Capecitabine vs capecitabine/BEV (15 mg/kg)

OS: 10.8 vs 12.9 vs 10.2 mos OS: 9.8 vs 11.2 mos

PFS: 6.2 vs 10.6 mos RR: 34.8 vs 44.8% MDR: 7.1 vs 10.4 mos PFS: 4.7 vs 7.3 vs 2.7 mos

E3W

High

PFS

Miller et al. (2007) [26] Burger et al. (2007) [27]

Metastatic breast cancer Advanced ovarian cancer

First line

III

722

E2W

High

PFS

First line

III

1873

High

PFS

Perren et al. (2011) [28]

Ovarian cancer – high risk early stage and advanced Advanced ovarian/primary peritoneal/fallopian tube Advanced ovarian

Adjuvant

III

1578

Carboplatin/paclitaxel/placebo vs E3W carboplatin/paclitaxel/BEV (15 mg/kg)/Placebo maintenance vs carboplatin/paclitaxel/BEV (15 mg/kg)/BEV Maintenance (15 mg/kg) E3W Carboplatin/paclitaxel vs carboplatin/paclitaxel/BEV (7.5 mg/kg)

Low

PFS

PFS: 22.4 vs 24.1 mos

Recurrent platinum sensitive

III

484

Carboplatin/gemcitabine vs Carboplatin/gemcitabine/BEV (15 mg/kg)

E3W

High

PFS

PFS: 8.4 vs 12.4 mos

RR: 57.4 vs 78.5%

Second or third line

III

361

High

PFS

PFS: 3.4 vs 6.7 mos

RR: 12.6 vs 30.9%

Glioblastoma

Front line

III

637

Pegylated liposomal doxorubicin or E2W or E3W topotecan or weekly paclitaxel ± bevacizumab (10 or 15 mg/kg) Chemoradiotherapy(temozolomide)/placebo E2W vs chemoradiotherapy/BEV (10 mg/kg)

High

OS and PFS

OS: 15.7 vs 16.1 mos (ns) PFS: 8.2 vs 14.1

Aghajanian et al. (2012) [29]

Pujade-Lauraine et al. (2013) [30] Gilbert et al. (2013) [31]

Paclitaxel vs paclitaxel/BEV (10 mg/kg)

PFS: 4.1 vs 5.7 mos

OS: 10.3 vs PFS: 4.5 vs 6.2 12.3 mos PFS: 4.86 vs TRR: 9.1 vs 4.17 (ns) mos 19.8% OS: 15.1 vs 14.5 (ns) PFS: 5.9 vs OS: 25.2 vs 26.7 11.8 mos mos (ns) PFS: 10.3 vs OS: 39.3 vs 38.7 11.2 vs 14.1 vs 39.7 mos (ns) mos

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First author (year) Organ

A.T. Falk et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx


Table 1 Summary of phase II/III clinical trials using one bevacizumab dose discussed in this review.

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4

PFS

OS

High

High

E2W

E2W III First line

732

Interferon alfa/placebo vs interferon alpha/BEV (10 mg/kg) Inteferon alfa/placebo vs interferon alpha/BEV (10 mg/kg 649 III First line

Metastatic renal cancer Metastatic renal cancer Escudier et al. (2010) [33] Rini et al. (2010) [34]

5FU, 5-fluorouracil; LV, leucovorin; IRI, Irinotecan; IFL, irinotecan, bolus fluorouracil and leucovorin; BEV, Bevacizumab; E2W, Every two weeks; PFS, progression free survival; TTP, time to progression; TRR, Tumor response rate; RR, response rate; Mo(s), Month(s); OS, Overall survival; MDR, Median duration of response; Ns, non significant. a Low doses refer to 2.5 mg/kg week-equivalent and high dose to 5 mg/kg week-equivalent of bevacizumab.

