Risk of gastrointestinal complications in cancer patients treated with immune checkpoint inhibitors: a meta-analysis
Abstract
Aim: We performed a meta-analysis of the risk of selected gastrointestinal toxicities associated with immune checkpoint inhibitors. Patients & methods: Eligible studies included randomized trials of patients with solid tumors on ipilimumab, nivolumab, pembrolizumab, tremelimumab, pidilizumab and atezolizumab, describing events of diarrhea, vomiting or colitis. Results: After exclusion of ineligible studies, a total of ten clinical trials were considered eligible for the meta-analysis. The relative risk of all-grade diarrhea, vomiting and colitis was 1.64 (95% CI: 1.19–2.26; p = 0.002), 0.72 (95% CI: 0.49–1.07; p = 0.1), 10.35 (95% CI: 5.78–18.53; p < 0.00001), respectively. Conclusion: Our meta-analysis has demonstrated that immune checkpoint inhibitors are associated with a significantly increased risk of all grade and high-grade colitis.
Papers of special note have been highlighted as: • of interest
References
- 1 . Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway. Pharmgenomics Pers. Med. 7, 357 (2014).
- 2 . Immune checkpoints aberrations and gastric cancer; assessment of prognostic value and evaluation of therapeutic potentials. Crit. Rev. Oncol. Hematol.
doi:10.1016/j.critrevonc.2015.08.015 (2015) (Epub ahead of print). - 3 Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711–723 (2010).• In this study, diarrhea was observed in 146 pts (38.4%), 43 pts (32.8%) and 26 pts (19.7%) in arms A, B and C.
- 4 Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364(26), 2517–2526 (2011).
- 5 Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma. N. Engl. J. Med. 369(2), 134–144 (2013).
- 6 Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer Res. 14(10), 3044–3051 (2008).
- 7 Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international Phase II trial. J. Clin. Oncol. 31(33), 4199–4206 (2013).
- 8 Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366(26), 2455–2465 (2012).
- 9 Safety and activity of pd1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, Phase 2 trial. Lancet Oncol. 15(1), 69–77 (2014).
- 10 . Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors: a meta-analysis. Future Oncol. 11(17), 2471–2784 (2015).
- 11 . Risk of endocrine complications in cancer patients treated with immune check point inhibitors; a meta-analysis. Future Oncol.
doi:10.2217/FON.15.222 (2015) (In press). - 12 Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270(5238), 985–988 (1995).
- 13 . Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5), 541–547 (1995).
- 14 Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc. Natl Acad. Sci. USA 100(8), 4712–4717 (2003).
- 15 . Cytotoxic T-lymphocyte-associated antigen 4 antibody-induced colitis and its management with infliximab. Dig. Dis. Sci. 54(11), 2538–2540 (2009).
- 16 Analysis of the onset and resolution of immune-related adverse events during treatment with ipilimumab in patients with metastatic melanoma. Presented at: Perspectives in Melanoma XII, Scheveningen, The Hague, The Netherlands, 2–4 October 2008 (Abstract O-015).
- 17 Ipilimumab‐induced toxicities and the gastroenterologist. J. Gastroenterol. Hepatol. 30(4), 657–666 (2015).
- 18 . Ipilimumab in a patient with known crohn's disease: to give or not to give? J. Crohn's Colitis 8(12), 1742–1742 (2014).
- 19 Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, Phase 2, dose-ranging study. Lancet Oncol. 11(2), 155–164 (2010).
- 20 . Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr. Opin. Immunol. 18(2), 206–213 (2006).
- 21 Potential immune biomarkers of gastrointestinal toxicities and efficacy in patients with advanced melanoma treated with ipilimumab with or without prophylactic budesonide. Presented at: ASCO Annual Meeting Proceedings. IL, USA, 30 May–01 June 2008.
- 22 Ipilimumab-associated colitis: CT findings. Am. J. Roentgenol. 200(5), W468–W474 (2013).
