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Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook

Open AccessPublished:March 26, 2020DOI:https://doi.org/10.1016/j.ctrv.2020.102017

      Highlights

      • Bevacizumab (Avastin®), a VEGF-A targeting monoclonal antibody, was the first approved angiogenesis inhibitor.
      • Approved in a range of solid tumor indications, bevacizumab is an important part of the standard of care in oncology.
      • The recently identified immune modulatory roles of VEGF provide a powerful rationale for combination therapies.
      • First clinical studies of the combination of bevacizumab with immune checkpoint inhibitors have shown efficacy.

      Abstract

      When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab’s initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies.
      In the past 15 years, our understanding of VEGF’s role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive.
      Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.

      Keywords

      Introduction

      Angiogenesis and VEGF as therapeutic targets in cancer

      Cancer cells differ fundamentally from normal cells, as a result of having acquired hallmark capabilities that enable tumor growth and progression [
      • Hanahan D.
      • Weinberg R.A.
      Hallmarks of cancer: the next generation.
      ]. Due to their high metabolic demands, growing solid tumors depend on vascularization for provision of nutrients and oxygen and disposal of metabolic waste products. Vascularization can be promoted by angiogenesis, i.e. the generation of new blood vessels by sprouting from existing blood vessels. In normal physiology, angiogenesis plays a vital role in the generation of new vasculature during embryogenesis, but it is mostly quiescent in the adult body, with transient activation during wound healing and the female reproductive cycle. While angiogenesis is tightly controlled by an intricate interplay of pro- and anti-angiogenic factors, it can be activated by growing solid tumors; this so-called “angiogenic switch” is recognized as a hallmark of solid tumors [
      • Hanahan D.
      • Weinberg R.A.
      Hallmarks of cancer: the next generation.
      ]. Indeed, it was shown in animal models that blood vessels were essential to support tumor growth beyond the size allowed by oxygen diffusion alone [
      • Ferrara N.
      • Hillan K.J.
      • Gerber H.P.
      • Novotny W.
      Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.
      ].
      Among tumor-secreted pro-angiogenic factors, Vascular Endothelial Growth Factors (VEGFs) and in particular VEGF-A, have been identified as key factors for inducing tumor angiogenesis. VEGFs activate VEGF signaling in endothelial cells by binding to VEGF receptor tyrosine kinases (VEGFR1-3) [
      • Ferrara N.
      • Gerber H.P.
      • LeCouter J.
      The biology of VEGF and its receptors.
      ]. By these means, VEGF can stimulate the proliferation and survival of endothelial cells and increase the permeability of vessels, thereby supporting the metabolic demands of the growing tumor. Given the importance of angiogenesis in tumor biology, drug development efforts in the past decades have been dedicated to targeting angiogenesis, with VEGF-A as a therapeutic target for inhibition of angiogenesis and normalization of tumor vasculature [
      • Ferrara N.
      • Hillan K.J.
      • Gerber H.P.
      • Novotny W.
      Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.
      ,
      • Ye W.
      The Complexity of Translating Anti-angiogenesis Therapy from Basic Science to the Clinic.
      ]. The validity of this approach was confirmed by a host of in vivo studies in a range of tumor models, demonstrating that inhibition of angiogenesis with a VEGF monoclonal antibody suppressed tumor growth [
      • Ferrara N.
      • Hillan K.J.
      • Gerber H.P.
      • Novotny W.
      Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.
      ].

      Angiogenesis-independent roles of VEGF in cancer development and progression

      The tumor microenvironment is a complex and interactive environment, composed of diverse cell types including endothelial cells, pericytes, immune cells and fibroblasts, as well as the extracellular matrix. Cancer cells influence their microenvironment by releasing extracellular signals, to induce tumor angiogenesis, stimulate cancer cell proliferation and promote immune tolerance to avoid recognition by the immune system. Recent research has shown that VEGF signaling, in particular VEGF-A induced signaling, has additional angiogenesis-independent roles in supporting tumor progression such as effects on: (i) cancer cells; promoting cancer cell proliferation, migration and invasiveness through the activation of vascular endothelial growth factor receptor (VEGFR) 1 signaling; (ii) cancer stem cells; promoting stemness through the activation the VEGFA/neuropilin-1 pathway and self-renewal through VEGFR2/STAT3 signaling; (iii) immune cells; immune suppression in the tumor microenvironment through VEGFR signaling in hematopoietic cells (VEGFR1), dendritic cells (VEGFR3), macrophages (VEGFR1 and VEGFR3), T cells (VEGFR-1 and VEGFR-2) and regulatory T cells (VEGFR1, VEGFR2 and NRP1) [
      • Li Y.L.
      • Zhao H.
      • Ren X.B.
      Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward?.
      ,
      • Yang J.
      • Yan J.
      • Liu B.
      Targeting VEGF/VEGFR to Modulate Antitumor Immunity.
      ,
      • Hegde P.S.
      • Wallin J.J.
      • Mancao C.
      Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics.
      ,
      • Rahma O.E.
      • Hodi F.S.
      The Intersection between Tumor Angiogenesis and Immune Suppression.
      ]. Specifically, VEGF signaling supports immune suppression by a wide range of mechanisms, including aberrant hematopoiesis, impaired maturation and function of dendritic cells and T cells, inhibition of trafficking and survival of activated T cells, as well as promoting the activity of immunosuppressive cells such as regulatory T cells and myeloid- derived suppressor cells [
      • Rahma O.E.
      • Hodi F.S.
      The Intersection between Tumor Angiogenesis and Immune Suppression.
      ]. Considering its role in promoting cancer immune tolerance, targeting of VEGF/VEGFR has been recognized as an approach to enhance antitumor immunity in cancer patients, particularly in combination with cancer immunotherapies.

      Development of bevacizumab, the first therapy targeting VEGF

      The first available anti-angiogenic therapy was bevacizumab (Avastin®, F. Hoffmann La-Roche AG, Switzerland), a humanized monoclonal antibody that binds to all circulating, soluble VEGF-A isoforms. By binding to VEGF-A, bevacizumab prevents the interaction of VEGF-A with VEGFR and thereby inhibits the activation of VEGF signaling pathways that promote neovascularization. In vivo studies demonstrated that bevacizumab inhibits vessel growth, induces regression of newly formed vessels, and normalizes the vasculature to facilitate the delivery of cytotoxic chemotherapy and also has direct effects on tumor cells [
      • Ferrara N.
      • Hillan K.J.
      • Gerber H.P.
      • Novotny W.
      Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.
      ]. Based on its mode of action, clinical development of bevacizumab was focused on tumor types known to be driven by angiogenesis. Specifically, an important role of VEGF in cancer progression was supported by the association of elevated intra-tumoral VEGF expression levels with poorer prognosis or more aggressive disease in several solid tumor types, including metastatic colorectal cancer (mCRC) [
      • Des Guetz G.
      • Uzzan B.
      • Nicolas P.
      • Cucherat M.
      • Morere J.F.
      • Benamouzig R.
      • et al.
      Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature.
      ], non-small-cell lung cancer (NSCLC) [
      • Seto T.
      • Higashiyama M.
      • Funai H.
      • Imamura F.
      • Uematsu K.
      • Seki N.
      • et al.
      Prognostic value of expression of vascular endothelial growth factor and its flt-1 and KDR receptors in stage I non-small-cell lung cancer.
      ], metastatic breast cancer (mBC) [
      • Foekens J.A.
      • Peters H.A.
      • Grebenchtchikov N.
      • Look M.P.
      • Meijer-van Gelder M.E.
      • Geurts-Moespot A.
      • et al.
      High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer.
      ,
      • Manders P.
      • Beex L.V.
      • Tjan-Heijnen V.C.
      • Span P.N.
      • Sweep C.G.
      Vascular endothelial growth factor is associated with the efficacy of endocrine therapy in patients with advanced breast carcinoma.
      ], glioblastoma multiforme (GBM) [
      • Flynn J.R.
      • Wang L.
      • Gillespie D.L.
      • Stoddard G.J.
      • Reid J.K.
      • Owens J.
      • et al.
      Hypoxia-regulated protein expression, patient characteristics, and preoperative imaging as predictors of survival in adults with glioblastoma multiforme.
      ] and ovarian cancer (OC) [
      • Paley P.J.
      • Staskus K.A.
      • Gebhard K.
      • Mohanraj D.
      • Twiggs L.B.
      • Carson L.F.
      • et al.
      Vascular endothelial growth factor expression in early stage ovarian carcinoma.
      ]. Furthermore, renal cell carcinoma (RCC) specifically is recognized as a highly vascular cancer, with dysregulation of hypoxia-inducible factor (HIF) resulting in particularly high levels of VEGF expression [
      • Gao X.
      • McDermott D.F.
      Combinations of Bevacizumab With Immune Checkpoint Inhibitors in Renal Cell Carcinoma.
      ]. Clinical studies with bevacizumab have been conducted in a wide range of indications [
      • Ferrara N.
      • Adamis A.P.
      Ten years of anti-vascular endothelial growth factor therapy.
      ], including the first pivotal studies demonstrating the clinical value of bevacizumab in mCRC and NSCLC, and subsequent pivotal studies in RCC, mBC, GBM, OC and cervical cancer (CC) (Table 1). These studies demonstrated clinical benefits of bevacizumab, mainly used in combination with chemotherapy, across a wide range of solid tumor types. This review provides an overview of clinical experience and lessons learned in the 15 years since the initial approval of bevacizumab. Furthermore, promising results obtained in clinical studies with bevacizumab as part of novel combination treatment approaches are highlighted.
      Table 1Overview of pivotal clinical trials with bevacizumab in approved indications.
      Study name and ID



      Reference
      Study designPatient population

      (N)
      Total number of enrolled patients.
      Treatment lineTreatment arms
      Number of patients included in primary endpoint analysis for each arm.


      (n)
      Dose and regimenEndpointsMedian PFS

      (mths)
      At specified analysis timepoint.
      HR

      (95%CI)

      p-value
      Median OS

      (mths)
      At specified analysis timepoint.
      HR

      (95%CI)

      p-value
      Metastatic colorectal cancer
      AVF2107g

      (NCT00109070)



      Hurwitz H et al (2004) NEJM

      • Hurwitz H.
      • Fehrenbacher L.
      • Novotny W.
      • Cartwright T.
      • Hainsworth J.
      • Heim W.
      • et al.
      Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.




      Hurwitz H et al (2005) JCO

      • Hurwitz H.I.
      • Fehrenbacher L.
      • Hainsworth J.D.
      • Heim W.
      • Berlin J.
      • Holmgren E.
      • et al.
      Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer.
      Phase 3

      blinded

      randomized

      controlled
      mCRC

      (N = 813)
      1L
      • Bev + IFL (n = 402)¢
      • IFL
        (n = 411)






      • Bev + FL
        (n = 110) treatment arm discontinued after first interim analysis demonstrating safety of IFL + Bev
      • Bev:5 mg/kg/every 2 wks
      • I: 125 mg/m2 weekly for 4 wks/6 wks cycle
      • F: 500 mg/m2 weekly for 4 wks/6 wks cycle
      • L: 20 mg/m2 weekly for 4 wks/6 wks cycle
      • 1°: OS
      • 2°: PFS, RR, DOR, SFTY, QoL
      Bev + IFL vs IFL:

      10.6 vs 6.2
      0.54

      (0.45–0.66)

      p0.0001
      and in bold: p-value statistically significant.
      Bev + IFL vs CIFL: 20.3 vs 15.6

      (F/U at 385 deaths)
      0.66

      (0.54–0.81)

      p0.0001
      and in bold: p-value statistically significant.
      Bev + FL vs IFL

      8.8 vs 6.8
      0.86

      (0.60–1.24)

      p = 0.42
      Bev + FL vs IFL

      18.3 vs 15.1
      0.82

      (0.59–1.15)

      p = 0.25)
      AVF0780g



      Kabbinavar F et al (2003) JCO

      • Kabbinavar F.
      • Hurwitz H.I.
      • Fehrenbacher L.
      • Meropol N.J.
      • Novotny W.F.
      • Lieberman G.
      • et al.
      Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer.
      Phase 2,

      open-label

      randomized

      controlled
      mCRC

      (N = 104)
      1L
      • BevL + FU/LV
        (n = 35)
      • BevH + FU/LV
        (n = 33)
      • FU/LV
        (n = 36)
      • BevL: 5 mg/kg/every 2 wks
      • BevH:10 mg/kg/every 2 wks
      • FU 500 mg/m2 + LV 500 mg/m2weekly, 6 wks/8 wks cycle
      • 1°: PFS
      • 2°: OS, RR
      BevL + FU/LV vs FU/LV:

      9.0 vs 5.2
      0.46

      (0.34–0.73)

      p = 0.005
      and in bold: p-value statistically significant.
      BevL + FU/LV vs FU/LV: 17.7 vs 13.60.52

      (NR)

      p = 0.73
      BevH + FU/LV vs FU/LV

      7.2 vs 5.2
      0.66

      (0.54–0.81)

      p = 0.22
      BevH + FU/LV vs FU/LV: 15.2 vs 13.61.01

      (NR)

      p = 0.98
      NO16966

      (NCT00069095)



      Saltz LB et al (2008) JCO

      • Saltz L.B.
      • Clarke S.
      • Diaz-Rubio E.
      • Scheithauer W.
      • Figer A.
      • Wong R.
      • et al.
      Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.
      Phase 2

      blinded

      randomized

      controlled
      mCRC

      (N = 1400)
      1L
      • BevH + XELOX
        (n = 350)
      • BevL + FOLFOX
        (n = 349)
      • XELOX
        (n = 350)
      • FOLFOX-4
        (n = 351)
      • BevL: 5 mg/kg/every 2 wks
      • BevH:7.5 mg/kg/every 3 wks
      • XELOX: (CP: 1000 mg/m2/bid/2 wks/3 wks cycle; OX: 130 mg/m2/3 wks)
      • FOLFOX: (FU: 400 mg/m2/; LV: 200 mg/m2; OX: 200 mg/m2) D1&2/q2 wks
      • 1°: PFS
      • 2°: PFS, OS, BOR, TTF, TtR, DOR
      BevH + XELOX vs XELOX:

      9.4 vs 8.6
      0.77

      (0.63–0.94)
      Using the on-treatment PFS definition, significant results were evident in both the XELOX (HR, 0.61; 97.5% CI, 0.48 to 0.78; P < 0.0001) and FOLFOX-4 subgroups (HR, 0.65; 97.5% CI, 0.50 to 0.84; P = 0.0002).


      p = 0.00263
      Using the on-treatment PFS definition, significant results were evident in both the XELOX (HR, 0.61; 97.5% CI, 0.48 to 0.78; P < 0.0001) and FOLFOX-4 subgroups (HR, 0.65; 97.5% CI, 0.50 to 0.84; P = 0.0002).
      and in bold: p-value statistically significant.
      BevH + XELOX vs XELOX:

      21.4 vs 19.2
      0.84

      (0.68–1.04)

      p = ns
      BevL + FOLFOX vs FOLFOX:

      9.3 vs 7.4


      0.89

      (0.73–1.08)
      Using the on-treatment PFS definition, significant results were evident in both the XELOX (HR, 0.61; 97.5% CI, 0.48 to 0.78; P < 0.0001) and FOLFOX-4 subgroups (HR, 0.65; 97.5% CI, 0.50 to 0.84; P = 0.0002).


      p = 0.18713
      Using the on-treatment PFS definition, significant results were evident in both the XELOX (HR, 0.61; 97.5% CI, 0.48 to 0.78; P < 0.0001) and FOLFOX-4 subgroups (HR, 0.65; 97.5% CI, 0.50 to 0.84; P = 0.0002).
      BevL + FOLFOX vs FOLFOX:

      21.2 vs 20.3
      0.89

      (0.73–1.08)

      p = 0.077
      Bev + XELOX/FOLFOX vs XELOX/FOLFOX

      9.4 vs 8.0

      (at median F/U 15.6mths)
      0.83

      (0.72–0.95)

      p = 0.0023
      and in bold: p-value statistically significant.
      Bev + XELOX/FOLFOX vs XELOX/FOLFOX

      21.3 vs 19.9

      (at median F/U 27.6 mths)
      0.89

      (0.76–1.03)

      p = ns
      E3200

      NCI-2012–02417

      (NCT00025337)



      Giantonio BJ et al (2007) JCO

      Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25(12):1539–44. https://doi.org/10.1200/JCO.2006.09.6305.