PFS: 6.2 vs 10.6 mos OS: ns RR: 13 vs 31% PFS: 5.4 vs 10.2 mos OS: 17.4 vs PFS: 10.6 vs 15.5 18.3 mos (ns) mos OS and PFS High Chemoradiotherapy(temozolomide)/placebo E2W vs chemoradiotherapy/BEV1 (10 mg/kg) 921 Front line Glioblastoma Henriksson et al. (2013) [32]

III

Line First author (year) Organ

Table 1 (Continued)

Phase Number of patients

Regimen

BEV schedule

BEV dose equivalent testeda

Primary objective


Secondary results (medians)


patients were pooled, there was a 55% reduction in the hazard of progressing compared to the placebo arm. Efficacy seemed in favor of the 5 mg-arm with a prolonged median overall survival of 21.5 months vs 13.8 months in the control arm and 16.1 months in the 10 mg/kg arm. Hurwitz et al. [21] tested a 5 mg/kg bevacizumab addition to Irinotecan (IRI)/FU/LV vs the same regimen plus placebo for untreated metastatic colon cancer with efficacy in this setting: the primary objective of overall survival was in favor of bevacizumab (20.3 months vs 15.6 months). A randomized phase II clinical trial followed [40], comparing 5-FU/LV with placebo (median OS 12.9 months) or bevacizumab at the dose of 5 mg/kg (median OS 16.6 months) for first-line metastatic colon cancer who were unable to receive irinotecan. These results led to the approval by national authorities of bevacizumab (5 mg/kg) combined with fluorouracil/leucovirin. However, the eastern cooperative oncology group study E3200 [22] compared a FOLFOX4 regimen with or without bevacizumab at 10 mg/kg E2W or bevacizumab alone. This choice was justified on clinical data in studies of renal and lung cancer which used high-dose bevacizumab. The addition of bevacizumab to Folfox4 led to an increased median overall survival of 12.9 months vs 10.8 months. It led to the approval of bevacizumab for both doses by the EMA and high-dose only by the FDA. Two studies evaluated bevacizumab after first-line progression of patients who had previously received it. Second-line addition of 2.5 mg/kg week-equivalent bevacizumab has proved its benefit in overall survival and progression free survival [23]. To determine the best dose, the EAGLE Study [36], a randomized phase III compared FOLFIRI plus bevacizumab 5 mg/kg E2W vs FOLFIRI plus bevacizumab 10 mg/kg E2W. This is the first and only study to have directly compared two-doses of bevacizumab, the main objective was to find a longer significant PFS with a dose augmentation: the results were negative. 4.2. Advanced and metastatic non-small cell lung cancer (NSCLC) In 2003, Johnson et al. [37] published a randomized phase II trial comparing bevacizumab 7.5 mg/kg or 15 mg/kg E3W (E3W) plus carboplatin and paclitaxel or carboplatin paclitaxel alone for advanced or metastatic lung cancer. Addition of bevacizumab resulted in higher response rate but only patients with 15 mg/kg bevacizumab regimen had a significant longer median time to progression (7.4 months for the 15 mg/kg bevacizumab group vs 4.2 months in the control group p = 0.023 and 5.9 months in the low-dose group). The study lacked sufficient power to make a definitive conclusion of a relationship between dose and effect. Based on these results, Sandler et al. [24] conducted a phase III study for advanced/metastatic non squamous NSCLC comparing Paclitaxel–carboplatin alone or with bevacizumab at the dose of 15 mg/kg E3W. Patients receiving bevacizumab presented a median overall survival of 12.3 months vs 10.3 months (p = 0.003). The AVAiL [38] study compared cisplatin and



Line

Phase

Number of patients Regimen

BEV schedule BEV dose equivalent testeda

Kabbinavar et al. (2003) [35]

Metastatic colon

First-line

II

104

E2W

Low and high

Tamagawa et al. (2013) [36]

Metastatic colon

Second-line

II

370

E2W

Low and high

Johnson et al. (2004) [37]

Advanced/ metastatic NSCLC

Any previously treated

II

99

E3W

Low and high

OS: 14.9 vs 11.6 TTP and TRR TTP 4.2 s 4.3 vs 7.4 mos vs 17.7 TRR: 18.8 vs 28.1 vs 31.5%