- 23 . Ipilimumab-induced colitis on FDG PET/CT. Clin. Nucl. Med. 37(6), 629–630 (2012).
- 24 . Clustered genomic variants specific to patients who develop immune-related colitis after ipilimumab for prediction of toxicity. J. Clin. Oncol. 32, 5s (2014) (suppl; abstr 9024).
- 25 . Early administration of infliximab for severe ipilimumab-related diarrhea in a critically ill patient. Ann. Pharmacother. 48(6), 806–810 (2014).
- 26 . Diarrhoea in a patient with metastatic melanoma: Ipilimumab ileocolitis treated with infliximab. World J. Gastrointest. Pharmacol. Ther. 4, 80–82 (2013).
- 27 . Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30(21), 2691–2697 (2012).
- 28 . An analysis of the effectiveness of specific guidelines for the management of ipilimumab-mediated diarrhea/colitis: prevention of gastrointestinal perforation and/or colectomy. J. Clin. Oncol. 26(15S), (2008) (suppl; abstr 9063).
- 29 . Preferred reporting items for systematic reviews and meta-analyses: the prisma statement. Ann. Intern. Med. 151(4), 264–269 (2009).
- 30 . Meta-analysis in clinical trials. Control. Clin. Trials 7(3), 177–188 (1986).
- 31 . Measuring inconsistency in meta-analyses. BMJ 327(7414), 557 (2003).
- 32 Adjuvant ipilimumab versus placebo after complete resection of high-risk stage iii melanoma (eortc 18071): a randomised, double-blind, Phase 3 trial. Lancet Oncol. 16(5), 522–530 (2015).
- 33 Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIb/IV non–small-cell lung cancer: results from a randomized, double-blind, multicenter Phase II study. J. Clin. Oncol. 30(17), 2046–2054 (2012).
- 34 Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J. Clin. Oncol. 31(5), 616–622 (2013).
- 35 Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372(4), 320–330 (2015).
- 36 Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (ca184–043): a multicentre, randomised, double-blind, Phase 3 trial. Lancet Oncol. 15(7), 700–712 (2014).
- 37 Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N. Engl. J. Med. 373(2), 123–135 (2015).
- 38 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. 16(4), 375–384 (2015).
- 39 Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter Phase 2 trial. Ann. Oncol. 24(1), 75–83 (2013).
- 40 . At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J. Leukoc. Biol. 94(1), 25–39 (2013).
- 41 Regulation of surface and intracellular expression of CTLA4 on mouse T cells. J. Immunol. 157(11), 4762–4770 (1996).
- 42 Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366(26), 2443–2454 (2012).
- 43 . Risk of selected gastrointestinal toxicities in patients with advanced non-small cell lung cancer receiving erlotinib: a systematic review and meta-analysis. Expert Rev. Anticancer Ther. 15(4), 465–475 (2015).
- 44 . Risk of selected gastrointestinal toxicities in breast cancer patients treated with regimens containing lapatinib; a pooled analysis of randomized controlled studies. Expert Rev. Anticancer Ther. 14(10), 1229–1242 (2014).
- 45 . Risk of oral and gastrointestinal mucosal injury in patients with solid tumors treated with everolimus, temsirolimus or ridaforolimus: a comparative systematic review and meta-analysis. Expert Rev. Anticancer Ther. 15(7), 847–858 (2015).
- 46 . Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy. Am. J. Roentgenol. 197(6), W992–W1000 (2011).
- 47 Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J. Immunother. (Hagerstown, Md.: 1997) 30(8), 825 (2007).
- 48 . Risk of severe diarrhea associated with ipilimumab in cancer patients. J. Clin. Oncol. 32, 5s (2014) (suppl; abstr 9634).
- 49 Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372(26), 2521–2532 (2015).
- 50 Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373(1), 23–34 (2015).
- 51 Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372(21), 2006–2017 (2015).