Table Info

Table 4.

Ongoing studies

Trial	Phase	Setting	Stage	Patients	Treatment	Primary end points
Beverly trial NCT02633189	III	Metastatic, first line	IV stage	200	Erlotinib + Bevacizumab vs. Erlotinib	PFS
Brilliant trial NCT02655536	II	Metastatic, first line	IV stage, brain metastases	109	Erlotinib + Bevacizumab vs. Erlotinib	PFS
Ava-Ta trial NCT03126799	II	Metastatic, first line	IV stage	128	Erlotinib + Bevacizumab vs. Bevacizumab	PFS
NCT02803203	I/II	Metastatic, first line	IV stage	50	Osimertinib + Bevacizumab	PFS
BOOSTER NCT03133546	II	Metastatic, second line	IV stage, T790M mutated	155	Osimertinib + Bevacizumab vs. Osimertinib	PFS
ACCRU NCT02971501	II	Metastatic, first line	IV stage, brain metastases	112	Osimertinib + Bevacizumab vs. Osimertinib	PFS
OWONBNSCLCLM NCT04148898	II	Metastatic, first line	IV stage, leptomeningeal metastases	80	Osimertinib + Bevacizumab vs. Osimertinib	ORR and iPFS
NCT04181060	III	Metastatic, first line	IV stage	300	Osimertinib + Bevacizumab vs. Osimertininib	PFS
NCT03909334	II	Metastatic, first line	IV stage, also in patients with brain metastases	150	Osimertinib + Ramucirumab vs. Osimertinib	PFS
NCT02789345	I	Metastatic, first line	IV stage, T790M mutated	74	Osimertinib + Ramucirumab + Necitumumab	DLTs

iPFS: intracranial progression-free survival

Declarations

Author contributions

GP and AM conceived the paper and prepared the majority of the first draft, while the other authors contributed further sections. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

AM declares the following speakers’ bureau: Roche, Takeda, Pfizer, Boehringer Ingelheim, AstraZeneca, MSD Oncology, BMS. The other authors declare that no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat. 1995;36:127–37. [DOI] [PubMed]

Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med. 1999;77:527–43. [DOI] [PubMed]

Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76. [DOI] [PubMed]

Ciardiello F, Tortora G. EGFR antagonist in cancer treatment. N Engl J Med. 2008;358:1160–74. [DOI] [PubMed]

Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50. [DOI] [PubMed]

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 non-squamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009;27:1227–34. [DOI] [PubMed]

Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384:665–73. [DOI] [PubMed]

Reck M, Mellemgaard A, Novello S, Postmus PE, Gaschler-Markefski B, Kaiser R, et al. Change in non-small-cell lung cancer tumor size in patients treated with nintedanib plus docetaxel: analyses from the phase III LUME-Lung 1 study. Onco Targets Ther. 2018;11:4573–82. [DOI] [PubMed] [PMC]

Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19:5548–57. [DOI] [PubMed]

10.

Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al.; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–32. [DOI] [PubMed]

11.

Costanzo R, Montanino A, Di Maio M, Piccirillo MC, Sandomenico C, Giordano P, et al. Advanced non-small-cell lung cancer with epidermal growth factor receptor mutations: current evidence and future perspectives. Expert Rev Anticancer Ther. 2013;13:1207–18. [DOI] [PubMed]

12.

Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al.; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629–40. [DOI] [PubMed] [PMC]

13.

Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378:113–25. [DOI] [PubMed]

14.

Riedel F, Götte K, Li M, Hörmann K, Grandis JR. EGFR antisense treatment of human HNSCC cell lines down-regulates VEGF expression and endothelial cell migration. Int J Oncol. 2002;21:11–6. [DOI] [PubMed]

15.

Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol. 1997;151:1523–30. [PubMed] [PMC]

16.

Hirata A, Ogawa S, Kometani T, Kuwano T, Naito S, Kuwano M, et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res. 2002;62:2554–60. [PubMed]

17.