      Phase 3

      open-label

      randomized

      controlled
      Advanced or metastatic CRC

      (N = 821)
      2L
      • Bev
        (n = 243)
      • Bev + FOLFOX
        (n = 287)
      • FOLFOX
        (n = 291)
      • Bev: 10 mg/kg/every 2 wks
      • FOLFOX:(FU: 1000 mg/m2;
        LV: 400 mg/m2; OX: 85 mg/m2/D1 only) D1&2/q2wks
      • 1°: OS
      • 2°: PFS, RR (RECIST), SFTY
      Bev + FOLFOX vs FOLFOX:

      7.3 vs 4.7

      (at median F/U: 28mths)

      0.52

      (0.42–0.65)

      p0.0001
      and in bold: p-value statistically significant.
      Bev + FOLFOX vs FOLFOX:

      12.9 vs 10.8

      (at median F/U: 28mths)

      Bev: 10.2
      0.75

      (0.63–0.89)

      p = 0.0011
      and in bold: p-value statistically significant.
      ML18147

      (NCT00700102)



      Bennoua J et al. (2013) Lancet

      • Bennouna J.
      • Sastre J.
      • Arnold D.
      • Osterlund P.
      • Greil R.
      • Van Cutsem E.
      • et al.
      Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.
      Phase 3

      open-label

      randomized

      controlled
      mCRC, progressing within 3 mths after discontinuation of

      1L treatment with bev + chemo

      (N = 820)
      2L
      • Bev + chemo (n = 409)
      • Chemo
        (n = 411)




      Chemo = oxaliplatin- or irinotecan-based, depending on previous 1L treatment, at discretion of investigator
      • Bev: 5 mg/kg/every 2 wk or 7.5 mg/kg/every 3 wks
      • 1°: OS (from randomization)
      • 2°: PFS, OS (from start of 1L treatment), RR (RECIST), SFTY, on-treatment PFS
      Bev + chemo vs chemo:

      5.7 vs 4.1

      (at median F/U: 9.6 and 11.1mths in bev + chemo and chemo groups, respectively)
      0.68

      (0.59–0.78)

      p < 0.0001
      and in bold: p-value statistically significant.
      Bev + chemo vs chemo:

      11.2 vs 9.8

      (at median F/U: 9.6 and 11.1mths in bev + chemo and chemo groups, respectively)
      0.81

      (0.69–0.94);

      p = 0.0062
      and in bold: p-value statistically significant.
      Non-small cell lung cancer
      E4599

      NCI-2012–02947

      (NCT00021060)



      Sandler A et al (2006) NEJM

      • Sandler A.
      • Gray R.
      • Perry M.C.
      • Brahmer J.
      • Schiller J.H.
      • Dowlati A.
      • et al.
      Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
      Phase 2/3

      open-label

      randomized

      controlled
      Advanced (stage IIIB/IV)/Recurrent/Metastatic NSCLC (not squamous type) (N = 850)1L
      • Bev + PTX + CB
        (n = 417)
      • PTX + CB
        (n = 433)
      • Bev: 15 mg/kg/every 3 wks
      • PTX: 200 mg/m2 + CB: AUC6 every 3 wks
      • 1°: OS
      • 2°: PFS, BMKR
      Bev + PTX + CB vs PTX + CB:

      6.2 vs 4.5

      (median F/U:19 mths, min 18 mths, 779 events)
      0.66

      (0.56–0.76)

      p0.001
      and in bold: p-value statistically significant.
      Bev + PTX + CB vs PTX + CB:

      12.3 vs 10.3

      (median F/U:19 mths, min 18 mths, 649 deaths)
      0.79

      (0.67–0.92)

      p = 0.003
      and in bold: p-value statistically significant.
      AVAiL

      /BO117704

      (NCT00806923)

      Reck M et al, (2009), JCO,

      Reck M et al, (2010) AnnOnco

      • Reck M.
      • von Pawel J.
      • Zatloukal P.
      • Ramlau R.
      • Gorbounova V.
      • Hirsh V.
      • et al.
      Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.
      ,
      • Reck M.
      • von Pawel J.
      • Zatloukal P.
      • Ramlau R.
      • Gorbounova V.
      • Hirsh V.
      • Leighl N.
      Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL).
      Phase 3

      open-label

      randomized

      controlled
      Advanced (stage IIIB/IV)/Recurrent/Metastatic NSCLC (not squamous type) (N = 1043)1L
      • BevL + CIS + GEM
        (n = 345)
      • BevH + CIS + GEM
        (n = 351)
      • CIS + GEM
        (n = 347)
      • BevL: 7.5 mg/kg/every 3 wks
      • BevH:15 mg/kg/every 3 wks
      • CIS: 80 mg/m2 + GEM: 1250 mg/m2 D1 + 8/q3 wks
      • 1°: PFS
      • 2°: OS, TTF, RR, DOR, SFTY
      BevL + CIS + GEM vs CIS + GEM:

      6.7 vs 6.1
      0.75

      (0.62–0.91)

      p = 0.0026
      and in bold: p-value statistically significant.


      0.82
      BevL + CIS + GEM vs CIS + GEM:

      13.6 vs 13.1
      0.93

      (0.78–1.11)

      p = 0.420
      BevH + CIS + GEM vs CIS + GEM:

      6.5 vs 6.1

      (at F/U min 7 months or 430 events; 665 PFS events)
      (0.68–0.98)

      p = 0.0301
      and in bold: p-value statistically significant.
      BevH + CIS + GEM vs CIS + GEM:13.4 vs 13.1

      (at F/U: greater than 12.5 mths, max 32 mths; 715 deaths)
      1.03

      (0.86–1.23)

      p = 0.076
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      JO25567
      No NCT number as clinical Trial not registered with clinicaltrials.gov.


      Seto, T et al (2014) Lancet

      • Seto T.
      • Kato T.
      • Nishio M.
      • Goto K.
      • Atagi S.
      • Hosomi Y.
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study.
      Phase 2

      open-label

      randomized

      controlled
      Advanced (stage IIIB/IV or recurrent activated EGFR NSCLC (not squamous type) (N = 152)1L
      • Bev + ERL
        (n = 75)
      • ERL
        (n = 77)
      • Bev: 15 mg/kg/every 3 wks
      • ERL: 150 mg/day
      • 1°: PFS
      • 2°: OS, SFTY
      Bev + ERL vs ERL:

      16.0 vs 9.7

      0.54

      (0.36–0.79)

      p = 0.0015
      and in bold: p-value statistically significant.
      NRNR
      NEJ026
      No NCT number as clinical Trial not registered with clinicaltrials.gov.


      Saito, H et al (2019) Lancet

      • Saito H.
      • Fukuhara T.
      • Furuya N.
      • Watanabe K.
      • Sugawara S.
      • Iwasawa S.
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial.
      Phase 3

      open-label

      randomized
      Advanced (stage IIIB/IV or recurrent activated EGFR NSCLC (not squamous type) (N = 152)1L
      • Bev + ERL
        (n = 114)
      • ERL
        (n = 114)
      • Bev: 15 mg/kg/every 3 wks
      • ERL: 150 mg/day
      • 1°: PFS
      • 2°: OS, SFTY
      Bev + ERL vs ERL:

      16.9 vs 13.3

      (median F/U 12.4 mths)
      0.605

      (0.42–0.89)

      p = 0.016
      and in bold: p-value statistically significant.
      NRNR
      IMpower150

      GO29436 (NCT02366143)

      Socinski et al (2018) NEJM

      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • Orlandi F.
      • Stroyakovskiy D.
      • Nogami N.
      • et al.
      for the IMpower150 Study Group. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.
      Phase 3

      open-label

      randomized
      Stage IV NSCLC, including EGFR/ALK alterations and low PD-L1 expression

      (N = 1202)
      1L
      • Bez + ATZ + PTX + CB
        (n = 400)
      • Bev + PTX + CB
        (n = 400)
      • ATZ + PTX + CB
        (n = 404)
      • Bev: 15 mg/kg
      • ATZ: 1200 mg
      • PTX: 200 mg/kg + CB: AUC6
      • (all every 3 wks/4–6 wks cycle)
      • 1°: PFS, PD
      • 2°: PFS, PD, OR, DOR, OS, BCHM, QoL
      ATZ + Bev PTX + CB vs Bev PTX + CB

      8.3 vs 6.8

      0.59

      (0.50–0.70)

      p < 0.001
      and in bold: p-value statistically significant.
      ATZ + Bev PTX + CB vs Bev PTX + CB

      19.2 vs 14.7 mths
      0.78

      (0.64–0.96)

      p = 0.02
      and in bold: p-value statistically significant.
      Metastatic breast cancer^
      ECOG E2100

      (NCT00028990)



      Miller K et al (2007) NEJM

      • Miller K.
      • Wang M.
      • Gralow J.
      • Dickler M.
      • Cobleigh M.
      • Perez E.A.
      • et al.
      Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.
      Phase 3

      open-label

      randomized

      controlled
      HER2-negative, mBC (N = 673)1L
      • Bev + PTX
        (n = 326)
      • PTX
        (n = 347)
      • Bev: 10 mg/kg/every 2 wks
      • PTX: 90 mg/m2 D1/8/15 every 28 days
      • 1°: PFS
      • 2°: ORR, OS, SFTY, QoL
      Bev + PTX vs PTX:

      11.8 vs 5.9

      (FA: 624 PFS events)
      0.60

      p < 0.001
      and in bold: p-value statistically significant.
      Bev + PTX vs PTX:

      26.7 vs 25.2

      (FA: 483 deaths)
      0.88

      p = 0.16
      AVADO/BO17708

      (NCT00333775)



      Miles DW et al (2010) JCO

      • Miles D.W.
      • Chan A.
      • Dirix L.Y.
      • Cortes J.
      • Pivot X.
      • Tomczak P.
      • et al.
      Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer.
      Phase 3

      blinded

      randomized

      controlled
      HER2-negative, locally recurrent/metastatic breast cancer (N = 736)1L
      • BevL + DTX
        (n = 248)
      • BevH + DTX
        (n = 247)
      • DTX
        (n = 241)
      • BevL: 7.5 mg/kg/every 3 wks
      • BevH: 15 mg/kg/every 3 wks
      • DTX: 100 mg/m2 every 3 wks
      • 1°: PFS
      • 2°: OS, BOR, DOR, TTF, SFTY, QoL
      BevL + DTX vs DTX:

      9.0 vs 8.2
      0.86

      (0.72–1.04)

      p = 0.12

      0.77
      BevL + DTX vs DTX:

      30.8 vs 31.9
      1.05

      (0.81–1.36)

      p = 0.72
      BevH + DTX vs DTX:

      10.1 vs 8.2

      (median F/U: 25mths, 665 events)
      (0.64–0.93)

      p = 0.006
      and in bold: p-value statistically significant.
      BevH + DTX vs DTX:

      30.2 vs 31.9

      (FA: median F/U: 25mths, 394 deaths)
      1.03

      (0.7–1.33)

      p = 0.85
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      RIBBON-1

      BO20094

      (NCT00262067)



      Robert et al (2011) JCO

      • Robert N.J.
      • Dieras V.
      • Glaspy J.
      • Brufsky A.M.
      • Bondarenko I.
      • Lipatov O.N.
      • et al.
      RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer.
      Phase 3

      blinded

      randomized

      controlled
      HER2-negative, recurrent or metastatic breast cancer (N = 1237)1L
      • Bev + CP 1
        (n = 404)
      • Bev + PTX/DTX/DOX/EPI
        (n = 413)
      • CP
        (n = 206)
      • PTX/DTX/DOX/EPI
        (n = 207)
      • Bev: 15 mg/kg/every 3 wks
      • CP: 200 mg/m2 14 days/3 wks
      • PTX: 200 mg/m2/3 wks
      • DTX: 75/100 mg/m2/3 wks
      • DOX: 50–60 mg/m2/3 wks
      • EPI: 90–100 mg/m2/3 wks
      • 1°: PFS
      • 2°: OS, ORR, DOR, 1-year survival rate, SFTY
      Bev + CP vs CP:

      8.6 vs 5.7

      (median F/U: 15.6mths)
      0.69

      0.56–0.84

      p < 0.001
      and in bold: p-value statistically significant.
      Bev + CP vs CP:

      29.0 vs 21.2
      0.847

      0.63–1.14

      p = ns
      Bev + PTX/DTX/DOX/EPI vs PTX/DTX/DOX/EPI:

      9.2 vs 8.0

      (median F/U: 19.2mths)
      0.64

      0.52–0.80

      p < 0.001
      and in bold: p-value statistically significant.
      Bev + PTX/DTX/DOX/EPI vs PTX/DTX/DOX/EPI

      25.2 vs 23.8
      1.032

      0.77–1.38

      p = ns
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      Renal cell carcinoma
      AVOREN/BO17705

      (NCT00738530)



      Escudier B et al (2007) Lancet; Escudier B et al (2010) JCO

      • Escudier B.
      • Bellmunt J.
      • Negrier S.
      • Bajetta E.
      • Melichar B.
      • Bracarda S.
      • et al.
      Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival.
      ,
      • Escudier B.
      • Pluzanska A.
      • Koralewski P.
      • Ravaud A.
      • Bracarda S.
      • Szczylik C.
      • et al.
      investigators AT. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial.
      Phase 3

      blinded

      randomized

      controlled
      Metastatic clear cell RCC (N = 649)1L
      • Bev + IFNα2a
        (n = 327)
      • IFNα2a
        (n = 322)
      • Bev: 10 mg/kg/every 2 wks
      • IFNα2: 9 MIU/x3/wk
      1°: OS

      2°: PFS, ORR, SFTY
      Bev + IFNα2a vs IFNα2a: 10.2 vs 5.4

      (F/U: ~13mths,

      505 events)
      0.63

      (0.52–0.75)

      p = 0.0001
      and in bold: p-value statistically significant.
      Bev + IFNα2a vs IFNα2a: 23.3 vs 21.3

      (F/U to 4.25 yrs]
      0.91

      (0.76–1.10)

      p = 0.3360
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      CALGB 90,206

      (NCT00072046)



      Rini BI et al (2008) JCO

      Rini BI et al (2010) JCO

      • Rini B.I.
      • Halabi S.
      • Rosenberg J.E.
      • Stadler W.M.
      • Vaena D.A.
      • Archer L.
      • et al.
      Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB 90206.
      ,
      • Rini B.I.
      • Halabi S.
      • Rosenberg J.E.
      • Stadler W.M.
      • Vaena D.A.
      • Ou S.-S.
      • et al.
      Bevacizumab Plus Interferon Alfa Compared With Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: CALGB 90206.
      Phase 3

      blinded

      randomized

      controlled
      Metastatic clear cell RCC (N = 732)1L
      • Bev + IFNα2a
        (n = 369)
      • IFNα2a
        (n = 363)
      • Bev: 10 mg/kg/every 2 wks
      • IFNα2: 9 MIU/x3/wk
      1°: OS

      2°: PFS, ORR, SFTY
      Bev + IFNα2a vs IFNα2a: 8.5 vs 5.2

      (F/U: ~657 events)
      0.71

      (0.61–0.83)

      p = 0.0001
      and in bold: p-value statistically significant.
      Bev + IFNα2a vs IFNα2a: 18.3 vs 17.4

