Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials

Ricardo Costa, Benedito A Carneiro, Mark Agulnik, Alfred W Rademaker, Sachin G Pai, Victoria M Villaflor, Massimo Cristofanilli, Jeffrey A Sosman, Francis J Giles, Ricardo Costa, Benedito A Carneiro, Mark Agulnik, Alfred W Rademaker, Sachin G Pai, Victoria M Villaflor, Massimo Cristofanilli, Jeffrey A Sosman, Francis J Giles

Abstract

Purpose: Nivolumab and pembrolizumab are antibodies against the programmed-death-receptor- 1 (PD-1) which are associated with distinct immune related adverse effects (AEs). This meta-analysis of randomized clinical trials aims to summarize current knowledge regarding the toxicity profile of these agents.

Methods: PubMed search was conducted in February of 2016. The randomized trials needed to have at least one of the study arms consisting of nivolumab or pembrolizumab monotherapy and a control arm containing no anti-PD-1 therapy. Data were analyzed using random effects meta-analysis for risk ratios. Heterogeneity across studies was analyzed using Q and I2 statistics.

Results: Nine randomized trials and 5,353 patients were included in our meta-analysis. There was evidence of significant heterogeneity between studies. The pooled relative risk (RR) for treatment-related all grade AEs and grade 3/4 AEs was 0.88 (95% CI 0.81-0.95;P=0.002) and 0.39 (95% CI 0.29-0.53; P<0.001) respectively favoring anti-PD-1 therapy versus standard of care approach. The RR of treatment-related death was 0.45 (95% CI 0.19-1.09; P=0.076). Patients treated with PD-1 inhibitors had an increased risk of hyperthyroidism [RR of 3.44 (95% CI 1.98-5.99; P<0.001)] and hypothyroidism [RR of 6.79 (95% CI 3.10-14.84; P<0.001)]. All grade pruritus and vitiligo were also more common among these patients. The pooled absolute risks of pneumonitis and hypophysitis were 2.65% and 0.47% respectively.

Conclusion: Approved PD-1 inhibitors are well tolerated, associated with significant low risk of severe treatment-related AEs and increased risk of thyroid dysfunction, pruritus, and vitiligo.

Keywords: adverse events; anti-PD1 antibodies; hypothyroidism; meta-analysis; pruritus.

Conflict of interest statement

CONFLICTS OF INTEREST

Ricardo Costa M.D., M.Sc.: In the past 2 years the author had research project funded, in whole or in part, by Bristol Myers Squibb.

Figures

Figure 1. Study flow diagram
Figure 1. Study flow diagram
Figure 2. Forest plots of relative risks…
Figure 2. Forest plots of relative risks of all grade AEs (A) and grade 3&4 AEs (B)
Abbreviations: Adverse events (AEs), immunotherapy therapy treatment arm (ITX), and control arm (CTX).

