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
Keywords
Introduction
Angiogenesis and VEGF as therapeutic targets in cancer
Angiogenesis-independent roles of VEGF in cancer development and progression
Development of bevacizumab, the first therapy targeting VEGF
- Paley P.J.
- Staskus K.A.
- Gebhard K.
- Mohanraj D.
- Twiggs L.B.
- Carson L.F.
- et al.
Study name and ID Reference | Study design | Patient population (N) | Treatment line | Treatment arms (n) | Dose and regimen | Endpoints | Median PFS (mths) | HR (95%CI) p-value | Median OS (mths) | HR (95%CI) p-value |
---|---|---|---|---|---|---|---|---|---|---|
Metastatic colorectal cancer | ||||||||||
AVF2107g (NCT00109070) Hurwitz H et al (2004) NEJM [20] Hurwitz H et al (2005) JCO [21] | Phase 3 blinded randomized controlled | mCRC (N = 813) | 1L |
|
|
| Bev + IFL vs IFL: 10.6 vs 6.2 | 0.54 (0.45–0.66) p ≤ 0.0001 | Bev + IFL vs CIFL: 20.3 vs 15.6 (F/U at 385 deaths) | 0.66 (0.54–0.81) p ≤ 0.0001 |
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 [23] | Phase 2, open-label randomized controlled | mCRC (N = 104) | 1L |
|
|
| BevL + FU/LV vs FU/LV: 9.0 vs 5.2 | 0.46 (0.34–0.73) p = 0.005 | BevL + FU/LV vs FU/LV: 17.7 vs 13.6 | 0.52 (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 13.6 | 1.01 (NR) p = 0.98 | |||||||
NO16966 (NCT00069095) Saltz LB et al (2008) JCO [24] | Phase 2 blinded randomized controlled | mCRC (N = 1400) | 1L |
|
|
| BevH + XELOX vs XELOX: 9.4 vs 8.6 | 0.77 (0.63–0.94) p = 0.00263 | 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) p = 0.18713 | 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 | 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 [25] 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 + FOLFOX vs FOLFOX: 7.3 vs 4.7 (at median F/U: 28mths) | 0.52 (0.42–0.65) p ≤ 0.0001 | 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 |
ML18147 (NCT00700102) Bennoua J et al. (2013) Lancet [22] | Phase 3 open-label randomized controlled | mCRC, progressing within 3 mths after discontinuation of 1L treatment with bev + chemo (N = 820) | 2L |
Chemo = oxaliplatin- or irinotecan-based, depending on previous 1L treatment, at discretion of investigator |
|
| 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 | 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 |
Non-small cell lung cancer | ||||||||||
E4599 NCI-2012–02947 (NCT00021060) Sandler A et al (2006) NEJM [30] | Phase 2/3 open-label randomized controlled | Advanced (stage IIIB/IV)/Recurrent/Metastatic NSCLC (not squamous type) (N = 850) | 1L |
|
|
| 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) p ≤ 0.001 | 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 |
AVAiL /BO117704 (NCT00806923) Reck M et al, (2009), JCO, Reck M et al, (2010) AnnOnco 34 , 35 | Phase 3 open-label randomized controlled | Advanced (stage IIIB/IV)/Recurrent/Metastatic NSCLC (not squamous type) (N = 1043) | 1L |
|
|
| BevL + CIS + GEM vs CIS + GEM: 6.7 vs 6.1 | 0.75 (0.62–0.91) p = 0.0026 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 | 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 | |||||||
JO25567 Seto, T et al (2014) Lancet [36] | Phase 2 open-label randomized controlled | Advanced (stage IIIB/IV or recurrent activated EGFR NSCLC (not squamous type) (N = 152) | 1L |
|
|
| Bev + ERL vs ERL: 16.0 vs 9.7 | 0.54 (0.36–0.79) p = 0.0015 | NR | NR |