Reck et al. (2009) Advanced/ metastatic [38] NSCLC

First-line

III

1043

E3W

Low and high

PFS

Miles et al. (2010) Metastatic [39] breast cancer

First line

III

736

E3W

Low and High PFS

PFS: 8.1 vs 9 vs 10 mos

Yang et al. (2003) Metastatic [56] renal cancer

Second line

II

116

E2W

1.5 mg/kg and PFS and RR High

PFS: 2.5 vs 3 vs 4.8 RR: 1.26 (ns) vs 2.55

5FU/LV/PBO vs 5FU/LV/BEV (5 mg/kg) vs 5FU/LV/BEV (10 mg/kg) FOLFIRI/BEV (5 mg/kg) vs FOLFIRI/BEV (10 mg/kg) Carboplatin/paclitaxel vs carboplatin/paclitaxel/ BEV (7.5 mg/kg) vs carboplatin/paclitaxel/ BEV (15 mg/kg) Carboplatin/gemcitabine/ placebo vs carboplatin/ gemcitabine/BEV (7.5 mg/kg) vs carboplatin/gemcitabine/ BEV (15 mg/kg) Docetaxel/placebo vs Docetaxel/BEV (7.5 mg/kg) vs Docetaxel/BEV (15 mg/kg) Placebo vs BEV (3 mg/kg) vs BEV (10 mg/kg)

Primary objective


TTP and TRR TPP: 5.2 vs 9.0 vs 7.2 mos TRR: 6 vs 14 vs 8 mos PFS PFS: 6.1 vs 6.4 (ns)

Secondary results (medians) OS: 13.8 vs 21.5 vs 16.1 mos

RR: 17.4 vs 17.6 (ns)

PFS: 6.1 vs 6.7 vs TRR 20.1 vs 34.1 6.5 mos vs 30.4%

TRR: 46.4 vs 55.2 vs 64.1% OS: 31 mos all arms (ns)

5FU, 5-fluorouracil; LV, leucovorin; IRI, Irinotecan; IFL, irinotecan, bolus fluorouracil and leucovorin; PBO, Placebo; BEV, Bevacizumab; E2W, Every two weeks; PFS, progression free survival; TTP, time to progression; TRR, Tumor response rate; RR, response rate; Mo(s), Month(s); OS, Overall survival; MDR, Median duration of response; Ns, non significant. a Low doses refer to 2.5 mg/kg week-equivalent and high dose to 5 mg/kg week-equivalent of bevacizumab.

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First author (year) Organ



Table 2 Summary of randomized phase II/III clinical trials using two doses discussed in this review.

5


6


Table 3 Approved doses of bevacizumab by the FDA and EMA.

Metastatic colon cancer

Metastatic breast cancer Lung cancer Glioblastoma Metastatic renal cancer Ovary/peritoneal

FDA

EMA

5 mg/kg E2W with bolus IFL 10 mg/kg E2W with FOLFOX4 5 mg/kg E2W or 7.5 mg/kg E3W with FOLFIRI or FOLFOX4 after progression of first line Not approved 15 mg/kg E3W 10 mg/kg E2W 10 mg/kg E2W Not approved

5 mg/kg or 10 mg/kg E2W7.5 mg/kg or 15 mg/kg E3W

gemcitabine with low dose bevacizumab (7.5 mg/kg), high dose bevacizumab (15 mg/kg) or placebo E3W. There was a significant hazard ratio for progression free survival in the low-dose bevacizumab group vs placebo: 6.7 vs 6.1 months [HR = 0.75 (p = 0.003]; and the high dose bevacizumab vs placebo: 6.5 vs 6.1 months [HR = 0.82 (p = 0.03)]. The study was not designed and lacked the power to compare the two doses of bevacizumab directly. A recent meta-analysis pooled data from 14 randomized phase II and III trials of bevacizumab in combination with platinum-based chemotherapy compared with chemotherapy alone [41]. Patients treated with bevacizumab plus chemotherapy presented a significant longer OS [HR = 0.90 95% CI 0.81–0.99, p = 0.03] and PFS [HR = 0.72 95% CI 0.66–0.79, p < 0.001]. Further analysis found no significant difference between the two bevacizumab doses for PFS and OS.