Herbst RS, Johnson DH, Mininberg E, Carbone DP, Henderson T, Kim ES, et al. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non–small-cell lung cancer. J Clin Oncol. 2005;23:2544–55. [DOI] [PubMed]

18.

Herbst RS, Johnson DH, Mininberg E, Carbone DP, Henderson T, Kim ES, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol. 2007;25:4743–50. [DOI] [PubMed]

19.

Herbst RS, O’Neill VJ, Fehrenbacher L, Belani CP, Bonomi PD, Hart L, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo controlled, phase 3 trial. Lancet. 2011;377:1846–54. [DOI] [PubMed] [PMC]

20.

Wang Y, Wang H, Jiang Y, Zhang Y, Wang X. A randomized phase III study of combining erlotinib with bevacizumab and panitumumab versus erlotinib alone as second-line therapy for Chinese patients with non-small-cell lung cancer. Biomed Pharmacother. 2017;89:875–9. [DOI] [PubMed]

21.

Besse B, Le Moulec S, Mazières J, Senellart H, Barlesi F, Chouaid C, et al. Bevacizumab in patients with non-squamous non-small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, phase ii study. Clin Cancer Res. 2015;21:1896–903. [DOI] [PubMed]

22.

Johnson BE, Kabbinavar F, Fehrenbacher L, Hainsworth J, Kasubhai S, Kressel B, et al. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2013;31:3926–34. [DOI] [PubMed]

23.

Dingemans AM, de Langen AJ, van den Boogaart V, Marcus JT, Backes WH, Scholtens HT, et al. First-line erlotinib and bevacizumab in patients with locally advanced and/or metastatic non-small-cell lung cancer: a phase II study including molecular imaging. Ann Oncol. 2011;22:559–66. [DOI] [PubMed]

24.

Zappa F, Droege C, Betticher D, von Moos R, Bubendorf L, Ochsenbein A. Bevacizumab and erlotinib (BE) first-line therapy in advanced non-squamous non-small-cell lung cancer (NSCLC) (stage IIIB/IV) followed by platinum-based chemotherapy (CT) at disease progression: a multicenter phase II trial (SAKK19/05). Lung Cancer. 2012;78:239–44. [DOI] [PubMed]

25.

Ciuleanu T, Tsai CM, Tsao CJ, Milanowski J, Amoroso D, Heo DS, et al. A phase 2 study of erlotinib in combination with bevacizumab versus chemotherapy plus bevacizumab in the first line treatment of advanced non-squamous non-small cell lung cancer. Lung Cancer. 2013;82:276–81. [DOI] [PubMed]

26.

Thomas M, Fischer J, Andreas S, Kortsik C, Grah C, Serke M, et al. Erlotinib and bevacizumab versus cisplatin, gemcitabine and bevacizumab in unselected non-squamous nonsmall cell lung cancer. Eur Respir J. 2015;46:219–29. [DOI] [PubMed]

27.

Morabito A, De Maio E, Di Maio M, Normanno N, Perrone F. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. Oncologist. 2006;11:753–64. [DOI] [PubMed]

28.

Blumenschein GR Jr, Gatzemeier U, Fossella F, Stewart DJ, Cupit L, Cihon F, et al. Phase II, multicenter, uncontrolled trial of singleagent sorafenib in patients with relapsed or refractory, advanced non-small-cell lung cancer. J Clin Oncol. 2009; 27:4274–80. [DOI] [PubMed]

29.

Spigel DR, Burris HA 3rd, Greco FA, Shipley DL, Friedman EK, Waterhouse DM, et al. Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2011;29:2582–9. [DOI] [PubMed]

30.

Novello S, Scagliotti GV, Rosell R, Socinski MA, Brahmer J, Atkins J, et al. Phase II study of continuous daily sunitinib dosingin patients with previously treated advanced non-small cell lung cancer. Br J Cancer. 2009;101:1543–8. [DOI] [PubMed] [PMC]

31.