      (median F/U 46.2 months]
      0.86

      (0.73–1.01)

      p = 0.069
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      Glioblastoma¢
      AVF3708g

      (NCT00345163)



      Friedman HS et al (2009) JCO

      • Friedman H.S.
      • Prados M.D.
      • Wen P.Y.
      • Mikkelsen T.
      • Schiff D.
      • Abrey L.E.
      • et al.
      Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma.
      Phase 2

      open-label

      randomized
      Relapsed (1st/2nd) GBM (N = 167)2L
      • Bev + IRI
        (n = 115)
      • Bev
        (n = 114)
      • Bev: 10 mg/kg/ 2 wks
      • IRI: 340 OR 125 mg/m2 every 2 wks
      • 1°: OR, PFS (at 6mths)
      • 2°: OS, DOR, SFTY
      Bev + IRI vs Bev:

      5.6 (4.4–6.2) vs

      4.2 (2.9–5.8)

      (F/U: min 6mths for all patients)
      NABev + IRI vs Bev:

      8.7 (7.8–10.9) vs

      9.2 (8.2–10.7)

      (F/U: min 8mths for all patients)
      NA
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      EORTC 26101/MO22968

      (NCT01290939)



      Wick W et al (2017) NEJM

      • Wick W.
      • Gorlia T.
      • Bendszus M.
      • Taphoorn M.
      • Sahm F.
      • Harting I.
      • et al.
      Lomustine and Bevacizumab in Progressive Glioblastoma.
      Phase 3,

      open-label

      randomized
      Relapsed (1st) GBM

      (N = 437)
      2L
      • Bev + LO
        (n = 288)
      • LO
        (n = 149)
      • Bev: 10 mg/kg/ 2 wks
      • LO: 90 mg/m2 every 6 wks
      • 1°: OS
      • 2°: PFS, RR, DOR, SFTY, BCHM
      Bev + LO vs LO:

      4.2 vs 1.5

      (401 progression events)
      0.49

      (0.39–0.61)

      p < 0.001
      and in bold: p-value statistically significant.
      Bev + LO vs LO:

      9.1 (8.1–10.1) vs

      8.6 (7.6–10.4)

      (329 events)
      0.95

      (0.74–1.21)

      p = 0.65
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      AvaGlio/BO21990 (NCT00943826)



      Chinot OL et al (2014) NEJM

      • Chinot O.L.
      • Wick W.
      • Mason W.
      • Henriksson R.
      • Saran F.
      • Nishikawa R.
      • et al.
      Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.
      Phase 3

      blinded

      randomized

      controlled
      Newly diagnosed GBM, WHO perform status ≤ 2

      (N = 921)
      1L
      • Bev + RT + TMZ
        (n = 463)
      • RT + TMZ
        (n = 458)
      Initial
      • Bev: 10 mg/kg/ 2 wks/6 wks,
      • RT: 2 Gy/5 days/weekly/6 wks
      • TMZ: 75 mg/m2 daily up to 49 days
      Maintenance:
      • Bev: 10 mg/kg/ 2 wks/28 days/6 cycles
      • TMZ: 150–200 mg/m2 D1-5
      Monotherapy:
      • Bev: 15 mg/kg/ 3 wks to PD
      • 1°: PFS/OS
      • 2°: PFS/OS/SFTY/QoL
      Bev + RT + TMZ vs RT + TMZ:

      10.6 vs 6.2

      (median F/U ~ 14mths, 741 events)
      0.64

      (0.55–0.74)

      p < 0.0001
      and in bold: p-value statistically significant.
      Bev + RT + TMZ vs RT + TMZ:

      16.8 vs 16.7

      (median F/U ~ 16mths, 741 events)
      0.88

      (0.72–1.02)

      p = 0.10
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      RTOG0825

      (NCT00884741)



      Gilbert MR et al. (2014) NEJM

      • Gilbert M.R.
      • Dignam J.J.
      • Armstrong T.S.
      • Wefel J.S.
      • Blumenthal D.T.
      • Vogelbaum M.A.
      • et al.
      A randomized trial of bevacizumab for newly diagnosed glioblastoma.
      Phase 3

      double-blinded

      randomized

      placebo-controlled
      Newly diagnosed GBM, Karnofsky perform status ≥ 70 (N = 637)1L
      • Bev + RT + TMZ (n = 320)
      • RT + TMZ
        (n = 317)
      Initial:
      • Bev: 10 mg/kg every 2 wks, up to 24 doses
      • RT: 2 Gy/5 days/weekly/6 wks
      • TMZ: 75 mg/m2 daily up to 49 days
      Maintenance:
      • TMZ: 150–200 mg/m2 D1-5/28 days/6–12 cycles
      • 1°: OS and PFS (co-primary)
      Bev + RT + TMZ vs RT + TMZ:

      10.7 vs 7.3

      (median F/U 20.5 mths, 512 events)
      0.79

      (0.66–0.94)

      p < 0.007
      and in bold: p-value statistically significant.
      Bev + RT + TMZ vs RT + TMZ:

      15.7 vs 16.1

      (median F/U 20.5 mths, 413 events)
      1.13

      (0.93–1.37)

      p < 0.21
      and in bold: p-value statistically significant.
      Ovarian, fallopian tube and primary peritoneal cancer
      GOG-0218

      NCI-2009–00590

      (NCT00262847)



      Burger et al (2011) NEJM

      • Burger R.A.
      • Brady M.F.
      • Bookman M.A.
      • Fleming G.F.
      • Monk B.J.
      • Huang H.
      • et al.
      Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer.




      Tewari et al (2019)

      • Tewari K.S.
      • Burger R.A.
      • Enserro D.
      • Norquist B.M.
      • Swisher E.M.
      • Brady M.F.
      • et al.
      Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer.
      Phase 3

      blinded

      randomized

      controlled
      Advanced (Stage IIIB-IV) OC, FTC or PPC, post debulking surgery

      (N = 1873)
      1L
      • Bev6 + PTX + CB:
        (n = 625)
      • Bev22 + PTX + CB:
        (n = 623)
      • PTX + CB
        (n = 625)
      • Bev6: 15 mg/kg/ 3 wks/6 cycles
      • Bev22: 15 mg/kg/ 3 wks/22 cycles
      • PTX: 175 mg/m2 + CB: AUC6 every 3 wks/6 cycles
      • 1°: PFS
      • 2°: OS, SFTY, QoL
      Bev6 + PTX + CB vs PTX + CB:

      11.2 vs 10.3
      0.908

      (0.795–1.040)

      p = 0.16
      Bev6 + PTX + CB vs PTX + CB:

      38.7 vs 39.3
      1.036

      (0.83–1.30)

      p = 0.76
      Bev22 + PTX + CB vs PTX + CB: 14.1 vs 10.3

      (F/U: 17.4mths, 1201 events)
      0.717

      (0.625–0.824)

      p0.001
      and in bold: p-value statistically significant.
      Bev22 + PTX + CB vs PTX + CB:

      39.7 vs 39.3

      (F/U: 17.4mths, 444 deaths)
      1.036

      (0.73–1.15)

      p = 0.45
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      Bevconc+maint + PTX + CB vs PT + CB:

      43.4 vs 41.1

      Bevconc PTX + CB

      vs PTX + CB:

      40.8 vs 41.1
      0.96

      (0.85–1.09)

      p = 0.53

      1.06

      (0.94–1.20)

      p = 0.34
      ICON7

      (NCT00483782)



      Perren et al (2011) NEJM,



      Oza AM et al (2015) Lancet Onco

      • Oza A.M.
      • Cook A.D.
      • Pfisterer J.
      • Embleton A.
      • Ledermann J.A.
      • Pujade-Lauraine E.
      • et al.
      Icon trial investigators. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial.
      ,
      • Perren T.J.
      • Swart A.M.
      • Pfisterer J.
      • Ledermann J.A.
      • Pujade-Lauraine E.
      • Kristensen G.
      • et al.
      Icon Investigators. A phase 3 trial of bevacizumab in ovarian cancer.
      Phase 3

      open label

      randomized

      controlled
      Advanced (Stage IIIB-IV) or high-risk Stage I/IIA OC, FTC or PPC, post debulking surgery

      (N = 1528)
      1L
      • Bev6 + PTX + CB
      • (n = 719)
      • Bev18 + PTX + CB
      • (n = 470)
      • PTX + CB
      • (n = 696)
      • Bev6: 7.5 mg/kg/
      • 3 wks/6 cycles
      • Bev18: 7.5 mg/kg/
      • 3 wks/22 cycles
      • PTX: 175 mg/m2 + CB: AUC5/6 every 3 wks/6 cycles)
      • 1°: PFS
      • 2°: OS, ORR, DOR, PFI, SFTY, QoL, HEc
      Bevall + PTX + CB vs PTX + CB:

      19.9 vs 17.5

      (F/U at median 19.4 and 16.3 mths)
      0.93

      (0.83–1.05)

      p = 0.25
      Bevall + PTX + CB vs PTX + CB:

      58.6 vs 58.0

      (F/U at median 48.8 and 48.6 mths)
      0.99

      (0.85–1.14)

      p = 0.85
      Subgroup analyses high-risk subset
      High-risk of progression subgroup, defined at time of primary progression-free survival analysis (stage IV disease, inoperable stage III disease, or suboptimally debulked [greater than1cm] stage III disesae).
      :
      Bevall + PTX + CB vs PTX + CB:

      16.0 vs 10.5

      (F/U: at median 15.6 and 10.1 mths)
      0.73

      (0.610.88)

      p = 0.001
      and in bold: p-value statistically significant.
      Bevall + PTX + CB vs PTX + CB

      39.7 vs 30.2

      (F/U at median 38.9 and 29.0 mths)
      0.78

      (0.630.97)

      p = 0.03
      and in bold: p-value statistically significant.


      AVF4095g/

      OCEANS

      (NCT00434642)



      Aghajanian C et al (2012) JCO; Aghajanian C et al (2015) GynOnco

      • Aghajanian C.
      • Blank S.V.
      • Goff B.A.
      • Judson P.L.
      • Teneriello M.G.
      • Husain A.
      • et al.
      OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.
      ,
      • Aghajanian C.
      • Goff B.
      • Nycum L.R.
      • Wang Y.V.
      • Husain A.
      • Blank S.V.
      Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer.
      Phase 3

      blinded

      randomizedcontrolled
      Recurrent platinum sensitive OC, FTC or PPC (N = 484)2L
      • Bev + CB + GEM
      • (n = 242)
      • CB + GEM : CB + GEM
      • (n = 242)
      • Bev: 15 mg/kg/
      • every 3 wks
      • GEM: 1000 mg/m2
      • +CB: AUC4)
      • D1 + 8/q3w
      • 1°: PFS
      • 2°: ORR, OS, DOR
      Bev + CB + GEM vs CB + GEM:

      12.4 vs 8.4

      (F/U: ~24mths,

      338 events)
      0.484

      (0.388–0.605)

      p0.0001
      and in bold: p-value statistically significant.
      Bev + CB + GEM vs CB + GEM:

      33.6 vs 32.9

      (F/U: ~57mths,

      353 events)
      0.952

      (0.77–1.17)

      p = 0.6479
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      GOG-0213/ML01187

      (NCT00565851)



      Coleman RL et al (2017) Lancet Oncol, Coleman RT et al (2018) ASCO

      • Coleman R.L.
      • Enserro D.
      • Spirtos N.
      • Herzog T.J.
      • Sabbatini P.
      • Armstrong D.K.
      • et al.
      Abstract 5501: A phase III randomized controlled trial of secondary surgical cytoreduction (SSC) followed by platinum-based combination chemotherapy (PBC), with or without bevacizumab (B) in platinum-sensitive, recurrent ovarian cancer (PSOC): A NRG Oncology/Gynecologic Oncology Group (GOG) study. 2018 ASCO Annual Meting.
      ,
      • Coleman R.L.
      • Brady M.F.
      • Herzog T.J.
      • Sabbatini P.
      • Armstrong D.K.
      • Walker J.L.
      • et al.
      Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial.
      Phase 3

      open label

      randomized

      controlled
      Recurrent platinum sensitive OC, FTC or PPC

      (N = 674)
      2L
      • Bev + PTX + CB
      • (n = 377)
      • PTX + CB
      • (n = 337)
      • Bev: 15 mg/kg/
      • 3 wks/6 cycles
      • PTX: 175 mg/m2 + CB: AUC5 every 3 wks/6 cycles
      • 1°: OS
      • 2°: PFS, SFTY, QoL, BMKR
      Bev + PTX + CB vs PTX + CB:

      13.8 vs 10.4

      (F/U: 49.6mths)
      0.628

      (0.534–0.739)

      p0.0001
      and in bold: p-value statistically significant.
      Bev + PTX + CB vs PTX + CB:

      42.2 vs 37.3

      (F/U: 49.6mths, 215 deaths)
      0.823

      (0.68–1.00)

      p = 0.0447
      and in bold: p-value statistically significant.
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      AURELIA

      MO22224 (NCT00976911)



      Pujade-Lauraine E et al (2014) JCO

      • Pujade-Lauraine E.
      • Hilpert F.
      • Weber B.
      • Reuss A.
      • Poveda A.
      • Kristensen G.
      • et al.
      Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial.
      Phase 3

      open label

      randomized

      controlled
      Recurrent platinum resistant OC, FTC or PPC (N = 361)2L
      • Bev + pgDOX + PTX/TCN
      • (n = 377)
      • pgDOX + PTX/TCN
      • (n = 182)
      • Bev: 10 mg/kg/2 wks OR 15 mg/kg/3 wks
      • pgDOX: 40 mg/m2/4 wks;
      • PTX: 1.25 mg/m2/D1, 8, 15/4 wks;
      • TCN: 4 mg/m2/D1, 8, 15/4 wks OR 1.25 mg/m2/D1, 5/3 wks
      • 1°: PFS
      • 2°: OS, ORR, SFTY, QoL
      Bev + pgDOX + PTX/TCN vs pgDOX + PTX/TCN:

      6.7 vs 3.4

      (F/U: ~13.5mths)
      0.480

      (0.38–0.60)

      p0.001
      and in bold: p-value statistically significant.
      Bev + pgDOX + PTX/TCN vs pgDOX + PTX/TCN:

      16.6 vs 13.3

      (F/U: ~70% death)
      0.85

      (0.85–1.08)

      p = 0.174
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      Cervical cancer
      GOG-0240

      NCI-2009–01084

      (NCT00803062)



      Tewari KS et al (2014) NEJM;

      Tewari KS et al (2017) Lancet

      • Tewari K.S.
      • Sill M.W.
      • Long 3rd, H.J.
      • Penson R.T.
      • Huang H.
      • Ramondetta L.M.
      • et al.
      Improved survival with bevacizumab in advanced cervical cancer.
      ,
      • Tewari K.S.
      • Sill M.W.
      • Penson R.T.
      • Huang H.
      • Ramondetta L.M.
      • Landrum L.M.
      • et al.
      Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).
      Phase 3

      open label

      randomized

      controlled
      Persistent or Recurrent (stage IVB) CC (N = 452)1L/2L
      • Bev + PTX + CIS (n = 115)
      • Bev + PTX + TCN
      • (n = 112)
      • PTX + CIS
      • (n = 114)
      • PTX + TCN
      • (n = 111)
      • Bev: 15 mg/kg/
      • 3 wks
      • CIS: 50 mg/m2 every 3 wks;
      • PTX: 135 OR 175 mg/m2 every 3 wks;
      • TCN: 0.75 mg/m2 D1/3 every 3 wks
      • 1°: OS, PFS, TR, SFTY
      • 2°: QoL, BMKR
      Bev + PTX + CIS/PTX + TCN l vs PTX + CIS/PTX + TCN:

      8.2 vs 5.9

      (F/U: ~20.8mths, 367 events)
      0.67

      (0.54–0.82)

      p = 0.002
      and in bold: p-value statistically significant.
      Bev + PTX + CIS/PTX + TCN vs PTX + CIS/PTX + TCN l:

      16.8 vs 13.3

      (FA:348 deaths)
      0.77

      (0.62–0.95)

      p = 0.007
      and in bold: p-value statistically significant.
      Bev + PTX + CIS vs PTX + CIS:

      8.2 vs 5.9
      updated clinical trials.gov data.
      0.67
      updated clinical trials.gov data.