10 mg/kg E2W or 15 mg/kg E3W 7.5 mg/kg or 15 mg/kg E3W Not approved 10 mg/kg E2W 15 mg/kg E3W

survival. The AVADO trial compared docetaxel alone vs docetaxel plus bevacizumab at 7.5 mg/kg and 15 mg/kg E3W [39]. The 15 mg/kg bevacizumab arm showed superior PFS compared to placebo plus docetaxel (median 10.1 months vs 8.2 months, p = 0.006), the 7.5 mg/kg arm showed no statistical difference (median PFS 9.0 months, p = 0.12) in the unstratified analysis. However in the stratified analysis that censored for non-protocol therapy before disease progression (11% in the 7.5 mg arm and 7% in the 15 mg arm), the increase of PFS became significant for 7.5 mg arm (p = 0.045). The response was only significant in the 15 mg arm vs placebo (64.1% vs 46.4, p = 0.07). No comparison was performed between the two arms. With the combined data of these trials, the FDA removed the indication of bevacizumab for metastatic breast cancer. The EMA removed the label for combination with docetaxel, to date only the taxol or capecitabine combination is approved.

4.3. Metastatic breast cancer 4.4. Advanced ovarian cancer Cobleigh et al. [19] presented data on a phase I/II doseescalation of bevacizumab in previously treated metastatic breast cancer. Patients were treated by bevacizumab only every 2 weeks. Objective responses were documented in seven (9.3%) of 75 patients: one (1.3%) at the dose of 3 mg/kg of bevacizumab, 3 (4%) at 10 mg/kg and 1 (1.3%) at 20 mg/kg. Although the highest response rate was seen at 10 mg/kg E2W, the author could not conclude about the effectiveness of a higher or lower dose. However, patients at the 20 mg/kg dose presented a high incidence of nausea and vomiting, thus preconizing the 10 mg/kg E2W dose. While widely used in other cancers, the 5 mg/kg E2W dose was not tested. The first published phase III trial on previously treated metastatic breast cancer [25] compared capecitabine vs capecitabine–bevacizumab at the dose of 15 mg E3W. Although objective response rate was significantly improved with addition of bevacizumab (19.8% vs 9.1%, p = 0.001), it did not improve PFS. ECOG 2100 trial [26] randomized paclitaxel alone vs paclitaxel plus bevacizumab 10 mg/kg E2W for previously untreated metastatic breast cancer. The addition of bevacizumab significantly prolonged progression-free survival [11.8 vs 5.9 months, HR = 0.60, p < 0.001], no difference was found for overall

Burger et al. [42] presented results from a phase II study for recurrent ovarian or primary peritoneal cancer with a 15 mg/kg bevacizumab monotherapy E3W showing interesting results with low toxicity, even for prolonged treatment. Many other phase II showed similar results with high dose bevacizumab alone or in combination with chemotherapy [43–46]. This regimen inspired a phase III international trial GOG-0218 [27] for a front line regimen for stage III or stage IV with debulking surgery epithelial ovarian cancer, comparing carboplatin–paclitaxel plus placebo vs carboplatin–paclitaxel plus bevacizumab at 15 mg/kg E3W for 5 cycles vs carboplatin–paclitaxel–bevacizumab for 21 cycles. The median progression-free survival was 10.3 months in the control group, 11.2 in the bevacizumabinitiation group and 14.1 in the bevacizumab-throughout group. This confirms the efficacy of bevacizumab monotherapy which slows the ineluctable progression. No phase II studies gave any interest in low dose. We only have the results of a small retrospective series stating that low dose bevacizumab (5 mg/kg and 7.5 mg/kg E3W) combined with chemotherapy could be active in heavily pretreated mostly platinum resistant ovarian cancer with good tolerance and




