Nivolumab for patients with recurrent glioblastoma progressing on bevacizumab: a retrospective case series

Abstract

A single institution retrospective evaluation of nivolumab following disease progression on bevacizumab in adults with recurrent glioblastoma (GBM) with an objective of determining progression free survival (PFS). There is no accepted therapy for recurrent GBM after failure of bevacizumab. 16 adults, ages 52–72 years (median 62), with recurrent GBM were treated. All patients had previously been treated with surgery, concurrent radiotherapy and temozolomide, and post-radiotherapy temozolomide. Bevacizumab (with or without lomustine) was administered to all patients at first recurrence. Patients were treated with nivolumab only (3 mg/kg) once every 2 weeks at second recurrence. One cycle of nivolumab was defined as 2 treatments. Neurological evaluation was performed bi-weekly and neuroradiographic assessment every 4 weeks. A total of 37 treatment cycles (median 2) were administered of nivolumab in which there were 14 Grade 2 adverse events (AEs) and Grade 3 AEs in two patients. No Grade 4 or 5 AEs were seen. Following 1 month of nivolumab, seven patients demonstrated progressive disease and discontinued therapy. No patient demonstrated a response though nine patients demonstrated neuroradiographic stable response. Survival in the entire cohort ranged from 2 to 6 months with a median of 3.5 months (CI 2.8, 4.2). Median and 6-month PFS at 6 months was 2.0 months (range 1–5 months; CI 1.3, 2.7) and 0% respectively. Nivolumab salvage therapy demonstrated no survival advantage in patients with recurrent bevacizumab refractory GBM emphasizing a continued unmet need in neuro-oncology.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    de Groot JF (2015) High-grade gliomas. Continuum (Minneap Minn). Neuro-oncology 21(2):332–344

    Google Scholar 

  2. 2.

    Woehrer A, Bauchet L, Barnholtz-Sloan JS (2014) Glioblastoma survival: has it improved? Evidence from population-based studies. Curr Opin Neurol 27(6):666–674

    PubMed  Google Scholar 

  3. 3.

    Domingo-Musibay E, Galanis E (2015) What next for newly diagnosed glioblastoma? Future Oncol 11(24):3273–3283

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Weller M, Cloughesy T, Perry JR, Wick W (2013) Standards of care for treatment of recurrent glioblastoma—are we there yet? Neuro-oncology 15(1):4–27

    Article  PubMed  Google Scholar 

  5. 5.

    Park JK, Hodges T, Arko L et al (2010) Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol 28(24):3838–3843

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Brem H, Piantadoei S, Burger PC et al (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 345(8956):1008–1012

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Attenello FJ, Mukherjee D, Datoo G et al (2008) Use of Gliadel (BCNU) wafer in the surgical treatment of malignant glioma: a 10-year institutional experience. Ann Surg Oncol 15(10):2887–2893

    Article  PubMed  Google Scholar 

  8. 8.

    Bogdana Suchorska B, Weller M, Tabatabai G et al (2016) Complete resection of contrast-enhancing tumor volume is associated with improved survival in recurrent glioblastoma—results from the DIRECTOR trial. Neuro-oncology 18(4):549–556

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Clarke JL, Ennis MM, Yung WK et al (2011) Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma? Neuro-oncology 13(10):1118–1124

    Article  PubMed  Google Scholar 

  10. 10.

    Torcuator R, Thind R, Patel et al (2010) The role of salvage re-irradiation for malignant gliomas that progress on bevacizumab. J Neuro-oncol 97(3):401–407

    CAS  Article  Google Scholar 

  11. 11.

    Combs SE, Thilmann C, Edler L et al (2005) Efficacy of fractionated stereotactic re-irradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol 23(24):8863–8869

    Article  PubMed  Google Scholar 

  12. 12.