      (0.54–0.82)

      p = 0.002
      and in bold: p-value statistically significant.
      updated clinical trials.gov data.
      Bev + PTX + CIS vs PTX + CIS

      17.5 vs 14.3
      0.68

      (0.48–0.97)

      p = 0.04
      and in bold: p-value statistically significant.
      Bev + PTX + TCN vs PTX + TCN

      7.36 vs 5.29
      updated clinical trials.gov data.
      NR
      updated clinical trials.gov data.


      p = NR
      updated clinical trials.gov data.
      Bev + PTX + TCN vs PTX + TCN

      16.2 vs 12.7

      (F/U: ~20.8mths, 223 events)
      0.74

      (0.53–1.05)

      p = 0.09
      Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      Abbreviations: AUC(X): dose calculated to produce an area under the concentration–time curve of (X) mg per milliliter; Bev: Bevacizumab; BMKR: Biomarker assessment; BOR: Best overall response; CP: Capecitabine; CB: Carboplatin; CIS: Cisplatin; CT: Chemotherapy; DOR: Duration of response; DTX: Docetaxel; EGFR: Epidermal growth factor receptor; EPI: Epirubicin; ERL: Erlotinib; GEM: Gemcitabine; FOLFOX: Folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX); FU: fluorouracil; F/U: Follow-up; HEc: Health Economics; FA: Final analysis; FIGO: International Federation of Gynecology and Obstetrics; HER2: human epidermal growth factor receptor 2 (EGFR2/HER2); IFNα2a: Interferon-alfa 2a LV: leucovorin; LO: Lomustine; OX: oxilaplatin; mth(s): month(s); NR: Not reported/recorded; ns: not significant; OR: objective response; ORR: objective response rate; OS: Overall survival; PD: Progressive disease; PFI: Progression-free interval; PFS: Progression-free survival; PTX: Paclitaxel; QoL: Quality of life; RECIST: response evaluation criteria in solid tumors; RR: Response rate; RT: Radiotherapy; TCN: Topotecan; TMZ: temozolomide: TTF: Time to treatment failure; TtR: Time to response; SFTY: Safety/Toxicity; wk(s): week(s); XELOX: capecitabine (XEL/Xeloda) and oxaliplatin (OX); yr(s): year(s) 1L: First-line treatment; 2L: Second-line treatment.
      Footnotes: Underlined indicates combination targeted therapy.
      ^Only approved for use in EU.
      ¢Only approved for use in US.
      * and in bold: p-value statistically significant.
      Total number of enrolled patients.
      § Number of patients included in primary endpoint analysis for each arm.
      # At specified analysis timepoint.
      ¤ Using the on-treatment PFS definition, significant results were evident in both the XELOX (HR, 0.61; 97.5% CI, 0.48 to 0.78; P < 0.0001) and FOLFOX-4 subgroups (HR, 0.65; 97.5% CI, 0.50 to 0.84; P = 0.0002).
      ¥ Potential confounding influence on overall survival due to cross-over or treatment with subsequent therapies administered after progressive disease in greater than 10% patients.
      No NCT number as clinical Trial not registered with clinicaltrials.gov.
      + High-risk of progression subgroup, defined at time of primary progression-free survival analysis (stage IV disease, inoperable stage III disease, or suboptimally debulked [greater than1cm] stage III disesae).
      updated clinical trials.gov data.

      Clinical experience with bevacizumab

      Initially approved for treatment of mCRC in the United States (US) and the European Union (EU) in 2004 and 2005, respectively, bevacizumab is now approved in a range of solid tumor indications (Fig. 1), and currently marketed in 134 countries worldwide. As one of the first therapies targeting the tumor microenvironment [
      • Ferrara N.
      • Hillan K.J.
      • Gerber H.P.
      • Novotny W.
      Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.
      ], the addition of bevacizumab to standard-of-care chemotherapy provided a novel and effective therapeutic option in a range of advanced cancers with poor prognosis, which had seen only minor improvements in treatment options before the advent of targeted therapies (Table 1). Although more than a dozen other anti-angiogenic therapies - mostly small molecule multi-kinase inhibitors targeting the VEGF and/or other pro-angiogenic or oncogenic signaling pathways - have been approved in the meantime [
      • Ferrara N.
      • Adamis A.P.
      Ten years of anti-vascular endothelial growth factor therapy.
      ,
      • Al-Abd A.M.
      • Alamoudi A.J.
      • Abdel-Naim A.B.
      • Neamatallah T.A.
      • Ashour O.M.
      Anti-angiogenic agents for the treatment of solid tumors: Potential pathways, therapy and current strategies - A review.
      ,
      • Rajabi M.
      • Mousa S.A.
      The Role of Angiogenesis in Cancer Treatment.
      ], bevacizumab remains the most widely used and most thoroughly characterized angiogenesis inhibitor. Since 1997, more than 37 000 patients have been treated with bevacizumab in manufacturer-sponsored clinical trials across a broad range of indications (Table 2) [

      Roche AG. Avastin/bevacizumab Periodic Benefit-Risk Evaluation Report/Periodic Safety Update Report 1092163; 2019.

      ]. Overall, it is estimated that more than 3 500 000 patients have received bevacizumab as part of their cancer treatment. The clinical impact of bevacizumab in each approved indication is discussed in more detail below.
      Figure thumbnail gr1
      Fig. 1Timeline of bevacizumab approvals. Abbreviations: 1L: First-line treatment; 2L: Second-line treatment; ALK: anaplastic lymphoma kinase; BC: breast cancer; CC: Cervical cancer; CRC: Colorectal cancer; EGFR: Epidermal growth factor receptor; EMA: European Medicines Agency; FDA: (US) Food and Drug Administration; FTC: Fallopian tube cancer; GBM: Glioblastoma; PPC: Primary peritoneal cancer; NSCLC: Non-small-cell lung cancer, Nsq-NSCLC: non-squamous non-small-cell lung cancer; RCC: Renal cell carcinoma. Footnotes: * Provisional approval granted under FDA’s accelerated approval program based on surrogate endpoint. Full approval granted, based on totality of evidence of bevacizumab in GBM.
      Table 2Overall patient exposure to bevacizumab in clinical trial and post-marketing setting.
      IndicationPatient exposure in manufacturer-sponsored clinical trials
      Completed, current and ongoing as per February 2019 [19].
      Estimated patient exposure in post-marketing setting
      As per February 2019 [19].
      Gastrointestinal cancer/CRC12 3192 024 159
      Breast cancer10 242325 154
      Lung cancer/NSCLC8 316630 173
      Renal cancer1 30543 247
      Glioblastoma multiforme1 08397 728
      Female reproductive tract cancer and cervical cancer/OC, FTC, PPC + CC1 907326 062
      Other cancer2 02429 237
      Total37 1963 500 59
      Abbreviations: CC: Cervical cancer; CRC: Colorectal cancer; FTC: Fallopian tube cancer; NSCLC: Non-small cell lung cancer; OC: Ovarian cancer; PPC; Primary peritoneal cancer.
      Footnotes:
      Completed, current and ongoing as per February 2019

      Roche AG. Avastin/bevacizumab Periodic Benefit-Risk Evaluation Report/Periodic Safety Update Report 1092163; 2019.

      .
      § As per February 2019

      Roche AG. Avastin/bevacizumab Periodic Benefit-Risk Evaluation Report/Periodic Safety Update Report 1092163; 2019.

      .

      Metastatic colorectal cancer

      Colorectal cancer is one of the most common cancers and patients frequently present with metastatic disease. Prior to the availability of targeted therapies, treatment options for patients with mCRC were limited to chemotherapeutic agents. In 2004, AVF2107g, the first phase 3 study evaluating bevacizumab in first-line treatment of mCRC demonstrated significantly longer survival of patients with the addition of bevacizumab to chemotherapy (irinotecan, fluorouracil and leucovorin) compared to chemotherapy alone (10.6 vs 6.2 months, hazard ratio [HR] 0.66; p < 0.001) [
      • Hurwitz H.
      • Fehrenbacher L.
      • Novotny W.
      • Cartwright T.
      • Hainsworth J.
      • Heim W.
      • et al.
      Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
      ,
      • Hurwitz H.I.
      • Fehrenbacher L.
      • Hainsworth J.D.
      • Heim W.
      • Berlin J.
      • Holmgren E.
      • et al.
      Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer.
      ] (Table 1). These results led to the approval of bevacizumab as the first targeted therapy for patients with mCRC (Fig. 1). Several additional randomized studies with bevacizumab in mCRC followed, showing benefit of bevacizumab in combination with newer chemotherapy regimens (fluorouracil/leucovorin or capecitabine/oxaliplatin [XELOX]) in the first-line setting (AVF0780g and NO16966) and in combination with leucovorin/fluorouracil and oxaliplatin [FOLFOX] in the second-line setting (E3200), as well as the persistent benefit with bevacizumab treatment in multiple lines (e.g. ML18147) [
      • Bennouna J.
      • Sastre J.
      • Arnold D.
      • Osterlund P.
      • Greil R.
      • Van Cutsem E.
      • et al.
      Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.
      ,
      • Kabbinavar F.
      • Hurwitz H.I.
      • Fehrenbacher L.
      • Meropol N.J.
      • Novotny W.F.
      • Lieberman G.
      • et al.
      Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer.
      ,
      • Saltz L.B.
      • Clarke S.
      • Diaz-Rubio E.
      • Scheithauer W.
      • Figer A.
      • Wong R.
      • et al.
      Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.
      ,

      Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25(12):1539–44. https://doi.org/10.1200/JCO.2006.09.6305.

      ].
      While other anti-angiogenic agents are approved in mCRC, their use is limited to later treatment lines, [
      • Mody K.
      • Baldeo C.
      • Bekaii-Saab T.
      Antiangiogenic Therapy in Colorectal Cancer.
      ]. Several targeted therapies have become available in mCRC, including epidermal growth factor receptor (EGFR) inhibitors for KRAS, NRAS and BRAF wild-type mCRC, as well as BRAF and HER2 inhibitors for mCRC with BRAF mutations or human epidermal growth factor receptor 2 (HER2)-amplifications, respectively [
      • Van Cutsem E.
      • Cervantes A.
      • Adam R.
      • Sobrero A.
      • Van Krieken J.H.
      • Aderka D.
      • et al.
      ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Colon Cancer, Version 3.2019 - September 26, 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf.

      ]. Furthermore, the use of immune checkpoint inhibitors is a novel treatment approach for mCRC with microsatellite instability and DNA mismatch repair deficiency. Since its approval over a decade ago, bevacizumab remains a standard-of-care therapy in mCRC, recommended in combination with chemotherapy for induction and as maintenance treatment [
      • Van Cutsem E.
      • Cervantes A.
      • Adam R.
      • Sobrero A.
      • Van Krieken J.H.
      • Aderka D.
      • et al.
      ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Colon Cancer, Version 3.2019 - September 26, 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf.

      ].

      Non-small cell lung cancer

      Lung cancer is among the most common cancers in both in men and women, with the majority of patients presenting with advanced disease. Prior to the availability of targeted therapies, median survival for patients with non-squamous advanced NSCLC, the most common form of lung cancer, was only seven to eight months, despite aggressive platinum-based chemotherapy [
      • Schiller J.H.
      • Harrington D.
      • Belani C.P.
      • Langer C.
      • Sandler A.
      • Krook J.
      • et al.
      Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
      ]. Bevacizumab was among the first targeted therapies available for this cancer and the first drug to help these patients live longer than one year when added to chemotherapy. Approval in the first-line setting was based on results of the pivotal study E4599 which demonstrated a reduction in the risk of death by 21% (HR: 0.79, p = 0.003) with the addition of bevacizumab to carboplatin plus paclitaxel compared to carboplatin plus paclitaxel alone and an improvement in median OS from 10.3 to 12.3 months [
      • Sandler A.
      • Gray R.
      • Perry M.C.
      • Brahmer J.
      • Schiller J.H.
      • Dowlati A.
      • et al.
      Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
      ] (Table 1, Fig. 1). Further clinical studies confirmed progression-free survival (PFS) and overall survival (OS) benefits for bevacizumab in combination with chemotherapy in the first-line setting (AVAiL), as well as in the maintenance setting [
      • Barlesi F.
      • Scherpereel A.
      • Gorbunova V.
      • Gervais R.
      • Vikstrom A.
      • Chouaid C.
      • et al.
      Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial.
      ,
      • Barlesi F.
      • Scherpereel A.
      • Rittmeyer A.
      • Pazzola A.
      • Ferrer Tur N.
      • Kim J.H.
      • et al.
      Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089).
      ,
      • Patel J.D.
      • Socinski M.A.
      • Garon E.B.
      • Reynolds C.H.
      • Spigel D.R.
      • Olsen M.R.
      • et al.
      PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer.
      ,
      • Reck M.
      • von Pawel J.
      • Zatloukal P.
      • Ramlau R.
      • Gorbounova V.
      • Hirsh V.
      • et al.
      Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.
      ,
      • Reck M.
      • von Pawel J.
      • Zatloukal P.
      • Ramlau R.
      • Gorbounova V.
      • Hirsh V.
      • Leighl N.
      Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL).
      ].
      In about 10–20% of patients with metastatic NSCLC, targetable driver mutations are present, most frequently aberrations in the EGFR gene. Patients with EGFR-mutated tumors are usually treated with EGFR tyrosine kinase inhibitor (TKI) monotherapy; however, although multiple lines of TKI therapy are now available, resistance eventually occurs in almost all patients. Results of the pivotal study JO25567 showed that the addition of bevacizumab to the EGFR TKI erlotinib reduced the risk of disease progression by 46% (HR: 0.54, p = 0.015) compared to erlotinib alone [
      • Seto T.
      • Kato T.
      • Nishio M.
      • Goto K.
      • Atagi S.
      • Hosomi Y.
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study.
      ] (Table 1). Based on these results, the combination therapy of bevacizumab and erlotinib was recently approved for treatment of NSCLC with EGFR-activating mutations (Fig. 1). These results were further confirmed by two phase 3 studies (NEJ026 and Artemis) [
      • Saito H.
      • Fukuhara T.
      • Furuya N.
      • Watanabe K.
      • Sugawara S.
      • Iwasawa S.
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial.
      ,

      Zhou Q, Wu Y-L, Cheng Y, Liu Y, Chen G, Cui J, Yang N, et al. Abstract 1480O: CTONG 1509: Phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR-mutated NSCLC. In ESMO 2019 Congress; Barcelona, Spain. Annals of Oncology; 2019.

      ]. Besides EGFR TKIs, further targeted therapies have become available in the past decade for patients with NSCLC, targeting other molecular aberrations such as anaplastic lymphoma kinase (ALK), BRAF, neurotrophic tropomyosin receptor kinase (NTRK) and ROS1 [

      Planchard D, Popat D, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up - updated version published 18 September 2019 by the ESMO Guidelines Committee; 2019. https://www.esmo.org/content/download/227453/3874538/file/ESMO-CPG-mNSCLC-18SEPT2019.pdf.