7

efficacy: 26.7% and 46.7% of complete and partial response respectively [47]. Nevertheless, in the adjuvant setting for stages I–IV, the ICON7 phase III trial [28] compared carboplatin and paclitaxel E3W for 6 cycles or to this regimen plus bevacizumab 7.5 mg/kg E3W for 5 or 6 cycles and continued for 12 additional cycles. Median progression-free survival at 42 months was 22.4 months without bevacizumab vs 24.1 months with bevacizumab (p = 0.04). In a subgroup of high-risk patients (FIGO stage III/IV with residual disease >1 cm), a benefit in PFS (18.2 vs 14.5 months) and OS (36.6 vs 28.8 months) was reported [48]. This post hoc analysis of a population similar to GOG-0218 suggests that 2.5 mg/week equivalent bevacizumab could lead to the same extent of benefit. Two other phase III trials confirmed the efficacy of high dose bevacizumab combined with chemotherapy for both platinum-sensitive [29] and resistant [30] recurrent ovarian cancer.

the time to progression in the high-dose group as compared with the placebo group [HR = 2.55, p < 0.001], there was a non-significant small difference in the small dose group vs placebo (HR = 1.26, p = 0.056). No rational was presented for using the 1.5 mg/kg week-equivalent of bevacizumab. Unfortunately we do not have study reporting the efficacy of bevacizumab at 5 mg/kg E2W. Two phase III studies were simultaneously conducted comparing interferon alfa-2a plus placebo vs interferon alfa2a plus bevacizumab 10 mg/kg E2W [33,34] in the first line metastatic setting. Median duration of progression free survival was significantly longer in the bevacizumab group in both studies (10.2 vs 5.4 months, p = 0.0001 in AVOREN and 8.5 vs 5.2 months, p < 0.0001 in CALGB 90206). No phase III studies using low-dose bevacizumab and no direct comparison have been performed.

4.5. Glioblastomas

Bevacizumab has unique adverse-events that can usually be differentiated from cytotoxic drugs. Some of the common adverse events associated with use of bevacizumab include proteinuria, hypertension, epistaxis, gastro-intestinal perforation, thromboembolic events and hemorrhage. However some of these adverse events are serious and can be fatal. These adverse can impair the quality of life in patients with advanced and metastatic disease. Fortunately these serious adverse events are rare [57]. Meta-analysis of bevacizumab clinical trials [57] has shown that bevacizumab is accountable for an increased risk of adverse events [RR = 1.2 95% CI 1.15–1.24]. The small number of comparative studies, their small size and the low incidence of adverse events renders the comparison of adverse-events between low and high-dose difficult. However, we witnessed a tendency of a higher incidence of toxicities in the high-dose arms. For example, bevacizumab plus chemotherapy as first line treatment in patients with advanced non-small-cell lung cancer [41] significantly increased the risk of grade ≥3 proteinuria, hypertension, hemorrhage and neutropenia. Another example, in the Avail study, the overall incidence of serious adverse events was higher in the high-dose bevacizumab group (44%) than the low dose (35%) and placebo arms (35%) [38] but were mostly high-grade hypertension. In a metastatic breast cancer trial (AVADO), epistaxis, hypertension and proteinuria were more frequent in the 5 mg/kg week-equivalent compared to the low-dose arm [25]. However, in both cases they were not significant clinical events. In the EAGLE study [36], the only direct head-to-head trial comparing both doses, no difference was observed in terms of safety, however the population was selected as they had been previously treated with bevacizumab. A thorough meta-analysis of treatment-related mortality with bevacizumab [58] concluded that bevacizumab in combination with chemotherapy was associated with a higher