NEJ026 Saito, H et al (2019) Lancet [37] | Phase 3 open-label randomized | Advanced (stage IIIB/IV or recurrent activated EGFR NSCLC (not squamous type) (N = 152) | 1L |
|
|
| Bev + ERL vs ERL: 16.9 vs 13.3 (median F/U 12.4 mths) | 0.605 (0.42–0.89) p = 0.016 | NR | NR |
IMpower150 GO29436 (NCT02366143) Socinski et al (2018) NEJM [41] | Phase 3 open-label randomized | Stage IV NSCLC, including EGFR/ALK alterations and low PD-L1 expression (N = 1202) | 1L |
|
|
| ATZ + Bev PTX + CB vs Bev PTX + CB 8.3 vs 6.8 | 0.59 (0.50–0.70) p < 0.001 | ATZ + Bev PTX + CB vs Bev PTX + CB 19.2 vs 14.7 mths | 0.78 (0.64–0.96) p = 0.02 |
Metastatic breast cancer^ | ||||||||||
ECOG E2100 (NCT00028990) Miller K et al (2007) NEJM [43] | Phase 3 open-label randomized controlled | HER2-negative, mBC (N = 673) | 1L |
|
|
| Bev + PTX vs PTX: 11.8 vs 5.9 (FA: 624 PFS events) | 0.60 p < 0.001 | 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 [45] | Phase 3 blinded randomized controlled | HER2-negative, locally recurrent/metastatic breast cancer (N = 736) | 1L |
|
|
| 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 | 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 | |||||||
RIBBON-1 BO20094 (NCT00262067) Robert et al (2011) JCO [46]
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 vs CP: 8.6 vs 5.7 (median F/U: 15.6mths) | 0.69 0.56–0.84 p < 0.001 | 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 | Bev + PTX/DTX/DOX/EPI vs PTX/DTX/DOX/EPI 25.2 vs 23.8 | 1.032 0.77–1.38 p = ns | |||||||
Renal cell carcinoma | ||||||||||
AVOREN/BO17705 (NCT00738530) Escudier B et al (2007) Lancet; Escudier B et al (2010) JCO 49 , 50 | Phase 3 blinded randomized controlled | Metastatic clear cell RCC (N = 649) | 1L |
|
| 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 | Bev + IFNα2a vs IFNα2a: 23.3 vs 21.3 (F/U to 4.25 yrs] | 0.91 (0.76–1.10) p = 0.3360 |
CALGB 90,206 (NCT00072046) Rini BI et al (2008) JCO Rini BI et al (2010) JCO 51 , 52 | Phase 3 blinded randomized controlled | Metastatic clear cell RCC (N = 732) | 1L |
|
| 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 | Bev + IFNα2a vs IFNα2a: 18.3 vs 17.4 (median F/U 46.2 months] | 0.86 (0.73–1.01) p = 0.069 |
Glioblastoma¢ | ||||||||||
AVF3708g (NCT00345163) Friedman HS et al (2009) JCO [56] | Phase 2 open-label randomized | Relapsed (1st/2nd) GBM (N = 167) | 2L |
|
|
| Bev + IRI vs Bev: 5.6 (4.4–6.2) vs 4.2 (2.9–5.8) (F/U: min 6mths for all patients) | NA | Bev + IRI vs Bev: 8.7 (7.8–10.9) vs 9.2 (8.2–10.7) (F/U: min 8mths for all patients) | NA |
EORTC 26101/MO22968 (NCT01290939) Wick W et al (2017) NEJM [57] | Phase 3, open-label randomized | Relapsed (1st) GBM (N = 437) | 2L |
|
|
| Bev + LO vs LO: 4.2 vs 1.5 (401 progression events) | 0.49 (0.39–0.61) p < 0.001 | 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 |
AvaGlio/BO21990 (NCT00943826) Chinot OL et al (2014) NEJM [60] | Phase 3 blinded randomized controlled | Newly diagnosed GBM, WHO perform status ≤ 2 (N = 921) | 1L |
| Initial
|
| 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 | 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 |
RTOG0825 (NCT00884741) Gilbert MR et al. (2014) NEJM [61] | Phase 3 double-blinded randomized placebo-controlled | Newly diagnosed GBM, Karnofsky perform status ≥ 70 (N = 637) | 1L |
| Initial:
|