Socinski MA, Novello S, Brahmer JR, Rosell R, Sanchez JM, Belani CP, et al. Multicenter, phase II trial of sunitinib in previouslytreated, advanced non-small-cell lung cancer. J Clin Oncol. 2008;26:650–6. [DOI] [PubMed] [PMC]

32.

Scagliotti GV, Krzakowski M, Szczesna A, Strausz J, Makhson A, Reck M, et al. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. J Clin Oncol. 2012;30:2070–8. [DOI] [PubMed]

33.

Groen HJ, Socinski MA, Grossi F, Juhasz E, Gridelli C, Baas P, et al. A randomized, double-blind, phase II study of erlotinib with or without sunitinib for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC). Ann Oncol. 2013;24:2382–9. [DOI] [PubMed] [PMC]

34.

Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with vecizumab 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. Lancet Oncol. 2014;15:1236–44. [DOI] [PubMed]

35.

Yamamoto N, Seto T, Nishio M, Goto K, Okamoto I, Yamanaka T, et al. Erlotinib plus bevacizumab (EB) versus erlotinib (E) alone as first-line treatment for advanced EGFR mutation-positive non squamous non-small-cell lung cancer (NSCLC): survival follow-up results of JO25567. J Clin Oncol. 2018;36 suppl 15:9007. [DOI]

36.

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. Lancet Oncol. 2019;20:625–35. [DOI] [PubMed]

37.

Rosell R, Dafni U, Felip E, Curioni-Fontecedro A, Gautschi O, Peters S., et al. Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med. 2017;5:435–44. [DOI] [PubMed]

38.

Stinchcombe TE, Jänne PA, Wang X, Bertino EM, Weiss J, Bazhenova L, et al. Effect of erlotinib plus bevacizumab vs. erlotinib alone on progression-free survival in patients with advanced egfr-mutant non-small cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2019;[Epub ahead of print]. [DOI]

39.

Ichihara E, Hotta K, Nogami N, Kuyama S, Kishino D, Fujii M, et al. Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001. J Thorac Oncol. 2015;10:486–91. [DOI] [PubMed]

40.

Kitagawa C, Mori M, Ichiki M, Sukoh N, Kada A, Saito AM, et al. Gefitinib plus bevacizumab vs. gefitinib alone for EGFR mutant non-squamous non-small cell lung cancer. In Vivo. 2019;33:477–82. [DOI] [PubMed] [PMC]

41.

Hata A, Katakami N, Kaji R, Yokoyama T, Kaneda T, Tamiya M, et al. Afatinib plus bevacizumab combination after acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: multicenter, single-arm, phase 2 trial (ABC Study). Cancer. 2018;124:3830–8. [DOI] [PubMed]

42.

Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:1655–69. [DOI] [PubMed]

43.

Gridelli C, Ciardiello F, Gallo C, Feld R, Butts C, Gebbia V, et al. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol. 2012;30:3002–11. [DOI] [PubMed]

44.

Zhao B, Zhang W, Yu D, Xu J, Wei Y. Erlotinib in combination with bevacizumab has potential benefit in non-small cell lung cancer: a systematic review and meta-analysis of randomized clinical trials. Lung Cancer. 2018;122:10–21. [DOI] [PubMed]

45.

De Luca A, Gallo M, Aldinucci D, Ribatti D, Lamura L, D’Alessio A, et al. Role of the EGFR ligand/receptor system in the secretion of angiogenic factors in mesenchymal stem cells. J Cell Physiol. 2011;226:2131–8. [DOI] [PubMed]

46.

Ciardiello F, Bianco R, Caputo R, Caputo R, Damiano V, Troiani T, et al. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res. 2004;10:784–93. [DOI] [PubMed]

47.

Gridelli C, Rossi A, Ciardiello F, De Marinis F, Crinò L, Morabito A, et al. BEVERLY: Rationale and design of a randomized open-label phase III trial comparing bevacizumab plus erlotinib versus erlotinib alone as first-line treatment of patients with EGFR-mutated advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2016;17:461–5. [DOI] [PubMed]