Three phase II prospective series studied the efficacy of high-dose bevacizumab with or without irinotecan for recurrent glioblastomas with response rates ranging from 28.2 to 61% [49–51] leading to FDA approval in this setting. Some retrospective data are in favor of a low-dose efficacy, with no direct comparison whatsoever. In a retrospective series, Stark-Vance et al. [52] used low-dose bevacizumab 5 mg/kg E2W plus irinotecan with a 42% response rate. Using the same regimen, Raval et al. [53] found a 95.2% response rate with no vascular complication reported. Lorgis et al. [54] performed a retrospective analysis of clinical factors associated with patient survival with detailed data on bevacizumab doses. After multivariate analysis, only low dose ( 0.00001). Another meta-analysis [55], regrouped phase II studies to determine efficacy parameters and dose-response effect of bevacizumab: no difference in a dose-response relationship was found between low and high-dose. To our knowledge, no dose comparative studies have been performed. In the newly diagnosed context, two recent phase III trials [31,32] proposed high-dose 10 mg/kg E2W bevacizumab vs placebo with discordant result. The Avaglio study [32] found a significant better PFS [6.2 vs 10.6 months, p < 0.0001) while no difference was found in the RTOG 0825 trial [31]. 4.6. Metastatic renal cancer Yang et al. [56] proposed a phase II study comparing placebo, bevacizumab at 3 mg/kg E2W and bevacizumab at 10 mg/kg E2W for previously treated metastatic renal cancer with interferon. There was a significant prolongation of

5. Safety



8


incidence of fatal adverse events (FAE) [HR = 1.33 (CI 95% 1.02–1.73) p = 0.04]. 5 mg/week dose-equivalent was associated with a significantly increased risk of fatal adverse event [HR = 1.98 (CI 95% 1.20–3.27) p = 0.008]. 2.5 mg/kg/week dose-equivalent was not associated with a significant higher risk of fatal adverse event. No significant difference was found between the two groups (p = 0.32) probably due to the lack of statistical power. The interpretation of these data is to be cautious, as they regroup different tumor types and settings. A meta-analysis of high-grade hypertension risk with bevacizumab stated that these events may vary according to tumor types [59].

6. Discussion After two decades of development and nearly ten years of commercialization, the optimal dose of bevacizumab is still unknown. Randomized phase II studies were used to determine the optimal doses for phase III, unfortunately they lacked sufficient power to make any conclusion for a doseeffect relationship. The apparent benefit of high-dose with renal and lung cancer and low-dose with colorectal cancer could be a result of the hazard. Phase III trials comparing different doses are rare and mainly vs placebo while direct head-to-head comparison has been performed only once. Recommended doses approved by national authorities are variable for certain number of cancers (Table 3). While low dose efficacy for colorectal cancer has been proved and direct comparison has not shown difference, the EMA and FDA leave the dose choice to the prescriber. For lung cancer, only European authorities have approved low dose although no phase III series or meta-analysis have proved a superiority for high dose. In ovarian cancer, only high dose is approved even if a phase III has established low dose benefit in adjuvant setting. To this date, it seems reasonable as much as possible to use low dose bevacizumab in these diseases considering potential toxicity and cost. We did not find any direct evidence of a dose related toxicity with bevacizumab but post hoc meta-analysis seem to find an indirect higher incidence of adverse events for the high dose equivalent. In clinical trials, it seemed that the incidence, type and grade of toxicities were not associated to the dose, with some post hoc data and meta-analysis showing a tendency for a dose-related toxicity hypothesis. In many countries, national health services have restricted access to bevacizumab on the basis of cost-benefit calculations. A cost-effectiveness calculation [60] using quality-adjusted life-years compared low [28] vs high dose bevacizumab [27] for ovarian cancer in front line was in favor of low dose maintenance, however duration of maintenance was also lower. In this new era of constantly rising health care costs and drug costs, it is important to consider cost-benefit ratio of the drugs administered. If low dose bevacizumab maintenance is accepted then we can potentially treat twice the number of patients with about same drug costs.

