Gastrointestinal complications in patients treated with ipilimumab and nivolumab combination therapy or monotherapy
Abstract
Aim & methods: A retrospective study using the IBM Explorys Universe Database assessed the risk of gastrointestinal events (enterocolitis or diarrhea) among melanoma and lung cancer patients treated with ipilimumab and nivolumab combination or monotherapy. Results & conclusion: There were 904 melanoma patients (607 ipilimumab, 140 nivolumab and 157 combo) and 1641 lung cancer patients (68 ipilimumab, 1542 nivolumab and 31 combo). Approximately, 37% of lung patients and 46% of melanoma patients experienced at least one adverse event. After adjusting for covariates, patients receiving combination therapy were more likely to have a gastrointestinal event compared with ipilimumab monotherapy patients (melanoma hazard ratio: 1.54; 95% CI: 1.06–2.25; lung hazard ratio: 2.93; 95% CI: 1.09–7.89).
Supplementary Material
File (supplementary content.docx)
- Download
- 41.57 KB
References
Papers of special note have been highlighted as: • of interest
1.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Rev. Cancer 12(4), 252–264 (2012).
2.
Sliwkowski MX, Mellman I. Antibody therapeutics in cancer. Science 341(6151), 1192 (2013).
3.
Grosso JF, Jure-Kunkel MN. CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun. 13, 5 (2013).
4.
Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers and combinations. Sci. Transl. Med. 8(328), 328rv324–328rv324 (2016).
5.
Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am. J. Clin. Oncol. 39(1), 98–106 (2016).
• Provides a comprehensive review of biology behind cytotoxic T-lymphocyte-associated 4 and programmed cell death receptor 1 immunotherapy in cancer.
6.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J. Clin. 68(1), 7–30 (2018).
7.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J. Clin. 60(5), 277–300 (2010).
8.
Hodi FS, O'Day SJ, Mcdermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. New Engl. J. Med. 363(8), 711–723 (2010).
• First published Phase III trial of ipilimumab for metastatic melanoma reported that 7.3% of patients on ipilimumab experienced colitis.
9.
Weber JS, D'Angelo SP, Minor D 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 III trial. Lancet Oncol. 16(4), 375–384 (2015).
10.
Hodi FS, Chesney J, Pavlick AC et al. Two-year overall survival rates from a randomised Phase II trial evaluating the combination of nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma. Lancet Oncol. 17(11), 1558–1568 (2016).
11.
Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. New Engl. J. Med. 373(1), 23–34 (2015).
• 1:1:1 Phase III study comparing nivolumab, ipilimumab and the combination therapy, the respective proportion of patients who were diagnosed with colitis was 1.3, 11.6 and 11.8%.
12.
El-Khoueiry AB, Sangro B, Yau T et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, Phase I/II dose escalation and expansion trial. Lancet 389(10088), 2492–2502 (2017).
13.
Overman MJ, Mcdermott R, Leach JL et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, Phase II study. Lancet Oncol. 18(9), 1182–1191 (2017).
14.
Borghaei H, Paz-Ares L, Horn L et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. New Engl. J. Med. 373(17), 1627–1639 (2015).
15.
Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. New Engl. J. Med. 373(2), 123–135 (2015).
16.
Hellmann MD, Rizvi NA, Goldman JW et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, Phase I, multicohort study. Lancet Oncol. 18(1), 31–41 (2017).
17.
Michot JM, Bigenwald C, Champiat S et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur. J. Cancer 54, 139–148 (2016).
18.
Mearns ES, Bell JA, Galaznik A et al. Gastrointestinal adverse events with combination of checkpoint inhibitors in advanced melanoma: a systematic review. Melanoma Manag. 5(1), MMT01 (2018).
19.
Hassel JC, Heinzerling L, Aberle J et al. Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions. Cancer Treat. Rev. 57, 36–49 (2017).
• A study pooling safety data of 1551 patients from publicly available drug trials reported rates of any colitis and enterocolitis of 1.1% for nivolumab, 11.8% for ipilimumab and 14.5% for combination therapy.
20.
Ali AK, Watson DE. Pharmacovigilance assessment of immune-mediated reactions reported for checkpoint inhibitor cancer immunotherapies. Pharmacotherapy 37(11), 1383–1390 (2017).
• An analysis of data from the US FDA Adverse Event Reporting System found that colitis was the most commonly reported immune-related adverse event (IRAE) and it accounted for 553 (63.2%) of IRAE for ipilimumab and 72 (40.7%) of IRAEs for nivolumab.
21.
Melanoma (version 2.2018) (February 2, 2018), (2018). www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf.
22.
Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current diagnosis and management of immune related adverseeEvents (IRAEs) induced by immune checkpoint inhibitor therapy. Front. Pharmacol. 8, 49 (2017).
23.
Horvat TZ, Adel NG, Dang T-O et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J. Clin. Oncol. 33(28), 3193–3198 (2015).
• A single site retrospective review of IRAEs in 298 melanoma patients treated with ipilimumab including frequency, treatment approach and outcomes. A total of 19% discontinued therapy because of IRAEs with diarrhea being the most common cause, 35% required systemic corticosteroid treatment, but occurrence or treatment of IRAEs did not affect overall survival.