    Fogh SE, Andrews DW, Glass J et al (2010) Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol 28(18):3048–3053

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Wick W, Fricke H, Junge K et al (2014) A phase II, randomized, study of weekly APG101+ re-irradiation versus re-irradiation in progressive glioblastoma. Clin Cancer Res 20(24):6304–6313

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Perry J, Bélanger K, Mason WP et al (2010) Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 28:2051–2057

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Weller M, Tabatabai G, Kästner B et al (2015) MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the DIRECTOR trial. Clin Cancer Res 21(9):2057–2064

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Han SJ, Rolston JD, Molinaro AM et al (2014) Phase II trial of 7 days on/7 days off temozolomide for recurrent high-grade glioma. Neuro-oncology 16(9):1255–1262

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Stupp R, Wong ET, Kanner AA et al (2012) NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomized phase III trial of a novel treatment modality. Eur J Cancer 48:2192–2202

    Article  PubMed  Google Scholar 

  18. 18.

    van den Bent M, Taal W (2014) Are we done with dose-intense temozolomide in recurrent glioblastoma? Neuro-oncology 16(9):1161–1163

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Wick W, Puduvalli VK, Chamberlain MC et al (2010) Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 28(7):1168–1174

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Batchelor TT, Mulholland P, Neyns B et al (2013) Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31(26):3212–3225

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Norden AD, Young GS, Setayesh K et al (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70(10):779–787

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Friedman HS, Prados MD et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733–4740

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Kreisl TN, Kim L, Moore K et al (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27(5):740–745

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Nghiemphu PL, Liu W, Lee Y et al (2009) Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 72(14):1217–1222

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Taal W, Oosterkamp HM, Walenkamp AM et al (2014) Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomized controlled phase 2 trial. Lancet Oncol 15(9):943–953

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Field KM, Simes J, Nowak AK et al (2015) Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma. Neuro-oncology 17(11):1504–1513

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Wick W, Stupp R, Gorlia T et al (2016) EORTC 26101 phase III trial exploring the combination of bevacizumab and lomustine in patients with first progression of a glioblastoma. J Clin Oncol 33(15s) (Abstract 2001)

  28. 28.

    Quant EC, Norden AD, Drappatz J et al (2009) Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. Neuro-oncology 11(5):550–555

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Chamberlain MC, Johnston SK (2010) Salvage therapy with single agent bevacizumab for recurrent glioblastoma. J Neuro-oncol 96(2):259–269

    CAS  Article  Google Scholar 

  30. 30.

    Hovey EJ, Field KM, Rosenthal M et al (2015) Continuing or ceasing bevacizumab at disease progression: results from the CABARET study, a prospective randomized phase II trial in patients with recurrent glioblastoma. J Clin Oncol 33(15s) (suppl; abstr 2003)

  31. 31.

    Chamberlain MC, Grimm S, Phuphanich S, The Brain Tumor Investigational Consortium (BTIC) (2014) A phase 2 trial of verubulin for recurrent glioblastoma: a prospective study by the brain tumor investigational consortium (BTIC). J Neuro-oncol 118(2):335–343

    CAS  Article  Google Scholar 

  32. 32.

    Chamberlain MC, Johnston SA (2011) Salvage chemotherapy with single agent bendamustine for recurrent glioblastoma. J Neurooncol 105(3):523–530

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Ahluwalia MS, Rogers LR, Chaudhary RT et al (2016) A phase 2 trial of TRC105 with bevacizumab for bevacizumab refractory glioblastoma. J Clin Oncol 33(15s) (abstract 2035)

  34. 34.

    Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Tumeh PC, Harview CL, Yearly JH et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Reardon DA, Freeman D, Wu C et al (2014) Immunotherapy advances for glioblastoma. Neuro-oncology 16(11):1441–1458

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Wen P, Macdonald DR, Reardon DA, et al (2009) Proposal for updated response assessment criteria for high-grade gliomas: radiology assessment for neuro-oncology working group. J Clin Oncol 28:1963–1972

    Article  Google Scholar 

  39. 39.