References

    1. Kazandjian D, Khozin S, Blumenthal G, Zhang L, Tang S, Libeg M, Kluetz P, Sridhara R, Keegan P, Pazdur R. Benefit-Risk Summary of Nivolumab for Patients With Metastatic Squamous Cell Lung Cancer After Platinum-Based Chemotherapy: A Report From the US Food and Drug Administration. JAMA Oncol. 2016;2:118–22. doi: 10.1001/jamaoncol.2015.3934.
    1. Raedler LA. Opdivo (Nivolumab): Second PD-1 Inhibitor Receives FDA Approval for Unresectable or Metastatic Melanoma. Am Health Drug Benefits. 2015;8:180–3. doi:
    1. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373:1803–13. doi: 10.1056/NEJMoa1510665.
    1. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372:2521–32. doi: 10.1056/NEJMoa1503093.
    1. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G, Jr, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2015.
    1. Postow MA. Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book. 2015. pp. 76–83.
    1. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of Immunotherapy for the Practitioner. J Clin Oncol. 2015;33:2092–9. doi: 10.1200/JCO.2014.60.0379.
    1. Sano T, Uhara H, Mikoshiba Y, Kobayashi A, Uchiyama R, Tateishi K, Yamamoto H, Okuyama R. Nivolumab-induced organizing pneumonia in a melanoma patient. Jpn J Clin Oncol. 2016;46:270–2. doi: 10.1093/jjco/hyv199.
    1. Nakashima K, Naito T, Omori S, Yoshikawa S, Endo M, Kiyohara Y, Takahashi T. Organizing Pneumonia Induced by Nivolumab in a Patient with Metastatic Melanoma. J Thorac Oncol. 2016;11:432–3. doi: 10.1016/j.jtho.2015.10.004.
    1. Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, Postow MA, Wolchok JD. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26:2375–91. doi: 10.1093/annonc/mdv383.
    1. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373:23–34. doi: 10.1056/NEJMoa1504030.
    1. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:1627–39. doi: 10.1056/NEJMoa1507643.
    1. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:123–35. doi: 10.1056/NEJMoa1504627.
    1. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30. doi: 10.1056/NEJMoa1412082.
    1. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O’Day SJ, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–18. doi: 10.1016/S1470-2045(15)00083-2.
    1. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH, Jr., Lao CD, Linette GP, Thomas L, Lorigan P, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–84. doi: 10.1016/S1470-2045(15)70076-8.
    1. Abdel-Rahman O, ElHalawani H, Fouad M. Risk of gastrointestinal complications in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Immunotherapy. 2015;7:1213–27. doi: 10.2217/imt.15.87.
    1. Abdel-Rahman O, ElHalawani H, Fouad M. Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors: a meta-analysis. Future Oncol. 2015;11:2471–84. doi: 10.2217/fon.15.118.
    1. Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, Sequist LV, Smith DC, Leming P, et al. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2015;33:2004–12. doi: 10.1200/JCO.2014.58.3708.
    1. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54. doi: 10.1056/NEJMoa1200690.
    1. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28. doi: 10.1056/NEJMoa1501824.
    1. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol. 2015;33:1430–7. doi: 10.1200/JCO.2014.59.0703.
    1. JN Le DT Uram, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372:2509–20. doi: 10.1056/NEJMoa1500596.
    1. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372:311–9. doi: 10.1056/NEJMoa1411087.
    1. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–17. doi: 10.1016/S0140-6736(14)60958-2.
    1. Dienstmann R, Brana I, Rodon J, Tabernero J. Toxicity as a biomarker of efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs. Oncologist. 2011;16:1729–40. doi: 10.1634/theoncologist.2011-0163.
    1. Ravaud A, Schmidinger M. Clinical biomarkers of response in advanced renal cell carcinoma. Ann Oncol. 2013;24:2935–42. doi: 10.1093/annonc/mdt288.
    1. Gogas H, Ioannovich J, Dafni U, Stavropoulou-Giokas C, Frangia K, Tsoutsos D, Panagiotou P, Polyzos A, Papadopoulos O, Stratigos A, Markopoulos C, Bafaloukos D, Pectasides D, et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med. 2006;354:709–18. doi: 10.1056/NEJMoa053007.
    1. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Restifo NP, Haworth LR, Levy C, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043–53. doi: 10.1200/JCO.2005.06.205.
    1. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. Clin Cancer Res. 2016;22:886–94. doi: 10.1158/1078-0432.CCR-15-1136.
    1. Ongenae K, Van Geel N, Naeyaert JM. Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res. 2003;16:90–100. doi:
    1. Yasuda K, Igishi T, Kawasaki Y, Kato K, Matsumoto S, Katayama S, Sako T, Shigeoka Y, Suyama H, Sugitani A, Yamamoto M, Hitsuda Y, Shimizu E. Phase II study of weekly paclitaxel in patients with non-small cell lung cancer who have failed previous treatments. Oncology. 2004;66:347–52. doi: 10.1159/000079481.
    1. Graziano SL, Herndon JE, MA 2nd Socinski, Wang X, Watson D, Vokes E, Green MR, Cancer Leukemia Group B. Phase II trial of weekly dose-dense paclitaxel in extensive-stage small cell lung cancer: cancer and leukemia group B study 39901. J Thorac Oncol. 2008;3:158–62. doi: 10.1097/JTO.0b013e318161225e.
    1. Baselga J, Campone M, Piccart M, Burris HA, HS 3rd Rugo, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9. doi: 10.1056/NEJMoa1109653.
    1. Stewart LA, Clarke M, Rovers M, Riley RD, Simmonds M, Stewart G, Tierney JF, Group P-ID. Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. JAMA. 2015;313:1657–65. doi: 10.1001/jama.2015.3656.
    1. LVH Michael Borenstein, Higgins Julian P. T., Rothstein Hannah R. Introduction to meta-analysis. John Wiley & Sons, West; Sussex UK: 2009. doi:
    1. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101. doi:
    1. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34. doi:

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