      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer, Verion 7.2019 - August 30, 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

      ]. Furthermore, the advent of cancer immunotherapy has profoundly transformed the treatment landscape of NSCLC, with immune checkpoint inhibitors achieving durable responses in subsets of patients [

      Planchard D, Popat D, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up - updated version published 18 September 2019 by the ESMO Guidelines Committee; 2019. https://www.esmo.org/content/download/227453/3874538/file/ESMO-CPG-mNSCLC-18SEPT2019.pdf.

      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer, Verion 7.2019 - August 30, 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

      ]. Recently, the combination of the immune checkpoint inhibitor atezolizumab and bevacizumab was approved in non-squamous NSCLC, based on the pivotal study IMpower150, which demonstrated a reduction in the risk of progression by 38% (HR 0.62, p < 0.001) with the addition of atezolizumab to bevacizumab and chemotherapy compared to bevacizumab and chemotherapy alone; this benefit was observed regardless of EGFR and ALK status [
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • Orlandi F.
      • Stroyakovskiy D.
      • Nogami N.
      • et al.
      for the IMpower150 Study Group. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.
      ].
      Even though the treatment landscape for NSCLC has substantially evolved, bevacizumab likely remains an important part of the treatment landscape in the future, including as a partner in combinations with other targeted therapies such as erlotinib and atezolizumab [

      Planchard D, Popat D, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up - updated version published 18 September 2019 by the ESMO Guidelines Committee; 2019. https://www.esmo.org/content/download/227453/3874538/file/ESMO-CPG-mNSCLC-18SEPT2019.pdf.

      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer, Verion 7.2019 - August 30, 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

      ].

      Metastatic breast cancer

      Breast cancer is the most common cancer in women, with a particularly dire prognosis for women with advanced and metastatic breast cancer. Median survival remains at only around three years, despite a range of available treatment options, including chemotherapeutic agents, as well as endocrine agents and trastuzumab for estrogen-receptor-positive and HER2-positive breast cancers, respectively [
      • Cardoso F.
      • Senkus E.
      • Costa A.
      • Papadopoulos E.
      • Aapro M.
      • Andre F.
      • et al.
      4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4).
      ]. In particular, the treatment of patients with triple-negative breast cancer (TNBC) is a clinical challenge due to the lack of targeted therapies, and for this subset of patients bevacizumab offered the first targeted treatment option. The pivotal study ECOG 2100 in HER2-negative mBC demonstrated a reduction in the risk of disease progression by 40% (HR: 0.60, p < 0.001) with the addition of bevacizumab to paclitaxel compared to paclitaxel alone [
      • Miller K.
      • Wang M.
      • Gralow J.
      • Dickler M.
      • Cobleigh M.
      • Perez E.A.
      • et al.
      Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.
      ] (Table 1), resulting in the approval of bevacizumab for first-line treatment of mBC (Fig. 1). Subsequent studies with bevacizumab in the first-line and second-line setting confirmed significant improvements in median PFS; however, as for many commonly used chemotherapy regimens in mBC, a clear OS benefit could not be demonstrated [
      • Brufsky A.M.
      • Hurvitz S.
      • Perez E.
      • Swamy R.
      • Valero V.
      • O'Neill V.
      • et al.
      RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer.
      ,
      • Miles D.W.
      • Chan A.
      • Dirix L.Y.
      • Cortes J.
      • Pivot X.
      • Tomczak P.
      • et al.
      Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer.
      ,
      • Robert N.J.
      • Dieras V.
      • Glaspy J.
      • Brufsky A.M.
      • Bondarenko I.
      • Lipatov O.N.
      • et al.
      RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer.
      ]. While bevacizumab’s approval in the mBC indication was reversed by the US Food and Drug Administration (FDA) approximately two years following its initial approval due to reassessment of its risk/benefit balance, this assessment has been controversial and bevacizumab remains approved for mBC in the EU, as well as many other countries. Moreover, based on results from the RIBBON-1 study [
      • Robert N.J.
      • Dieras V.
      • Glaspy J.
      • Brufsky A.M.
      • Bondarenko I.
      • Lipatov O.N.
      • et al.
      RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer.
      ], the indication was extended to include first-line treatment of mBC in combination with capecitabine in patients where other chemotherapy options including taxanes or anthracyclines are not considered appropriate.
      Despite divergent regulatory assessments, bevacizumab continues to be recommended in selected patients with mBC [
      • Cardoso F.
      • Senkus E.
      • Costa A.
      • Papadopoulos E.
      • Aapro M.
      • Andre F.
      • et al.
      4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4).
      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Breast Cancer, Version 3.2019 - September 6, 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.

      ]. In recent years, a range of novel targeted therapies have become available for the treatment of mBC, including EGFR/HER2 pathway inhibitors other than trastuzumab, CDK4/6 inhibitors, poly ADP ribose polymerase (PARP)-inhibitors for breast cancer (BRCA) gene-mutated advanced breast cancer, and immune checkpoint inhibitors for first-line treatment of metastatic TNBC.

      Renal cell carcinoma

      Roughly one third of patients of patients with RCC present with advanced or metastatic disease, which is associated with very low 5-year survival rates. Prior to the availability of other targeted therapies, the standard of care treatment for these patients was surgery combined with interferon alfa 2b and median survival was only approximately seven months [
      • Li P.
      • Wong Y.N.
      • Armstrong K.
      • Haas N.
      • Subedi P.
      • Davis-Cerone M.
      • et al.
      Survival among patients with advanced renal cell carcinoma in the pretargeted versus targeted therapy eras.
      ]. Bevacizumab was the first antiangiogenic treatment to show clinical efficacy in advanced RCC. The pivotal study AVOREN demonstrated a reduction in the risk of disease progression (secondary endpoint) by 37% (HR: 0.63, p = 0.0001) with the addition of bevacizumab to interferon alfa 2b compared to interferon alfa 2b alone [
      • Escudier B.
      • Bellmunt J.
      • Negrier S.
      • Bajetta E.
      • Melichar B.
      • Bracarda S.
      • et al.
      Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival.
      ,
      • Escudier B.
      • Pluzanska A.
      • Koralewski P.
      • Ravaud A.
      • Bracarda S.
      • Szczylik C.
      • et al.
      investigators AT. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial.
      ] (Table 1), which, however, did not translate into an OS benefit (primary endpoint). Based on these results, bevacizumab was approved for treatment of RCC in the first-line setting in combination with interferon alfa 2b (Fig. 1). The results from the pivotal study were confirmed in the subsequent CALGB 902065 study [
      • Rini B.I.
      • Halabi S.
      • Rosenberg J.E.
      • Stadler W.M.
      • Vaena D.A.
      • Archer L.
      • et al.
      Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB 90206.
      ,
      • Rini B.I.
      • Halabi S.
      • Rosenberg J.E.
      • Stadler W.M.
      • Vaena D.A.
      • Ou S.-S.
      • et al.
      Bevacizumab Plus Interferon Alfa Compared With Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: CALGB 90206.
      ].
      Angiogenesis is a prominent characteristic of RCC and many anti-angiogenic agents have since been approved in RCC, including the VEGFR1-3 inhibitor tivozanib, the multi-kinase inhibitors sorafenib, sunitinib, pazopanib, axitinib, cabozantinib and lenvatinib, as well as the mammalian target of rapamycin (mTOR) inhibitors temsirolimus and everolimus that additionally target oncogenic signaling [
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • Rioux-Leclercq N.
      • Bex A.
      • Khoo V.
      • et al.
      Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Kidney Cancer, Version 2.2020 - August 5 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf.

      ]. Anti-angiogenic therapy remains a standard treatment approach in RCC, with bevacizumab as an important treatment option among other available angiogenesis inhibitors. Recently, cancer immunotherapy was added to the arsenal for treatment of RCC [
      • Gao X.
      • McDermott D.F.
      Combinations of Bevacizumab With Immune Checkpoint Inhibitors in Renal Cell Carcinoma.
      ], with the combination of the PD-1 inhibitor nivolumab and the anti-CTLA-4 antibody ipilimumab for first-line treatment for poor- and intermediate-risk advanced RCC [
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • Rioux-Leclercq N.
      • Bex A.
      • Khoo V.
      • et al.
      Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Kidney Cancer, Version 2.2020 - August 5 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf.

      ]. Furthermore, a combination therapy targeting both immune checkpoints and angiogenesis, the PD-L1 inhibitor avelumab and multi-kinase inhibitor axitinib has been approved by the FDA and the European Medicine Agency (EMA), and promising results from the IMmotion151 study investigating the combination of bevacizumab and atezolizumab further support this novel treatment approach.

      Glioblastoma

      GBM is a rare but devastating cancer, with a median survival of 15 months despite aggressive treatment with radio- and chemotherapy [
      • Stupp R.
      • Brada M.
      • van den Bent M.J.
      • Tonn J.C.
      Pentheroudakis G, ESMO Guidelines Working Group. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ]. Chemotherapeutic treatment options are limited to agents crossing the blood–brain barrier, which are associated with potential adverse reactions. In this difficult-to-treat disease, bevacizumab has shown unprecendented response rates. The pivotal study AVF3708g in relapsed or progressing GBM demonstrated PFS benefits compared to historic controls in recurrent GBM, with a median PFS of 4.2 months and 5.6 months with bevacizumab as a single agent and in combination with irinotecan, respectively [
      • Friedman H.S.
      • Prados M.D.
      • Wen P.Y.
      • Mikkelsen T.
      • Schiff D.
      • Abrey L.E.
      • et al.
      Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma.
      ] (Table 1). Based on these results, bevacizumab was approved for treatment of relapsed or progressing GBM in the US and other countries, but not in the EU (Fig. 1). Subsequently, the phase 3 study EORTC 26101 confirmed the PFS benefit, demonstrating a reduction in the risk of disease progression (secondary endpoint) by 51% (HR: 0.49, p < 0.0001) with the addition of bevacizumab to lomustine compared to lomustine alone [
      • Wick W.
      • Gorlia T.
      • Bendszus M.
      • Taphoorn M.
      • Sahm F.
      • Harting I.
      • et al.
      Lomustine and Bevacizumab in Progressive Glioblastoma.
      ]. However, the observed PFS benefits did not translate into an OS benefit in these pivotal studies. Nevertheless, epidemiologic data provide indirect evidence that the availability of bevacizumab positively impacts OS in this patient population, as cancer registry data show an increase in median survival, the timing of which coincides with the approval of bevacizumab in this indication [
      • Johnson D.R.
      • Leeper H.E.
      • Uhm J.H.
      Glioblastoma survival in the United States improved after Food and Drug Administration approval of bevacizumab: a population-based analysis.
      ,
      • Johnson D.R.
      • Omuro A.M.P.
      • Ravelo A.
      • Sommer N.
      • Guerin A.
      • Ionescu-Ittu R.
      • et al.
      Overall survival in patients with glioblastoma before and after bevacizumab approval.
      ].
      In first-line treatment of GBM, the pivotal study AvaGlio/BO21990 demonstrated a reduction in the risk of disease progression (co-primary endpoint) by 36% (HR: 0.64, p < 0.0001) with the addition of bevacizumab to radiotherapy and temozolomide compared to radiotherapy and temozolomide alone, though this did not translate into an OS benefit (co-primary endpoint), similar results were obtained in the RTOG0825 study [
      • Chinot O.L.
      • Wick W.
      • Mason W.
      • Henriksson R.
      • Saran F.
      • Nishikawa R.
      • et al.
      Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.
      ,
      • Gilbert M.R.
      • Dignam J.J.
      • Armstrong T.S.
      • Wefel J.S.
      • Blumenthal D.T.
      • Vogelbaum M.A.
      • et al.
      A randomized trial of bevacizumab for newly diagnosed glioblastoma.
      ]. Notably, bevacizumab was the first pharmacologic treatment for patients with GBM demonstrating clear-cut evidence of a longer maintenance of quality of life and performance status [
      • Chinot O.L.
      • Wick W.
      • Mason W.
      • Henriksson R.
      • Saran F.
      • Nishikawa R.
      • et al.
      Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.
      ]. Furthermore, treatment with bevacizumab was associated with reduced glucocorticoid requirements, which are used to treat brain edema in patients with GBM but have potentially serious side effects, causing notable morbidity. In the bevacizumab treatment group, a higher proportion of patients who were receiving glucocorticoids at baseline were able to discontinue glucocorticoids compared to radiotherapy and temozolomide alone (66.3 vs 47.1%), and the time to initiation of glucocorticoids was longer in patients who were not receiving glucocorticoids at baseline (12.3 months vs 3.7 months) (Table 1).
      Based on known biomarkers of GBM, therapies targeting EGFR, platelet-derived growth factor receptor (PDGFR) or other molecular alterations, as well as immune checkpoint inhibitors have been investigated in clinical trials, in combination with bevacizumab or sequentially, albeit with limited success [
      • Touat M.
      • Idbaih A.
      • Sanson M.
      • Ligon K.L.
      Glioblastoma targeted therapy: updated approaches from recent biological insights.
      ]. Bevacizumab remains the only approved anti-angiogenic agent and targeted therapy in GBM and continues to be among the preferred recommended regimens [

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Central Nervous System Cancers, Version 3.2019 - October 18, 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf.

      ] in countries in which it is approved for this indication. Efforts to further optimize treatment approaches are ongoing [
      • Kim M.M.
      • Umemura Y.
      • Leung D.
      Bevacizumab and Glioblastoma: Past, Present, and Future Directions.
      ].

      Ovarian, fallopian tube and primary peritoneal cancer

      OC, FTC and PPC are insidious and patients frequently present with advanced disease. Although most patients achieve remission after initial treatment, the rate of recurrence is high and most patients eventually relapse. Prior to the availability of targeted therapies, the treatment approach remained largely unchanged for over 40 years and was limited to surgical debulking and platinum-based chemotherapy. Bevacizumab was the first targeted therapy approved for treatment of advanced OC, FTC and PP and represented a much-needed new therapeutic option that could delay tumor progression compared with chemotherapy alone. Approval in the front-line setting was based on the results from the pivotal study GOG-0218, which showed a significant increase in median PFS from 10.3 months to 14.1 months with the addition of bevacizumab [
      • Tewari K.S.
      • Burger R.A.
      • Enserro D.
      • Norquist B.M.
      • Swisher E.M.
      • Brady M.F.
      • et al.
      Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer.
      ,
      • Burger R.A.
      • Brady M.F.
      • Bookman M.A.
      • Fleming G.F.
      • Monk B.J.
      • Huang H.
      • et al.
      Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer.
      ] (Table 1; Fig. 1). Although in GOG-0218 there was no significant difference in OS between treatment arms in the overall population, in the subgroup of patients with stage IV disease, bevacizumab used concurrently to chemotherapy followed by maintenance treatment demonstrated an improvement in OS compared to chemotherapy alone (median OS 42.8 months vs 32.6 months, HR 0.75) [
      • Tewari K.S.
      • Burger R.A.
      • Enserro D.
      • Norquist B.M.
      • Swisher E.M.
      • Brady M.F.
      • et al.
      Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer.
      ]. The efficacy of bevacizumab in the front-line setting was confirmed in ICON7, and further key phase 3 clinical trials in the platinum-sensitive (OCEANS and GOG-0213) and platinum-resistant (AURELIA) setting led to its approval in the recurrent setting [
      • Oza A.M.
      • Cook A.D.
      • Pfisterer J.
      • Embleton A.
      • Ledermann J.A.
      • Pujade-Lauraine E.
      • et al.
      Icon trial investigators. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial.
      ,
      • Perren T.J.
      • Swart A.M.
      • Pfisterer J.
      • Ledermann J.A.
      • Pujade-Lauraine E.
      • Kristensen G.
      • et al.
      Icon Investigators. A phase 3 trial of bevacizumab in ovarian cancer.
      ,
      • Aghajanian C.
      • Blank S.V.
      • Goff B.A.
      • Judson P.L.
      • Teneriello M.G.
      • Husain A.
      • et al.
      OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.
      ,
      • Aghajanian C.
      • Goff B.
      • Nycum L.R.
      • Wang Y.V.
      • Husain A.
      • Blank S.V.
      Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer.
      ,
      • Coleman R.L.
      • Enserro D.
      • Spirtos N.
      • Herzog T.J.
      • Sabbatini P.
      • Armstrong D.K.
      • et al.
      Abstract 5501: A phase III randomized controlled trial of secondary surgical cytoreduction (SSC) followed by platinum-based combination chemotherapy (PBC), with or without bevacizumab (B) in platinum-sensitive, recurrent ovarian cancer (PSOC): A NRG Oncology/Gynecologic Oncology Group (GOG) study. 2018 ASCO Annual Meting.
      ,
      • Coleman R.L.
      • Brady M.F.
      • Herzog T.J.
      • Sabbatini P.
      • Armstrong D.K.
      • Walker J.L.
      • et al.
      Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial.
      ,
      • Pujade-Lauraine E.
      • Hilpert F.
      • Weber B.
      • Reuss A.
      • Poveda A.
      • Kristensen G.
      • et al.
      Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial.
      ] (Table 1, Fig. 1).
      Five years later, bevacizumab remains an important standard of care and the only approved anti-angiogenic agent for treatment of OC, FTC and PPC [

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 2.2019 - September 17, 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf.