    Piccioni DE, Selfridge J, Mody RR et al (2014) Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy. Neuro-oncology 16(5):815–822

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Sathornsumetee S, Desjardins A, Vredenburgh JJ et al (2010) Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro-oncology 12(12):1300–1310

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Reardon DA, Desjardins A, Vredenburgh JJ et al (2009) Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study. Br J Cancer 101(12):1986–1994

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Vredenburgh J, Desjardins JA, Herndon JE 2nd et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Brenner AJ, Cohen YC, Vredenburgh JJ et al (2016) Ofranogene obadenovec (VB-111), an anti-cancer gene therapy in combination with bevacizumab to improve overall survival compared to bevacizumab monotherapy in patients with rGBM: a phase 2 historically controlled trial. J Clin Oncol 33(15s) (abstract 2074)

  44. 44.

    Bota DA, Desjardins A, Mason WP et al (2016) Phase 1, multicenter, open-label, dose escalation, study of marizomib (MRZ) and bevacizumab (BEV) in WHO grade IV malignant glioma (G4 MG). J Clin Oncol 34(18s) (abstract 2037)

  45. 45.

    Goldlust SA, Nabors LB, Mohile N et al (2016) Phase 1/2 trial of bevacizumab plus TPI 287, a brain penetrable anti-microtubule agent, in patients with recurrent glioblastoma. J Clin Oncol 34(18s) (abstract 2055)

  46. 46.

    Nayak L, Hays JL, Muzikansky A et al (2016) A phase I study of MLN0128 and bevacizumab in patients with recurrent glioblastoma and other solid tumors. J Clin Oncol 33(15s) (abstract 2013)

  47. 47.

    Hoang-Xuan K, Hottinger A, Royer-Perron L et al (2016) Phase I/II study of S49076, a multi-target inhibitor of c-MET, AXL, FGFR in combination with bevacizumab in patients with recurrent glioblastoma. J Clin Oncol 33(15s) (abstract 2033)

  48. 48.

    Reardon DA, De Groot JF, Colman H et al (2016) Safety of pembrolizumab in combination with bevacizumab in recurrent glioblastoma (rGBM). J Clin Oncol 33(15s) (abstract 2010)

  49. 49.

    Borghaei H, Paz-Ares L, Horn L et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Garon EB, Rizvi NA, Hui R et al (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018–2028

    Article  PubMed  Google Scholar 

  51. 51.

    Topalian SL, Sznol M, McDermott DF et al (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32(10):1020–1030

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    McDermott DF, Drake CG, Sznol M et al (2015) Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol 33(18):2013–2020

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Hamanishi J, Mandai M, Ikeda T et al (2015) Safety and antitumor activity of anti–PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol 33(34):4015–4022

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Lesokhin Am, Ansell SM, Armand P et al (2016) Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol 34(23):2698–2704

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Roemer MGM, Advani RH, Ligon AH et al (2016) PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol 34(27):2690–2697

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Herbst RS, Soria JC, Kowanetz M et al (2014) Predictive correlates of response to the anti-PD-1 antibody MPDL3280A in cancer patients. Nature 515:563–567

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Champiat S, Ferte C, Lebel-Binay S et al (2014) Exomics and immunogenics: bridging mutational load and immune checkpoint efficacy. Oncoimmunology 3:e27817

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch repair deficiency. N Engl J Med 372:2509–2520

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Rizvi NA, Hellmann MD, Snyder A et al (2015) Cancer immunology: mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Bouffet E, Larouche V, Campbell BB et al (2016) Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 34(19):2206–2211

    Article  PubMed  Google Scholar 

  61. 61.

    Chiou VL, Burotto M (2015) Pseudoprogression and immune-related response in solid tumors. J Clin Oncol 33(31):3541–3543

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Author contribution

MC Chamberlain collected and analyzed data.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Marc C. Chamberlain.

Ethics declarations

Conflict of interest

The author reports no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chamberlain, M.C., Kim, B.T. Nivolumab for patients with recurrent glioblastoma progressing on bevacizumab: a retrospective case series. J Neurooncol 133, 561–569 (2017). https://doi.org/10.1007/s11060-017-2466-0

Download citation

Keywords

  • Nivolumab
  • Immune checkpoint inhibitor
  • Recurrent glioblastoma
  • Bevacizumab refractory