Moreover, considering the numerous potential mechanisms of action of bevacizumab, different doses could be necessary according to tumor stage, histological subtype, the type of combination or monotherapy use. Pharmacokinetics must also be considered when discussing of dosage. Monoclonal antibodies are usually considered to have the same characteristics in terms of pharmacokinetics independently of pharmacological targets and patient populations; the most common factor influencing their distribution is body size [61]. Scarce data are available for bevacizumab and most are provided by Genentech [62–65]. Using a non-linear mathematical model, bevacizumab halflife was estimated to be 20 days [62]. Body weight and gender were the covariates most significantly associated with interpatient variability of estimated clearance or distribution. Pharmacokinetic profiles were analyzed in 500 patients, but only for low-dose administrations: 5 mg/kg E2W, 7.5 mg/kg E3W, steady-state average was comparable for both biweekly and tri-weekly regimens. However there has been no published data on high dose or comparison between high and low-dose regimens in terms of pharmacokinetics. Since the prescription is already adapted to patients’ weight, we could consider it is a good standardized option to adapt for pharmacokinetics profiles variability. An option might be to prospectively assess bevacizumab concentrations using an assay [66]. Weight may be not only considered exclusively for pharmacokinetics matters. It might be necessary to adapt the dose to the patients’ profiles and weight distribution. Indeed adipose tissue can secrete VEGF, especially visceral fat [67]. There is some retrospective evidence that a high visceral fat area calculated from CT-scans is significantly associated to lower response and PFS to bevacizumab in metastatic colorectal cancer [68]. In the same setting, Faruk Aykan et al. [69] performed a prospective observational study showing shorter PFS for patients with high body-mass index. Similar data has been found for advanced epithelial ovarian cancer with high body-mass index associated with poorer outcome for patients treated with bevacizumab [70]. However, no prospective data backing this evidence has been published. Further knowledge on fat tissue, VEGF secretion and its relationship with bevacizumab could allow tailoring of doses. Disease stage can also play a major role. Angiogenesis is a key and necessary process in tumor growth and invasiveness. Tumors need to overbalance proangiogenic over antiangiogenic factors to be able to support its growth and metastases, also known as the “angiogenic switch”. This phenomenon could explain the efficacy of bevacizumab in advanced and metastatic setting only as it has become predominant in the disease natural history [71]. Bevacizumab has only demonstrated efficacy when combined with chemotherapy with the exception of glioblastoma and ovarian cancer. If we consider that the goal of bevacizumab is to enhance the effect of chemotherapy, we also need to perform early studies that assess drug combinations. According to Jain [72], when using antiangiogenics with




other drugs, there is a time window where vascular normalization enhances chemotherapy delivery to cancer cells. An insufficient dose will not be able to trigger this mechanism. On the contrary an excessive dose could lead to pruning of vessels and hypoxia inducing a more aggressive phenotype. Further prospective data need to be gathered on dose comparison of bevacizumab administration to provide better care for our patients. Large phase III trials with direct dose comparison could be performed with drawbacks as they would need large numbers of patients, have high costs, be time consuming to perform for each organ as we already have insufficient workforce and funds to perform as much as we would want. Another option could be to go back to early trials to find the optimal biological dose. In phase I trials cytotoxic chemotherapy approach use a dose-effect theory where higher doses translate to higher efficacy probability. With targeted therapies, tumor control could be achieved with lower doses. Instead of looking for MTD usually not reached in bevacizumab studies a new approach will be to perform early phase I–II studies with new predictive biomarkers to assess the efficacy and advantages of different bevacizumab doses to personalize treatment to cancer types and patients. Unfortunately no validated biomarkers have been defined even though hypertension and VEGF polymorphisms showed some potential [73]. We urgently need prospective validation of predictive factors of response to bevacizumab. Trials are currently ongoing, for example the COMET trial [74] investigates various biological (circulating endothelial cells, circulating tumor cells, plasmatic VEGFA, proteomic, VEGF polymorphisms, VGFA and FGF3 amplification) and imaging parameters (visceral fat volume) potentially related to the clinical benefit of the combination of bevacizumab and weekly paclitaxel in first line metastatic breast cancer in a homogeneously treated population in french cancer centers.