      ,
      • Colombo N.
      • Sessa C.
      • du Bois A.
      • Ledermann J.
      • McCluggage W.G.
      • McNeish I.
      • et al.
      Querleu D, ESMO-ESGO Ovarian Cancer Consensus Conference Working Group. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.
      ,

      Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C, ESMO Guidelines Working Group. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24 Suppl 6:vi24–32. https://doi.org/10.1093/annonc/mdt333.

      ]. Recently, new therapeutic options have demonstrated significant benefit and in particular the advent of PARP inhibitors, which target tumors with BRCA mutations or other deficiencies in homologous recombination DNA repair, has significantly changed the treatment landscape [

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 2.2019 - September 17, 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf.

      ,
      • Colombo N.
      • Sessa C.
      • du Bois A.
      • Ledermann J.
      • McCluggage W.G.
      • McNeish I.
      • et al.
      Querleu D, ESMO-ESGO Ovarian Cancer Consensus Conference Working Group. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.
      ,

      Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C, ESMO Guidelines Working Group. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24 Suppl 6:vi24–32. https://doi.org/10.1093/annonc/mdt333.

      ]. Several phase 3 trials are currently investigating bevacizumab in combination with PARP inhibitors (PAOLA-1) and immune checkpoint inhibitors (IMagyn050, ATALANTE, AGLO OVAR 2.29, NRG-GY009) [

      Kurtz JE, Marth C, Oaknin A, Asselain B, Baumann KH, Cibula D, Vergote I, et al. Abstract TPS5607: ATALANTE (ENGOT-ov29): A randomized, double-blinded, phase III study of atezolizumab versus placebo in patients with late relapse of epithelial ovarian, fallopian tube, or peritoneal cancer treated by platinum-based chemotherapy and bevacizumab. In 2018 ASCO Annual Meeting. Journal of Clinical Oncology; 2018. https://doi.org/10.1200/JCO.2018.36.15_suppl.TPS5607.

      ,

      Liu JF, Herold C, Luo W, Penson R, Horowitz N, Konstantinopoulos P, Castro C, et al. A phase 2 trial of combination nivolumab and bevacizumab in recurrent ovarian cancer. In ESMO 2018 Congress; Munich, Germany. Annals of Oncology; 2018. https://doi.org/10.1093/annonc/mdy285.

      ,

      Moore KN, Okamoto A, Wu F, Lin YG, Pignata S. Abstract 985TiP: IMagyn050/GOG3015/ENGOT-ov39: A randomized, double-blind, phase III study of atezolizumab vs placebo combined with chemotherapy + bevacizumab in stage III-IV ovarian, fallopian tube & peritoneal cancers (OC). In ESMO 2017 Congress; Madrid, Spain. Annals of Oncology; 2017.

      ]. First results from the PAOLA-1 study in front-line OC indicate a PFS benefit with the combination of bevacizumab and the PARP inhibitor olaparib in the maintenance setting [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Perol D.
      • Gonzalez-Martin A.
      • Berger R.
      • et al.
      Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian.
      ].

      Cervical cancer

      Patients with recurrent CC have a median survival of 12 to 24 months. Until a few years ago, no targeted therapies for CC were available, and treatment options were limited to chemotherapy, with only short-lived responses [
      • Friedlander M.
      • Grogan M.
      U. S. Preventative Services Task Force. Guidelines for the treatment of recurrent and metastatic cervical cancer.
      ]. Bevacizumab represented the first significant progress in many years in the treatment of persistent or recurrent CC, filling a high unmet medical need and setting the global standard for this patient population. The pivotal study GOG-0240 demonstrated a reduction in the risk of death by 23% (HR: 0.77, p = 0.007) and a reduction in the risk of disease progression by 33% (HR: 0.67, p = 0.002) with the addition of bevacizumab to paclitaxel and cisplatin or paclitaxel and topotecan compared to paclitaxel and cisplatin or paclitaxel and topotecan alone, [
      • Tewari K.S.
      • Sill M.W.
      • Long 3rd, H.J.
      • Penson R.T.
      • Huang H.
      • Ramondetta L.M.
      • et al.
      Improved survival with bevacizumab in advanced cervical cancer.
      ,
      • Tewari K.S.
      • Sill M.W.
      • Penson R.T.
      • Huang H.
      • Ramondetta L.M.
      • Landrum L.M.
      • et al.
      Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).
      ] (Table 1), resulting in the approval of bevacizumab (Fig. 1).
      Bevacizumab remains the only approved anti-angiogenic therapy in CC, and continues to be recommended by the guidelines as the standard of care [
      • National Comprehensive Cancer
      Network (NCCN). Guidelines Insights: Cervical Cancer, Version 2.2015, Featured Update to the NCCN Guidelines.
      ,
      • Marth C.
      • Landoni F.
      • Mahner S.
      • McCormack M.
      • Gonzalez-Martin A.
      • Colombo N.
      • et al.
      Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Cervical Cancer, Version 5.2019 - September 16, 2019; 2019. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf.

      ]. Recently, the immune checkpoint inhibitor pembrolizumab has been approved for use in recurrent and metastatic CC expressing the programmed cell death protein 1 (PD-1) [

      United States Food and Drug Administration (U.S. FDA). Pembrolizumab approval for cervical cancer; 2018.

      ,
      • Pfaendler K.S.
      • Liu M.C.
      • Tewari K.S.
      Bevacizumab in Cervical Cancer: 5 Years After.
      ]. The combination of bevacizumab with the immune checkpoint inhibitor atezolizumab and chemotherapy is currently being evaluated in the phase 3 study BEATcc.

      Safety profile across indications

      Bevacizumab’s safety profile is mainly based on its use in combination with the respective standard chemotherapy regimens in a range of advanced malignancies. Based on its pharmacokinetic (PK) profile and mode of action, no clinically significant interactions are expected or were observed between bevacizumab and chemotherapies or vice versa [

      European Medicines Agency (EMA). Avastin Summary of Product Characteristics (SmPC); 2017.

      ,

      United States Food and Drug Administration (U.S. FDA). Avastin US Prescribing Information (USPI); 2018.

      ]. More recently, studies of combination therapies with bevacizumab and other monoclonal antibodies such as atezolizumab have shown that the safety profile of the combination treatment was consistent with the safety profiles of the individual treatments, and no new safety signals were identified [
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • Orlandi F.
      • Stroyakovskiy D.
      • Nogami N.
      • et al.
      for the IMpower150 Study Group. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.
      ].
      The most frequent adverse events in patients treated with bevacizumab include hypertension, fatigue or asthenia, diarrhea and abdominal pain [

      European Medicines Agency (EMA). Avastin Summary of Product Characteristics (SmPC); 2017.

      ,

      United States Food and Drug Administration (U.S. FDA). Avastin US Prescribing Information (USPI); 2018.

      ] (Table 3). Bevacizumab is associated with a dose-dependent increased incidence of hypertension, which requires monitoring of blood pressure during treatment and can, in most cases, be successfully managed with standard antihypertensive treatment. Furthermore, bevacizumab is associated with the development of proteinuria, with the highest incidence in renal cancer, the severity of which may range from asymptomatic to nephrotic syndrome; therefore, monitoring is recommended.
      Table 3Important adverse events associated with bevacizumab.
      Adverse eventIncidence all grades
      All incidence values based upon calculated incidence from Bevacizumab / Avastin® PSUR/PBRER [19].
      Bleeding/Hemorrhage39.1% (2524/6449)

      Up to 44.2% (354/801) in NSCLC
      Pulmonary hemorrhage2.1% (134/6449)

      Up to 8.9% (71/801) in NSCLC
      Proteinuria10.5% (729/6950)

      Up to 20.2% (68/337) in RC
      Arterial thromboembolic events

      (ATE)
      2.5% (173/6950)

      Up to 3.8% (24/624) in GBM
      Hypertension27.1% (1881/6950)

      Up to 36.4% (227/624) in GBM
      Congestive heart failure

      (CHF)
      1.2% (78/6449)

      Up to 3.3% (46/1399) in BC
      Wound healing complications3.2% (204/6449)

      Up to 5.4% (34/624) in GBM
      GI perforations1.9% (121/6449)

      Up to 9.2% (20/218) in CC
      Posterior Reversible Encephalopathy Syndrome (PRES)0.2% (11/6449)
      Neutropenia43.1% (2777/6449)

      Up to 71.1% (1584/2208) in OC
      Venous thromboembolic events (VTE)6.7%% (469/6950).

      Up to 11.7% (159/1363) in CRC
      Fistulae (Non-GI)1.0% (64/6449)

      Up to 3.7% (8/218) in CC
      Thrombotic microangiopathy<0.1% (2/6449)
      Pulmonary hypertension0.1% (5/6449)
      Ovarian failureNone in clinical trials

      Sporadic cases reported
      Hypersensitivity and infusion reactions27.6% (1720/6449)

      Up to 35.5% (784/2208) in OC
      Gallbladder perforation<0.1% (1/6449) in OC
      Peripheral sensory neuropathy25.4% (1638/6449)

      Up to 61.5% (134/218) in CC
      Non-CHF/ATE cardiac disorders2.7% (174/6449)

      Up to 3.8% (85/2208) in OC
      Osteonecrosis of the jaw (ONJ)0.1% (4/6449).

      Up to 0.2% (3/1399) in BC
      Necrotizing fasciitis0% in clinical trials

      87 reported in ARISg and MedDRA safety databases
      Off-label intravitreal use17,332 cases reported in safety databases up to 31 December 2014:
      • SAEs: 23.3% (5595/17332)
      • Drug-related systemic AEs: 27.8% (4812/17332)
      • Anterior eye AEs: 8.9% (1537/17332)
      • Posterior eye AEs: 39.0% (6759/17332)
      Infection (use with temozolomide and radiotherapy in GBM)44.9% (2896/6449)

      Up to 52.7% (329/624) in GBM
      Thrombocytopenia26.8% (1726/6449)

      Up to 50.1% (1106/2208) in OC
      Abbreviations: AE: Adverse event; ATE: arterial thromboembolic event; BC: Breast cancer; CC: Cervical cancer; CHF: Congestive heart failure; CRC: Colorectal cancer; GBM: Glioblastoma; GI: Gastrointestinal; NA: Not applicable; NSCLC: Non-small cell lung cancer; OC: Ovarian cancer; RC: Renal cancer; SAEs: Serious adverse event.
      Footnotes:
      All incidence values based upon calculated incidence from Bevacizumab / Avastin® PSUR/PBRER

      Roche AG. Avastin/bevacizumab Periodic Benefit-Risk Evaluation Report/Periodic Safety Update Report 1092163; 2019.

      .
      The most frequent serious adverse events include gastrointestinal (GI) perforations, hemorrhage and arterial thromboembolism [

      European Medicines Agency (EMA). Avastin Summary of Product Characteristics (SmPC); 2017.

      ,

      United States Food and Drug Administration (U.S. FDA). Avastin US Prescribing Information (USPI); 2018.

      ] (Table 3). The highest incidence of potentially serious GI perforations was observed in patients with CC, where all affected patients had a history of prior pelvic radiation exposure. Further risk factors for GI perforation include colorectal cancer and other inflammatory GI disorders, anti-inflammatory medications and abdominal surgery or other procedures. Serious tumor-associated hemorrhage events were observed in specific indications, such as pulmonary hemorrhage/hemoptysis in NSCLC, or more rarely GI-bleeding in mCRC patients and central nervous system (CNS) bleeding in patients with CNS metastases. An increased incidence of arterial thromboembolism was observed across indications, and included cerebrovascular accidents, myocardial infarction, transient ischemic attacks, and other arterial thromboembolic reactions; risk factors include a history of arterial thromboembolism, diabetes or more than 65 years of age. Of note, patients with a history of lower than grade 4 thromobembolism, as well as patients on stable anticoagulant treatment were typically not excluded in clinical trials. In a safety study in front-line treatment of OC, where treatment with bevacizumab was continued until disease progression (median treatment duration 15.5 months), the first occurrence for most AEs of special interest was during early cycles of treatment, when bevacizumab was given concomitant to chemotherapy; however, in some patients proteinuria and hypertension appeared only after more prolonged bevacizumab exposure [
      • Oza A.M.
      • Selle F.
      • Davidenko I.
      • Korach J.
      • Mendiola C.
      • Pautier P.
      • et al.
      Efficacy and Safety of Bevacizumab-Containing Therapy in Newly Diagnosed Ovarian Cancer: ROSiA Single-Arm Phase 3B Study.
      ].
      Importantly, the use of bevacizumab is contraindicated during pregnancy, due to the essential role of VEGF-signaling in embryofetal development and angiogenesis, as evidenced in non-clinical studies by reproductive toxicity and malformations, and reported cases of fetal abnormalities in the post-marketing setting [

      European Medicines Agency (EMA). Avastin Summary of Product Characteristics (SmPC); 2017.

      ,

      United States Food and Drug Administration (U.S. FDA). Avastin US Prescribing Information (USPI); 2018.

      ]. Accordingly, bevacizumab must not be given to pregnant women, and the use of effective contraception during treatment, as well as up to six months after treatment, is recommended [

      European Medicines Agency (EMA). Avastin Summary of Product Characteristics (SmPC); 2017.

      ]. Furthermore, wound healing complications are related to bevacizumab’s mode of action, and therefore treatment initiation should be appropriately timed in relation to major surgeries.
      Overall, bevacizumab is well-tolerated in a diverse range of tumor types and in combination with a range of chemotherapy regimens. Based on extensive clinical and post-marketing experience, its safety profile is well-characterized and adverse events are manageable in the vast majority of cases.