| 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 | 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 |
Ovarian, fallopian tube and primary peritoneal cancer | ||||||||||
GOG-0218 NCI-2009–00590 (NCT00262847) Burger et al (2011) NEJM [66] Tewari et al (2019) [65] | Phase 3 blinded randomized controlled | Advanced (Stage IIIB-IV) OC, FTC or PPC, post debulking surgery (N = 1873) | 1L |
|
|
| 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) p ≤ 0.001 | 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 | |||||||
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 67 , 68 | 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 |
|
|
| 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: | ||||||||||
Bevall + PTX + CB vs PTX + CB: 16.0 vs 10.5 (F/U: at median 15.6 and 10.1 mths) | 0.73 (0.61–0.88) p = 0.001 | Bevall + PTX + CB vs PTX + CB 39.7 vs 30.2 (F/U at median 38.9 and 29.0 mths) | 0.78 (0.63–0.97) p = 0.03 | |||||||
AVF4095g/ OCEANS (NCT00434642) Aghajanian C et al (2012) JCO; Aghajanian C et al (2015) GynOnco 69 ,
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. 70 | Phase 3 blinded randomizedcontrolled | Recurrent platinum sensitive OC, FTC or PPC (N = 484) | 2L |
|
|
| Bev + CB + GEM vs CB + GEM: 12.4 vs 8.4 (F/U: ~24mths, 338 events) | 0.484 (0.388–0.605) p ≤ 0.0001 | 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 |
GOG-0213/ML01187 (NCT00565851) Coleman RL et al (2017) Lancet Oncol, Coleman RT et al (2018) ASCO 71 ,
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. J Clin Oncol. 2018; https://doi.org/10.1200/JCO.2018.36.15_suppl.5501 72
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 vs PTX + CB: 13.8 vs 10.4 (F/U: 49.6mths) | 0.628 (0.534–0.739) p ≤ 0.0001 | 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 |
AURELIA MO22224 (NCT00976911) Pujade-Lauraine E et al (2014) JCO [73] | Phase 3 open label randomized controlled | Recurrent platinum resistant OC, FTC or PPC (N = 361) | 2L |
|
|
| Bev + pgDOX + PTX/TCN vs pgDOX + PTX/TCN: 6.7 vs 3.4 (F/U: ~13.5mths) | 0.480 (0.38–0.60) p ≤ 0.001 | 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 |
Cervical cancer | ||||||||||
GOG-0240 NCI-2009–01084 (NCT00803062) Tewari KS et al (2014) NEJM; Tewari KS et al (2017) Lancet 82 , 83 | Phase 3 open label randomized controlled | Persistent or Recurrent (stage IVB) CC (N = 452) | 1L/2L |
|
|
| 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 | 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 |
Bev + PTX + CIS vs PTX + CIS: 8.2 vs 5.9 | 0.67 (0.54–0.82) p = 0.002 | Bev + PTX + CIS vs PTX + CIS 17.5 vs 14.3 | 0.68 (0.48–0.97) p = 0.04 | |||||||
Bev + PTX + TCN vs PTX + TCN 7.36 vs 5.29 | NR p = NR | 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 |
Clinical experience with bevacizumab
- Rajabi M.
- Mousa S.A.

Indication | Patient exposure in manufacturer-sponsored clinical trials | Estimated patient exposure in post-marketing setting |
---|---|---|
Gastrointestinal cancer/CRC | 12 319 | 2 024 159 |
Breast cancer | 10 242 | 325 154 |
Lung cancer/NSCLC | 8 316 | 630 173 |
Renal cancer | 1 305 | 43 247 |
Glioblastoma multiforme | 1 083 | 97 728 |
Female reproductive tract cancer and cervical cancer/OC, FTC, PPC + CC | 1 907 | 326 062 |
Other cancer | 2 024 | 29 237 |
Total | 37 196 | 3 500 59 |
Metastatic colorectal cancer
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.