7. Conclusion Bevacizumab has not proven a dose-relationship effect in clinical practice. Optimization of doses schemes could reduce potential dose-effect toxicities, potentiate synergetic effects with chemotherapy and permit the prescription to a larger population with a better cost-effectiveness ratio. Concerning colorectal, lung and first-line ovarian cancer, high level evidence shows that we should use low-dose in priority. However, in other cancers, with no comparative study, dose suggestion is not possible. This development needs to be achieved through direct comparison and incorporation of new dynamic biomarkers.

Conﬂict of interest statement None declared.

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Role of the funding source No funding source.

Reviewers Joseph Gligorov, M.D., Ph.D., Head of Expert Center for Senology, APHP Hôpital Tenon, ER2 UPMC Université Pierre et Marie Curie, 4 rue de la Chine 75020 Paris, France. Medical Oncology Dept., 4 rue de la Chine, F-75020 Paris, France Vishal Ranpura, M.D., Physician, Medstar Washington Hospital Center, Hematology/Oncology, 110 Irving Street NW, C 2151, Washington, DC 20010, United States

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Biographies Alexander T. Falk, M.D., is an oncologist at the Antoine Lacassagne Cancer Center in Nice, France. His interests are solid tumors, the use of novel technologies for his field and medico-economics. Jérôme Barrière, M.D., is a medical oncologist. His fields of interest are genitourinary, breast and central nervous system cancers. In addition to his clinical practice, he works on the role of telomeres in cancer (Ph.D. research work).



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Eric Fran¸cois, M.D., is a medical oncologist. He is the chief of the Medical Oncology Department of the Antoine Lacassagne Cancer Center in Nice, France. He is in charge of the digestive cancer comity. His interests include targeted therapy, elderly patients and colorectal cancer.

Philippe Follana, M.D., is a medical oncologist at the Antoine Lacassagne Cancer Center in Nice, France. His field of interests include research in breast, gynecologic and gastro-intestinal cancers. He is currently in charge of a Medical Oncology Unit.


A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma.

A systematic review of bevacizumab efficacy in breast cancer.

Bevacizumab: a review of its use in advanced cancer.

Dose - response relationship of bevacizumab in hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia treated with low dose intravenous bevacizumab.

High-dose sublesional bevacizumab (avastin) for pediatric recurrent respiratory papillomatosis.

Low-dose bevacizumab is effective in radiation-induced necrosis.

Switch to a single dose of aflibercept in bevacizumab nonresponders with AMD.

Safety of bevacizumab in patients with malignant gliomas: a systematic review.

Bevacizumab in combination with chemotherapy for the treatment of advanced ovarian cancer: a systematic review.

Evidence for the role of bevacizumab in the treatment of advanced metastatic breast cancer: a review.

Bevacizumab as adjuvant therapy in the management of pterygium: a systematic review and Meta-analysis.

Intravitreal bevacizumab for retinal capillary hemangioblastoma: A case series and literature review.

Bevacizumab in the pre-operative treatment of locally advanced rectal cancer: a systematic review.

Low-dose-intensity bevacizumab with weekly irinotecan for platinum- and taxanes-resistant epithelial ovarian cancer.

High Dose Intravitreal Bevacizumab for Refractory Pigment Epithelial Detachment in Age-related Macular Degeneration.

Transfer of single dose of intravitreal injection of ranibizumab and bevacizumab into milk of sheep.

Comparison of bevacizumab and ranibizumab in age-related macular degeneration: a systematic review and meta-analysis.

The optimal regimen of bevacizumab for recurrent glioblastoma: does dose matter?

HALF-DOSE PHOTODYNAMIC THERAPY COMBINED WITH BEVACIZUMAB FOR POLYPOIDAL CHOROIDAL VASCULOPATHY.

Very low dose bevacizumab for the treatment of epistaxis in patients with hereditary hemorrhagic telangiectasia.

Computed tomography dose optimisation in cystic fibrosis: A review.

Efficacy and safety of bevacizumab plus erlotinib versus bevacizumab or erlotinib alone in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis.

FOLFIRI-bevacizumab and concurrent low-dose radiotherapy in metastatic colorectal cancer: preliminary results of a phase I-II study.