24.
Hammers HJ, Plimack ER, Infante JR et al. Expanded cohort results from CheckMate 016: a Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J. Clin. Oncol. 33(15 Suppl.), 4516 (Abstract 4516) (2015).
25.
Janjigian YY, Bendell JC, Calvo E et al. CheckMate-032: Phase I/II, open-label study of safety and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC). J. Clin. Oncol. 34(15 Suppl.), 4010–4010 (2016).
26.
Overman MJ, Kopetz S, Mcdermott RS et al. Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results. J. Clin. Oncol. 34(15_suppl), 3501–3501 (2016).
27.
Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J. Clin. Epidemiol. 45(6), 613–619 (1992).
28.
SEER-Medicare: calculation of comorbidity weights (March 6, 2017). https://healthcaredelivery.cancer.gov/seermedicare/considerations/calculation.html.
29.
Phase IIIstudy of nivolumab or nivolumab plus ipilimumab versus ipilimumab alone in previously untreated advanced melanoma (CheckMate 067) (March 5, 2018). https://ClinicalTrials.gov/show/NCT01844505.
30.
Study of nivolumab (BMS-936558) compared with dacarbazine in untreated, unresectable, or metastatic melanoma (March 5, 2018). https://ClinicalTrials.gov/show/NCT01721772.
31.
Study of nivolumab (BMS-936558) plus ipilimumab compared with ipilimumab alone in the treatment of previously untreated, unresectable, or metastatic melanoma (March 5, 2018). https://ClinicalTrials.gov/show/NCT01927419.
32.
Bristol-Myers S. A study to compare BMS-936558 to the physician's choice of either dacarbazine or carboplatin and paclitaxel in advanced melanoma patients that have progressed following anti-CTLA-4 therapy (CheckMate 037) (March 5, 2018), (2016). https://ClinicalTrials.gov/show/NCT01721746.
Information & Authors
Information
Published In
Copyright
© 2018 Future Medicine Ltd.
History
Received: 18 July 2018
Accepted: 5 November 2018
Published online: 14 December 2018
Keywords:
Topics
Authors
Metrics & Citations
Metrics
Article Usage
Article usage data only available from February 2023. Historical article usage data, showing the number of article downloads, is available upon request.
Citations
How to Cite
Gastrointestinal complications in patients treated with ipilimumab and nivolumab combination therapy or monotherapy. (2018) Journal of Comparative Effectiveness Research. DOI: 10.2217/cer-2018-0072
Export citation
Select the citation format you wish to export for this article or chapter.
Citing Literature
- Süleyman Can, Are We Underestimating the Toxicity of Combination Immune Checkpoint Inhibitors? Real-World Evidence Challenging Current Guideline Predictions., Medical Science and Discovery, 10.36472/msd.v12i12.1343, 12, 12, (327-329), (2025).
- Agnès Calsina-Berna, Jesús González-Barboteo, Silvia Llorens-Torromé, Joaquim Julià-Torras, Antitumoral Agent-Induced Constipation: A Systematic Review, Cancers, 10.3390/cancers16010099, 16, 1, (99), (2023).
- Abdulaali R. Almutairi, Marion Slack, Brian L. Erstad, Ali McBride, Ivo Abraham, Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER–Medicare database, Therapeutic Advances in Drug Safety, 10.1177/2042098621991279, 12, (2021).
- Carolina Lopes, Sandra Morgado, Ana I. Plácido, Fátima Roque, Manuel Morgado, Critical Analysis of Immune Checkpoint Inhibitor Immunotoxicity Management, SN Comprehensive Clinical Medicine, 10.1007/s42399-020-00670-w, 3, 1, (84-94), (2021).
- Pauline Hulo, Yann Touchefeu, Estelle Cauchin, Isabelle Archambeaud, Nicolas Chapelle, Céline Bossard, Jaafar Bennouna, Acute Ulceronecrotic Gastritis With Cytomegalovirus Reactivation: Uncommon Toxicity of Immune Checkpoint Inhibitors in Microsatellite Instability–High Metastatic Colorectal Cancer, Clinical Colorectal Cancer, 10.1016/j.clcc.2020.04.006, 19, 4, (e183-e188), (2020).
- Abdulaali R. Almutairi, Ali McBride, Marion Slack, Brian L. Erstad, Ivo Abraham, Potential Immune-Related Adverse Events Associated With Monotherapy and Combination Therapy of Ipilimumab, Nivolumab, and Pembrolizumab for Advanced Melanoma: A Systematic Review and Meta-Analysis, Frontiers in Oncology, 10.3389/fonc.2020.00091, 10, (2020).
- Alice C. Shieh, Ezgi Guler, David Pfau, Ethan Radzinsky, Daniel A. Smith, Christopher Hoimes, Nikhil H. Ramaiya, Sree Harsha Tirumani, Imaging and clinical manifestations of immune checkpoint inhibitor-related colitis in cancer patients treated with monotherapy or combination therapy, Abdominal Radiology, 10.1007/s00261-019-02334-3, 45, 10, (3028-3035), (2019).