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.
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
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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.
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.
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
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Renal cell carcinoma
- Escudier B.
- Porta C.
- Schmidinger M.
- Rioux-Leclercq N.
- Bex A.
- Khoo V.
- et al.
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.
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Glioblastoma
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.
Ovarian, fallopian tube and primary peritoneal cancer
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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.
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.
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- et al.
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.
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.
Cervical cancer
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.
Safety profile across indications
Adverse event | Incidence all grades |
---|---|
Bleeding/Hemorrhage | 39.1% (2524/6449) Up to 44.2% (354/801) in NSCLC |
Pulmonary hemorrhage | 2.1% (134/6449) Up to 8.9% (71/801) in NSCLC |
Proteinuria | 10.5% (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 |
Hypertension | 27.1% (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 complications | 3.2% (204/6449) Up to 5.4% (34/624) in GBM |
GI perforations | 1.9% (121/6449) Up to 9.2% (20/218) in CC |
Posterior Reversible Encephalopathy Syndrome (PRES) | 0.2% (11/6449) |
Neutropenia | 43.1% (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 hypertension | 0.1% (5/6449) |
Ovarian failure | None in clinical trials Sporadic cases reported |
Hypersensitivity and infusion reactions | 27.6% (1720/6449) Up to 35.5% (784/2208) in OC |
Gallbladder perforation | <0.1% (1/6449) in OC |
Peripheral sensory neuropathy | 25.4% (1638/6449) Up to 61.5% (134/218) in CC |
Non-CHF/ATE cardiac disorders | 2.7% (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 fasciitis | 0% in clinical trials 87 reported in ARISg and MedDRA safety databases |
Off-label intravitreal use | 17,332 cases reported in safety databases up to 31 December 2014:
|
Infection (use with temozolomide and radiotherapy in GBM) | 44.9% (2896/6449) Up to 52.7% (329/624) in GBM |
Thrombocytopenia | 26.8% (1726/6449) Up to 50.1% (1106/2208) in OC |
Lessons learnt and future outlook
An broadly applicable strategy for treatment of solid tumors
- Nienhuser H.
- Schmidt T.
Identification of biomarkers for patient selection and monitoring
- Miles D.
- Cameron D.
- Bondarenko I.
- Manzyuk L.
- Alcedo J.C.
- Lopez R.I.
- et al.
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.
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.
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- Mueller B.
- Brady M.F.
- Mannel R.S.
- Burger R.A.
- Wei W.
- Marien K.M.
- et al.
Addressing resistance to angiogenesis inhibition with bevacizumab
- von Minckwitz G.
- Puglisi F.
- Cortes J.
- Vrdoljak E.
- Marschner N.
- Zielinski C.
- et al.
- 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.
- von Minckwitz G.
- Puglisi F.
- Cortes J.
- Vrdoljak E.
- Marschner N.
- Zielinski C.
- et al.
- 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.
Combination treatment partner (INN) | Type of drug | Molecular targets | Indication and study ID |
---|---|---|---|
Immune checkpoint inhibitors | |||
Atezolizumab | mAb | PD-L1 |
|
Durvalumab | mAb | PD-L1 |
|
PARP inhibitors | |||
Olaparib | Small molecule | PARP |
|
Immune checkpoint inhibitor and PARP inhibitor | |||
Niraparib and TSR042 | Small molecule and mAb | PARP and PD-1 |
|
Other targeted therapies | |||
Erlotinib | Small molecule | EGFR |
|
Cetuximab | mAb | EGFR |
|
Trastuzumab | mAb | HER2 |
|
Letrozole | Small molecule | Aromatase |
|
Temsirolimus | Small molecule | mTor |
|
Vorinostat | Small molecule | HDAC |
|
Combination with immune checkpoint inhibitors
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.
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.
Combination with PARP inhibitors
Conclusions
Declaration of Competing Interest
Acknowledgements
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