      Lessons learnt and future outlook

      An broadly applicable strategy for treatment of solid tumors

      In the 15 years since its first approval, bevacizumab has changed the treatment paradigm for a range of solid tumor indications by offering novel treatment options as the first or one of the first available targeted therapies. Although, in the meantime, a host of targeted therapies have become available, initiating the era of personalized medicine, bevacizumab still remains part of the standard of care in many indications. As a hallmark of cancer, targeting of angiogenesis had been proposed as a universal approach for the treatment of solid tumors. Despite its well-established efficacy, the precise modes of action of bevacizumab remain incompletely understood, and their individual contribution to its overall effect may be tumor-type specific [
      • Hegde P.S.
      • Wallin J.J.
      • Mancao C.
      Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics.
      ]. For example, in NSCLC, the initially predominant mode of action during induction treatment may be vascular normalization to improve the delivery of cytotoxic chemotherapeutic agents, while in the subsequent maintenance treatment phase, bevacizumab’s mode of action depends more on anti-angiogenic effects. In OC, where bevacizumab has demonstrated superior efficacy in a maintenance setting, the predominant mode of action of VEGF inhibition may be more dependent on its anti-angiogenic properties by preventing new vessel formation and reduction of microvascular permeability. In GBM, where bevacizumab has been shown to improve quality of life by decreasing the requirement for glucocorticosteroids, the anti-permeability mode of action of VEGF inhibition may be key. Since the initial characterization of the role of VEGF in angiogenesis, additional roles of VEGF in the complex tumor microenvironment were identified, which could be harnessed to further increase the efficacy of bevacizumab as a cancer therapy. Based on deeper understanding of the angiogenesis-independent roles of VEGF in tumor development, such as its immune-modulatory roles, promising approaches for combination treatments with potentially synergistic efficacy are currently being investigated.
      Across indications, bevacizumab has provided statistically significant and clinically meaningful PFS benefits as well as improvements in other efficacy measures, such as increased response rates, improved quality of life and reduced tumor size [
      • Ferrara N.
      • Adamis A.P.
      Ten years of anti-vascular endothelial growth factor therapy.
      ]. Statistically significant OS benefits were not observed in all studies; however, interpretation of OS is complex, since a relatively long post-progression period and lack of control for subsequent therapy are likely to obscure a potential benefit. In most studies with bevacizumab the primary endpoint was median PFS, which is generally considered a sensitive measure of drug activity and an appropriate endpoint for evaluating the treatment effect of cancer therapies [
      • Buyse M.
      • Burzykowski T.
      • Carroll K.
      • Michiels S.
      • Sargent D.J.
      • Miller L.L.
      • et al.
      Progression-free survival is a surrogate for survival in advanced colorectal cancer.
      ,
      • Montagnani F.
      • Di Leonardo G.
      • Pino M.S.
      • Martella F.
      • Perboni S.
      • Ribecco A.
      • et al.
      Progression-free Survival as a Surrogate End-point in Advanced Colorectal Cancer Treated with Antiangiogenic Therapies.
      ,
      • Korn R.L.
      • Crowley J.J.
      Overview: progression-free survival as an endpoint in clinical trials with solid tumors.
      ].
      While clinical benefits of VEGF-inhibition with bevacizumab have been demonstrated in a wide range of solid tumor indications, in some other solid tumors, including pancreatic cancer, gastric cancer and prostate cancer, bevacizumab showed no significant treatment effect. Potential reasons for the unresponsiveness to anti-angiogenic treatment include dense tumor stroma preventing sufficient perfusion of the tumor, redundancy of angiogenic factors resulting in treatment resistance and interference of other signaling pathways with angiogenic signaling [
      • Li Y.L.
      • Zhao H.
      • Ren X.B.
      Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward?.
      ,
      • Zhang Z.
      • Ji S.
      • Zhang B.
      • Liu J.
      • Qin Y.
      • Xu J.
      • et al.
      Role of angiogenesis in pancreatic cancer biology and therapy.
      ,
      • Bilusic M.
      • Wong Y.N.
      Anti-angiogenesis in prostate cancer: knocked down but not out.
      ,
      • Cereda V.
      • Formica V.
      • Roselli M.
      Issues and promises of bevacizumab in prostate cancer treatment.
      ,
      • Nienhuser H.
      • Schmidt T.
      Angiogenesis and Anti-Angiogenic Therapy in Gastric Cancer.
      ].

      Identification of biomarkers for patient selection and monitoring

      Unlike most other targeted therapies, bevacizumab is used in general patient populations not pre-selected by a biomarker. Despite intense efforts, no predictive biomarker has been identified that would enable a more personalized use of bevacizumab [
      • Jayson G.C.
      • Kerbel R.
      • Ellis L.M.
      • Harris A.L.
      Antiangiogenic therapy in oncology: current status and future directions.
      ,
      • Lambrechts D.
      • Lenz H.J.
      • de Haas S.
      • Carmeliet P.
      • Scherer S.J.
      Markers of response for the antiangiogenic agent bevacizumab.
      ]. Plasma levels of VEGF-A (pVEGFA) were investigated as a potential predictive biomarker for the clinical efficacy of bevacizumab in 14 pivotal randomized trials in 7 indications and in a study of samples from five clinical trials, with inconsistent or inconclusive results [
      • Miles D.W.
      • de Haas S.L.
      • Dirix L.Y.
      • Romieu G.
      • Chan A.
      • Pivot X.
      • et al.
      Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer.
      ,
      • Nixon A.B.
      • Pang H.
      • Starr M.D.
      • Friedman P.N.
      • Bertagnolli M.M.
      • Kindler H.L.
      • et al.
      Alliance for Clinical Trials In Oncology. Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance).
      ,
      • Van Cutsem E.
      • de Haas S.
      • Kang Y.K.
      • Ohtsu A.
      • Tebbutt N.C.
      • Ming Xu.J.
      • et al.
      Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial.
      ,
      • Hegde P.S.
      • Jubb A.M.
      • Chen D.
      • Li N.F.
      • Meng Y.G.
      • Bernaards C.
      • et al.
      Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab.
      ]. Further, a prospective evaluation of pVEGF in mBC (MERiDiAN) did not support baseline pVEGF-A as a predictive biomarker for bevacizumab efficacy [
      • Miles D.
      • Cameron D.
      • Bondarenko I.
      • Manzyuk L.
      • Alcedo J.C.
      • Lopez R.I.
      • et al.
      Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation.
      ,
      • Miles D.
      • Cameron D.
      • Hilton M.
      • Garcia J.
      • O'Shaughnessy J.
      Overall survival in MERiDiAN, a double-blind placebo-controlled randomised phase III trial evaluating first-line bevacizumab plus paclitaxel for HER2-negative metastatic breast cancer.
      ]. Other potential biomarkers of resistance to anti-angiogenic treatment which have been investigated in a range of indications include VEGF-D, angiopoietin 2 (Ang2), hepatocyte growth factor (HGF), placental growth factor (PlGF), stromal cell-derived factor 1 (SDF-1), microvascular density (MVD), interleukin (IL) 6 and IL-8 [
      • Lambrechts D.
      • Lenz H.J.
      • de Haas S.
      • Carmeliet P.
      • Scherer S.J.
      Markers of response for the antiangiogenic agent bevacizumab.
      ,
      • Nixon A.B.
      • Pang H.
      • Starr M.D.
      • Friedman P.N.
      • Bertagnolli M.M.
      • Kindler H.L.
      • et al.
      Alliance for Clinical Trials In Oncology. Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance).
      ,

      Weickhardt AJ, Williams D, Lee C, Simes J, Murone C, Wilson K, Cummins M, Australasian GI Trials Group, et al.. Abstract 3531: Vascular endothelial growth factors (VEGF) and VEGF receptor expression as predictive biomarkers for benefit with bevacizumab in metastatic colorectal cancer (mCRC): Analysis of the phase III MAX study. In 2011 ASCO Annual Meeting. Journal of Clinical Oncology; 2011. https://doi.org/10.1200/jco.2011.29.15_suppl.3531.

      ,

      Nixon AB, Halabi S, Shterev I, Starr MD, Brady JC, Dutcher JP, Hopkins JO, Alliance for Clinical Trials in Oncology, et al. Abstract 4520: Identification of predictive biomarkers of overall survival (OS) in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (I) with or without bevacizumab (B): Results from CALGB 90206 (Alliance). In 2013 ASCO Annual Meeting. Journal of Clinical Oncology; 2013. https://doi.org/10.1200/jco.2013.31.15_suppl.4520.

      ,
      • Boige V.
      • Malka D.
      • Bourredjem A.
      • Dromain C.
      • Baey C.
      • Jacques N.
      • et al.
      Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma.
      ,
      • Kopetz S.
      • Hoff P.M.
      • Morris J.S.
      • Wolff R.A.
      • Eng C.
      • Glover K.Y.
      • et al.
      Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance.
      ,
      • Matsusaka S.
      • Hanna D.L.
      • Cao S.
      • Zhang W.
      • Yang D.
      • Ning Y.
      • et al.
      Prognostic Impact of IL6 Genetic Variants in Patients with Metastatic Colorectal Cancer Treated with Bevacizumab-Based Chemotherapy.
      ,

      Secord AA, Tritchler D, Liu Y, Starr MD, Brady JC, Lankes HA, Hurwitz H, et al. Abstract 5521: Prognostic and predictive blood-based biomarkers (BMs) in patients (pts) with advanced epithelial ovarian cancer (EOC) treated with carboplatin–paclitaxel (CP) ± bevacizumab (BEV): Results from GOG-0218. In 2016 ASCO Annual Meeting. Journal of Clinical Oncology; 2016. https://doi.org/10.1200/JCO.2016.34.15_suppl.5521.

      ,
      • Bais C.
      • Mueller B.
      • Brady M.F.
      • Mannel R.S.
      • Burger R.A.
      • Wei W.
      • Marien K.M.
      • et al.
      Tumor Microvessel Density as a Potential Predictive Marker for Bevacizumab Benefit: GOG-0218 Biomarker Analyses.
      ]. Attempts to identify a VEGF-dependent, predictive vasculature gene signature did not provide positive results [
      • Brauer M.J.
      • Zhuang G.
      • Schmidt M.
      • Yao J.
      • Wu X.
      • Kaminker J.S.
      • et al.
      Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies.
      ]. In GBM, radiomic imaging, computer tomography (CT) perfusion, and delayed-contrast/perfusion magnetic resonance imaging (MRI) are investigated as non-invasive techniques/biomarkers of response to treatment with bevacizumab [
      • Grossmann P.
      • Narayan V.
      • Chang K.
      • Rahman R.
      • Abrey L.
      • Reardon D.A.
      • et al.
      Quantitative imaging biomarkers for risk stratification of patients with recurrent glioblastoma treated with bevacizumab.
      ]. In patients with isocitrate dehydrogenase (IDH) wild-type GBM, a “proneural” gene expression signature was identified as a molecular subgroup with better responses to bevacizumab in which a significant OS benefit compared to placebo was observed [
      • Sandmann T.
      • Bourgon R.
      • Garcia J.
      • Li C.
      • Cloughesy T.
      • Chinot O.L.
      • et al.
      Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial.
      ]. Thus, while some promising biomarkers have been investigated, a validated, predictive biomarker for response to bevacizumab remains elusive. As the biology of angiogenesis and its role in tumor development varies between indications, suitable biomarkers may likely be tumor type-specific.

      Addressing resistance to angiogenesis inhibition with bevacizumab

      As for other targeted therapies, particularly those inducing a cytostatic rather than cytotoxic response, the development of treatment resistance limits efficacy in the longer-term setting [
      • Ye W.
      The Complexity of Translating Anti-angiogenesis Therapy from Basic Science to the Clinic.
      ]. Both molecular changes within the tumor cells themselves as well as tumor-induced changes of the microenvironment contribute to resistance to anti-angiogenic therapy [
      • Jain R.K.
      Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia.
      ,
      • Ramjiawan R.R.
      • Griffioen A.W.
      • Duda D.G.
      Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?.
      ]. Angiogenesis may be re-activated by upregulation of VEGF-A itself, alternative members of the VEGF family or alternative pro-angiogenic pathways, such as PlGF, SDF-1/CXC-chemokine receptor (CXCR)-4 and CXCR7, HGF/Met [
      • Jain R.K.
      Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia.
      ,
      • Ramjiawan R.R.
      • Griffioen A.W.
      • Duda D.G.
      Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?.
      ]. Besides angiogenesis, tumor cells may adopt alternative modes of tumor vascularization, including co-option of existing vasculature, vasculogenic mimicry of cancer cells, vasculogenesis from cancer stem cell differentiation, the splitting of one vessel into multiple vessels (vessel intussusception) and vasculogenesis based on bone-marrow derived precursors of endothelial cells [
      • Ramjiawan R.R.
      • Griffioen A.W.
      • Duda D.G.
      Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?.
      ]. While the potential mechanisms of resistance to angiogenesis inhibition have become increasingly well-understood, there is so far limited success in translation of this knowledge to clinical strategies for overcoming resistance to treatment with bevacizumab. Clinical studies have investigated the concomitant use of a VEGFR inhibitor with bevacizumab, or targeting of angiogenic signaling molecules, including angiogtensin-2 (Ang-2), fibroblast growth factor (FGF), HGF activation of c-Met, delta-like ligand 4 (Dll4)-induced Notch signaling, hedgehog (HH) signaling or inhibition of Zeste homolog 2 (EZH2), an intracellular mediator of angiogenic signaling [
      • Comunanza V.
      • Bussolino F.
      Therapy for Cancer: Strategy of Combining Anti-Angiogenic and Target Therapies.
      ,
      • Carmeliet P.
      • Jain R.K.
      Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases.
      ,
      • Clarke J.M.
      • Hurwitz H.I.
      Understanding and targeting resistance to anti-angiogenic therapies.
      ,
      • Crea F.
      • Fornaro L.
      • Bocci G.
      • Sun L.
      • Farrar W.L.
      • Falcone A.
      • et al.
      EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis.
      ]. Combinations of bevacizumab with MET, Ang-2 and HH inhibitors are or have been under investigation in clinical trials (Table 4). Importantly, phase III studies in ovarian, colorectal and breast cancer have shown significant efficacy benefits with bevacizumab following re-treatment after disease progression in patients who had previously received a bevacizumab-containing regimens [
      • von Minckwitz G.
      • Puglisi F.
      • Cortes J.
      • Vrdoljak E.
      • Marschner N.
      • Zielinski C.
      • et al.
      Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial.
      ,
      • Pignata S.L.D.
      • Joly F.
      • Gallo C.
      • Colombo N.
      • Sessa C.
      • Bamias A.
      • Pisano C.
      • Selle F.
      • Zaccarelli E.
      • Scambia G.
      • Pautier P.
      • Nicoletto M.O.
      • De Giorti U.
      • Dubot C.
      • Bologna A.
      • Orditura M.
      • Ray-Coquard I.
      • Perrone F.
      • Daniele G.
      Abstract 5506: Chemotherapy plus or minus bevacizumab for platinumsensitive ovarian cancer patients recurring after a bevacizumab containing first line treatment: The randomized phase 3 trial MITO16B-MaNGO OV2BENGOT OV17. ASCO Annual Meeting; Chicago, IL, USA.
      ,
      • Bennouna J.
      • Sastre J.
      • Arnold D.
      • Osterlund P.
      • Greil R.
      • Van Cutsem E.
      • et al.
      Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.
      ]. In the ML18147 study, both PFS and OS were significantly improved when bevacizumab was added to chemotherapy in bevacizumab-experienced patients with mCRC (5.7 months vs 4.1 months; HR: 0.68 [95% CI 0.59–0.79]; p < 0.0001 and 11.2 months vs 9.8 months; HR: 0.81 [95% CI 0.69–0.94]; p < 0.0062) [
      • Bennouna J.
      • Sastre J.
      • Arnold D.
      • Osterlund P.
      • Greil R.
      • Van Cutsem E.
      • et al.
      Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.
      ]. In the TANIA study, PFS was significantly improved when bevacizumab was added to second-line chemotherapy in bevacizumab-experienced patients with HER2-negative locally recurrent or metastatic breast cancer (6.3 monthsvs 4.2 months, HR: 0.75 [95% CI 0.61–0.93], p = 0.0068) [
      • von Minckwitz G.
      • Puglisi F.
      • Cortes J.
      • Vrdoljak E.
      • Marschner N.
      • Zielinski C.
      • et al.
      Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial.
      ], though there were no significant differences in third-line PFS or OS [
      • Vrdoljak E.
      • Marschner N.
      • Zielinski C.
      • Gligorov J.
      • Cortes J.
      • Puglisi F.
      • et al.
      Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer.
      ]. Similarly, in the Mito-16b/Mango-OV2b study, PFS was significantly improved when bevacizumab was added to chemotherapy in bevacizumab-experienced patients with recurrent OC (8.8 months vs 11.8 months; HR: 0.51 [95% CI 0.41–0.64]; p < 0.001), though this did not translate into a significant OS benefit [
      • Pignata S.L.D.
      • Joly F.
      • Gallo C.
      • Colombo N.
      • Sessa C.
      • Bamias A.
      • Pisano C.
      • Selle F.
      • Zaccarelli E.
      • Scambia G.
      • Pautier P.
      • Nicoletto M.O.
      • De Giorti U.
      • Dubot C.
      • Bologna A.
      • Orditura M.
      • Ray-Coquard I.
      • Perrone F.
      • Daniele G.
      Abstract 5506: Chemotherapy plus or minus bevacizumab for platinumsensitive ovarian cancer patients recurring after a bevacizumab containing first line treatment: The randomized phase 3 trial MITO16B-MaNGO OV2BENGOT OV17. ASCO Annual Meeting; Chicago, IL, USA.
      ]. These data indicate that progression of disease in patients treated with a bevacizumab-containing regimen does not necessarily indicate irreversible resistance to bevacizumab.
      Table 4Overview of key ongoing or completed phase III studies of combination treatment with bevacizumab and targeted therapies.
      Combination treatment partner (INN)Type of drugMolecular targetsIndication and study ID
      Immune checkpoint inhibitors
      AtezolizumabmAbPD-L1
      • CC: NCT03556839/BEATcc
      • HCC: NCT04102098/IMbrave050, NCT03434379/IMbrave150
      • mCRC: NCT02997228/COMMIT
      • NSCLC
        Indication for combination treatment approved in the EU and US.
        : NCT02366143/Impower150
      • Ns-NSCLC: NCT03991403
      • OC/FTC/PPC: NCT02891824/ATALANTE, NCT03038100/IMagyn050, NCT03353831/AGO OVAR.2.29, NCT02839707/NRG-GY009
      • PM: NCT03762018/BEAT-meso
      • RCC: NCT024420821/IMmotion151
      DurvalumabmAbPD-L1
      • HCC: NCT03847428/EMERALD-2, NCT03778957/EMERALD-1
      PARP inhibitors
      OlaparibSmall moleculePARP
      • OC/FTC/PPC: NCT02477644/PAOLA-1
      Immune checkpoint inhibitor and PARP inhibitor
      Niraparib and TSR042Small molecule and mAbPARP and PD-1
      • OC/FTC/PPC: NCT03806049/ENGOT-OV42-NSGO/AVANOVA-Triplet
      Other targeted therapies
      ErlotinibSmall moleculeEGFR
      • mCRC: NCT00598156, NCT00265824/DREAM, NCT00598156/ACT1, NCT01229813/ACT2
      • NSCLC
        Indication for combination treatment approved in the EU.
        : NEJ026, NCT02759614/JO25567/Artemis, NCT02633189/BEVERLY, NCT00257608/ATLAS, NCT00130728/BeTa
      CetuximabmAbEGFR
      • mCRC: NCT01878422/ITCa
      • NSCLC: NCT00946712/S0819
      TrastuzumabmAbHER2
      • mBC: NCT00391092/AVEREL
      LetrozoleSmall moleculeAromatase
      • Adv. BC: NCT00545077/GEICAM2006-11, NCT00601900/GALGB 40,503/Alliance
      TemsirolimusSmall moleculemTor
      • Adv RCC: NCT00631371/INTORACT
      VorinostatSmall moleculeHDAC
      • GBM: NCT01236560
      Abbreviations: Adv: Advanced, ALK: anaplastic lymphoma kinase; BC: Breast cancer; mCRC: Colorectal cancer; CYP19: Aromatase; EGFR: Epidermal growth factor receptor; ER: Estrogen receptor; FTC: Fallopian tube cancer; HER2: Human epidermal growth factor growth factor receptor–2 (EGFR-2/ERBB2/neu); GBM: Glioblastoma; HCC: Hepatocellular carcinoma; HmAb: monoclonal antibody; mTOR: mammalian target of rapamycin; OC: Ovarian cancer; PANC: Pancreatic cancer; PARP: Poly (ADP-ribose) polymerase; PD–L1: Programmed death–ligand 1; PD–1: Programmed cell death protein 1; PM = Pleural Mesothelioma; PPC: Primary peritoneal cancer; VEGF–A: Vascular endothelial growth factor–A.
      Source: Clinicaltrials.gov, accessed 28 Nov 2019.
      Footnotes:
      * Indication for combination treatment approved in the EU and US.
      § Indication for combination treatment approved in the EU.

      Combination with immune checkpoint inhibitors

      Besides its key role in angiogenesis, VEGF was shown to have an angiogenesis-independent role in immune modulation, contributing to the suppression of adaptive immunity at several steps of the cancer immunity cycle [
      • Ramjiawan R.R.
      • Griffioen A.W.
      • Duda D.G.
      Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?.
      ,
      • Motz G.T.
      • Coukos G.
      The parallel lives of angiogenesis and immunosuppression: cancer and other tales.
      ]. Specifically, tumor-secreted VEGF inhibits the differentiation of hematopoietic stem cells to dendritic cells and the functional maturation of dendritic cells to antigen-presenting cells, inhibiting early steps of the cancer immunity cycle and promoting immune evasion of tumors. VEGF also interferes with later steps of the cancer immunity cycle by down-regulation of adhesion molecules on endothelial cells required for the rolling of leukocytes as well as their adhesion and transmigration, inhibiting tumor infiltration by T cells. Additional mechanisms of VEGF-mediated suppression of the adaptive immune system include the induction of apoptosis in T cells by activation of expression of FAS ligand on endothelial cells, and the expansion of immune-suppressive myeloid-derived suppressor cells [
      • Hegde P.S.
      • Wallin J.J.
      • Mancao C.
      Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics.
      ]. Due to the intimate relationship between angiogenesis and immunosuppression, there is a scientific rationale to investigate whether the addition of immune checkpoint inhibitors to bevacizumab could lead to synergism and more durable clinical benefit.
      The promise of a combined anti-angiogenic and immunotherapy approach is exemplified by the recent approval of bevacizumab in combination with atezolizumab and chemotherapy, based on the results of the IMpower150 trial in metastatic non-squamous (NSq)-NSCLC, demonstrating PFS and OS benefits of the combination treatment, without new safety signals compared to the individual treatments [
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • Orlandi F.
      • Stroyakovskiy D.
      • Nogami N.
      • et al.
      for the IMpower150 Study Group. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.
      ]. Interestingly, the benefits of the combination treatment were seen in the overall population regardless of programmed death-ligand 1 (PD-L1) expression status, and were further enhanced in patients with a high effector T cell gene signature, indicative of active adaptive immune responses.
      This potential synergy is further supported by results of a phase I clinical study (NCT02715531) investigating the combination of bevacizumab and atezolizumab for treatment of solid tumors. In patients with hepatocellular carcinoma (HCC), this study demonstrated significant improvement in the primary endpoint median PFS compared to atezolizumab alone (5.6 vs 3.4 months, HR 0.55, P = 0.0108) [
      • Lee M.
      • Ryoo B.-Y.
      • Hsu C.H.
      • Numata K.
      • Stein S.
      • Verret W.
      • et al.
      LBA39: Randomised efficacy and safety results for atezolizumab (Atezo) 1 bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC).
      ], while there had been no or limited responses with the individual therapies. This combination has been granted FDA granted breakthrough designation and is further investigated in the ongoing phase III study IMbrave150. First results demonstrate significant benefits for the co-primary endpoints PFS and OS (6.8 vs 4.2 months, HR 0.59, P < 0.0001 and not reached vs 13.2 months, HR 0.58, P = 0.0006) for the combination of bevacizumab with atezolizumab compared to sorafenib, with an ORR of 27% vs 12% (P < 0.0001) [

      Cheng A-L, Qin S, Ikeda M, Galle P, Ducreux M, Zhu A, Kim T-Y, et al. Abstract LBA3: IMbrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorefanib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). In ESMO Asia 2019; Singapore. Annals of Oncology; 2019. https://doi.org/10.1093/annonc/mdz446.002.

      ]. Results were consistent across clinical subgroups and the safety profile of the individual treatments, with no new safety signals identified with the combination treatment. Promising results have also been obtained in the IMmotion151 study with the combination of bevacizumab and atezolizumab compared to sunitinib in PD-L1-positive RCC [

      Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, et al. Abstract 578: IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). In Genitourinary Cancers Symposium 2018. Journal of Clinical Oncology; 2018. https://doi.org/10.1200/JCO.2018.36.6_suppl.578.

      ]. The combination of bevacizumab with immune checkpoint inhibitors is also under investigation for further indications in several ongoing phase III clinical trials, for example OC in both front-line (IMagyn050) and recurrent platinum-sensitive (ATALANTE) or platinum-resistant (AGO OVAR.2.29, NRG-GY009) settings and in front-line cervical cancer (BEATcc) [
      • Hegde P.S.
      • Wallin J.J.
      • Mancao C.
      Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics.
      ,
      • Gao X.
      • McDermott D.F.
      Combinations of Bevacizumab With Immune Checkpoint Inhibitors in Renal Cell Carcinoma.
      ] (Table 4).

      Combination with PARP inhibitors

      Pruning of tumor vasculature in response to anti-angiogenic therapy results in hypoxia, causing a mutagenic environment and downregulation of the homologous recombination DNA repair pathway [
      • Scanlon S.E.
      • Glazer P.M.
      Multifaceted control of DNA repair pathways by the hypoxic tumor microenvironment.
      ]. Targeting the base excision DNA repair pathway, PARP inhibitors induce synthetic lethality in tumor cells with homologous recombination deficiencies [
      • Lee J.M.
      • Ledermann J.A.
      • Kohn E.C.
      PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies.
      ]. Thus, combining bevacizumab with PARP inhibitors is proposed to sensitize cancer cells to the cytotoxic effects of PARP inhibitors, while mitigating consequences of VEGF-inhibition-related hypoxia. PARP-inhibitors are approved for treatment of BRCA-mutated cancers and BRCA-like cancers, such as OC and BC, and are being investigated in many additional cancer indications.  Accordingly, the combination of bevacizumab with PARP inhibitors was investigated in phase 3 clinical trials, including PAOLA-1, which evaluated olaparib plus bevacizumab in front-line OC maintenance treatment. In PAOLA-1, patients with newly diagnosed OC, FTC and PPC, regardless of BRCA mutation status, who have achieved a complete or partial response to platinum-based chemotherapy in combination with bevacizumab, were randomized to either olaparib plus bevacizumab or placebo plus bevacizumab [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Perol D.
      • Gonzalez-Martin A.
      • Berger R.
      • et al.
      Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian.
      ]. Results have demonstrated superiority of the combination of olaparib plus bevacizumab compared to bevacizumab alone in the primary endpoint (median PFS 22.1 vs 16.6 months, HR = 0.59, p < 0.001), with a safety profile consistent with those associated with the individual treatments. Pre-specified subgroup analyses showed that the observed benefit was driven by the subgroup of patients with BRCA mutant (median PFS 22.1 vs 16.6 months, HR = 0.31 [95% CI 0.20–0.47]) and homologous recombination deficiency (HRD)-positive tumors (median PFS 37.2 vs 21.7 months, HR = 0.33 [95% CI 0.25–0.45]), including HRD-positive tumors without BRCA mutation (median PFS 22.1 vs 16.6 months, HR 0.43; 95% CI, 0.28–0.66). In contrast, there was little benefit in the subgroups of patients with BRCA mutation-negative tumors (median PFS 18.9 vs 16.0 months, HR 0.71 [95% CI, 0.58–0.88]) and tumors with negative or unknown HRD status (median PFS 22.1 vs 16.6 months, HR 0.92; [95% CI, 0.72–1.17]).

      Conclusions

      The angoigenesis inhibitor bevacizumab was the first or among the first available targeted therapies for a range of solid tumors. By improving overall and/or progression-free survival in patients with no or only limited treatment options besides chemotherapy, bevacizumab has changed the treatment paradigm and became a standard of care in the treatment of advanced cancers. Other currently available anti-angiogenic agents have neither shown such consistent efficacy across indications, nor have a comparably well-established clinical efficacy and safety profile, based on extensive clinical and post-market experience.
      Rather than directly targeting cancer cells, bevacizumab targets the tumor microenvironment, characterized by complex interactions between cancer cells, normal cells and the extracellular matrix. Due to this complexity, the effects of VEGF-inhibition are likely tumor-type and microenvironment-specific. Furthermore, recent research has shown that VEGF has additional angiogenesis-independent roles in the complex tumor microenvironment, including the modulation of cancer immunity. To date, clinically validated, reliable biomarkers for treatment response and resistance to bevacizumab remain elusive, precluding a more personalized use of bevacizumab. While the understanding of mechanisms of resistance to anti-angiogenetic treatment has advanced, effective clinical approaches to overcome resistance to treatment with bevacizumab are not yet available.
      Since the initial approval of bevacizumab, a number of targeted cancer therapies have become available, transforming the treatment landscape in many solid tumor indications and creating opportunities for novel combination treatment approaches. Indeed, the combination of bevacizumab with immune checkpoint inhibitors has recently been approved in NSq-NSCLC, and further results showing clinical benefits with this combination have been obtained in clinical studies in patients with RCC and HCC and with PARP inhibitors in patients with OC. These promising results indicate that bevacizumab may enhance these novel targeted therapies, as has been shown when bevacizumab is combined with chemotherapy.
      Considering the vast and established evidence on the efficacy of bevacizumab in combination with chemotherapy and increasing evidence on further improved treatment outcomes when combined with other new treatments such as cancer immunotherapy or PARP inhibitors, bevacizumab is expected to remain a key agent in the treatment of cancer patients.

      Declaration of Competing Interest

      Dr. Garcia is employee of F. Hoffmann-La Roche Ltd. Dr. Hurwitz reports grants and personal fees from F. Hoffmann-La Roche Ltd./Genentech, Inc., outside the submitted work; and is employee of Genentech, Inc. Dr. Sandler is employee of Genentech, Inc.; in addition, Dr. Sandler has a patent related to a Taxol, Carboplatin, Tecentriq® and Avastin® regimen. Dr. Miles reports honoraria from F. Hoffmann-La Roche Ltd./Genentech, Inc. and acted in a consulting/advisory role for F. Hoffmann-La Roche Ltd./Genentech, Inc. outside the submitted work. Dr. Coleman reports grants from the NIH, the Gateway Foundation and the V Foundation; and grants from AstraZeneca, Merck, Clovis, Genmab, F. Hoffmann-La Roche Ltd./Genentech, Inc. and Janssen; and personal fees from AstraZeneca, Tesaro, Medivation, Clovis, Gamamab, Genmab Roche/Genentech, Janssen, Agenus, Regeneron and OncoQuest outside the submitted work. Dr. Deurloo is employee of F. Hoffmann-La Roche Ltd. Dr. Chinot reports honoraria and non-financial research support from F. Hoffmann-La Roche Ltd., and acted in a consulting/advisory role for F. Hoffmann-La Roche Ltd., outside the submitted work; in addition, Dr. Chinot has a patent related to a plasmatic biomarker of bevacizumab efficacy (Europe 12305565.9) issued to the Aix-Marseille University.

      Acknowledgements

      Medical writing support was provided by Dr. Daniela Kenzelmann-Broz (SFL Regulatory Affairs & Scientific Communication) and was funded by F. Hoffmann-La Roche Ltd . The authors particularly acknowledge Dr. Bettina Barton (F. Hoffmann La-Roche Ltd.) for her careful review of the manuscript. The authors thank all current and former researchers and investigators as well as patients and their families who participated in clinical trials establishing bevacizumab as a key agent in cancer therapy.

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