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Ipilimumab

Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK), 2011, updated March 2020. DermNet Editor in Chief: Adjunct A/Prof. Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell.


Ipilimumab — codes and concepts
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What is ipilimumab?

In March 2011, ipilimumab (YERVOY™; Bristol-Myers Squibb) gained US Food and Drug Agency (FDA) approval for the treatment of adult patients with stage III to IV melanoma unresponsive to previous therapy (stage IV disease, metastatic melanoma) [1].

Metastatic melanoma

Mechanism of action of ipilimumab

Regulatory pathways that limit the immune response to cancer are becoming well characterised. Ipilimumab is a fully human monoclonal antibody that activates the body's immune system to fight melanoma by inhibiting the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) molecule [1,2].

CTLA-4 is a molecule on T-cells that plays a critical role in regulating natural immune responses. The presence of CTLA-4 suppresses the immune system's response to disease, so blocking its activity stimulates the immune system to fight the melanoma.

Key clinical-trial evidence for ipilimumab

Three previous early-phase (phase II) clinical trials have shown that treatment with ipilimumab results in a one-year survival rate of 47% to 51% for people with stage III or IV melanoma, which is almost double the number not on this treatment [3,4].

Ipilimumab has also being tested in advanced (phase III) trials by itself and in combination with vaccines, other immunotherapies (such as interleukin-2), and chemotherapies (such as dacarbazine). Overall response rates ranged from 13% with ipilimumab plus vaccine in patients with stage IV disease to 17% and 22%, with ipilimumab plus dacarbazine or interleukin-2, respectively, in patients with metastatic disease. Responses have been long-lasting, with more than one-third of ipilimumab-treated patients with advanced melanoma experiencing a long-term survival benefit.

Recently published results of a randomized, controlled phase III trial have shown a first-ever significant overall survival benefit with ipilimumab compared with a cancer vaccine comprising HLA-A*0201–restricted peptides derived from the melanosomal protein, glycoprotein 100 (gp100) in patients with metastatic melanoma, previously treated unsuccessfully with aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin [5]. Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered intravenously with or without gp100 (2mg peptide by deep SC) every 3 weeks for up to four treatments.

  • The median overall survival was 10.0 months among 403 patients receiving ipilimumab plus gp100, compared with 6.4 months among 136 patients receiving gp100 alone (statistically significant, P<0.001).
  • The median overall survival with ipilimumab alone (in 137 patients) was 10.1 months (P=0.003).
  • No difference in overall survival was detected between the ipilimumab groups (P=0.76).
  • Grade 3 or 4 immune-related adverse events occurred in 10–15% of patients treated with ipilimumab and in 3% treated with gp100 alone. The most common immune-related adverse event was diarrhoea, which occurred at any grade in 27–31% of the patients in the ipilimumab groups.

Based on these results, the US FDA granted marketing approval for ipilimumab as second-line treatment for metastatic melanoma in adult patients. The FDA noted in its approval announcement that the common adverse effects that can result from autoimmune reactions associated with ipilimumab use include fatigue, diarrhoea, skin rash, endocrine deficiencies (gland or hormone), and inflammation of the intestines (colitis). Severe and some fatal autoimmune reactions were seen in 12.9% of patients treated with ipilimumab. Because of the unusual and severe adverse effects associated with ipilimumab, the therapy was approved with a Risk Evaluation and Mitigation Strategy to inform healthcare professionals about these serious risks. A medication guide has also been provided to patients to inform them about the therapy's potential adverse effects.

Ipilimumab in combination with nivolumab

The safety and efficacy of nivolumab in combination with ipilimumab and nivolumab monotherapy for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study [6].

A total of 945 patients were randomised to receive nivolumab in combination with ipilimumab (n = 314), nivolumab as monotherapy (n = 316), or ipilimumab as monotherapy (n = 315).

Patients in the combination arm received nivolumab 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over 90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks.

Patients in the nivolumab monotherapy arm received nivolumab 3 mg/kg every 2 weeks.

Patients in the comparator arm received ipilimumab 3 mg/kg and nivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo every 2 weeks.

Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments were conducted 12 weeks after randomisation then every 6 weeks for the first year, and every 12 weeks thereafter. The co-primary outcome measures were progression-free survival and overall survival.

At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63).

Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group.

No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone.

Thus, among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab.

Adjuvant ipilimumab vs high-dose interferon-alpha 2b

The currently approved adjuvant ipilimumab dose of 10 mg/kg IV was more toxic and not superior in efficacy to interferon-alpha 2b. Instead, adjuvant therapy with ipilimumab 3 mg/kg benefitted survival versus high-dose interferon-alpha 2b with significant improvement in overall survival [7].

1,670 adult patients with resected cutaneous melanoma were randomly assigned (1:1:1) to ipilimumab 3 mg/kg (n = 523), high-dose interferon-alpha 2b (n = 636) or ipilimumab 10 mg/kg (n = 511).

Comparison of ipilimumab 5 mg/kg versus high-dose interferon-alpha 2b used an intent-to-treat analysis of 1,051 cases and showed significant overall survival difference in favour of ipilimumab 3 mg/kg (hazard ratio [HR], 0.78; 95.6% repeated confidence interval [CI], 0.61–0.99; P = 0.044; Relapse free survival: HR, 0.85; 99.4% CI, 0.66–1.09; p = 0.065). For ipilimumab 10 mg/kg versus high-dose interferon-alpha 2b (n = 989), trends in favour of ipilimumab 10 mg/kg did not achieve statistical significance.

Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipilimumab 3 mg/kg, 79% receiving high-dose interferon-alpha 2b, and 58% receiving ipilimumab 10 mg/kg.

Pembrolizumab vs ipilimumab

KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries [8].

Patients (n = 834) were at least 18 years of age with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive and histologically confirmed advanced melanoma with known BRAFV600 status with up to one previous systemic therapy.

Patients were randomly assigned to intravenous pembrolizumab 10 mg/kg every 2 weeks (n = 279) or every 3 weeks (n = 277) or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks (n = 278).

Pembrolizumab treatment continued for up to 24 months.

Median overall survival was 32.7 months (95% CI 24.5–41.6) in the combined pembrolizumab groups and 15.9 months (13.3–22.0) in the ipilimumab group (hazard ratio [HR] 0.73, 95% CI 0.61–0.88, p=0.00049).

Median progression-free survival was 8·4 months (95% CI 6.6–11.3) in the combined pembrolizumab groups versus 3·4 months (2.9–4.2) in the ipilimumab group (HR 0.57, 95% CI 0.48–0.67, p<0.0001).

Grade 3––4 treatment-related adverse events occurred in 96 (17%) of 555 patients in the combined pembrolizumab groups and in 50 (20%) of 256 patients in the ipilimumab group; the most common of these events were colitis (11 [2%] vs 16 [6%]), diarrhoea (ten [2%] vs seven [3%]), and fatigue (four [<1%] vs three [1%]).

Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up.

Adverse events from ipilimumab

Ipilimumab can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation [8]. These are:

  • Immune-mediated enterocolitis
  • Immune-mediated hepatitis
  • Immune-mediated dermatitis
  • Immune-mediated neuropathies
  • Immune-mediated endocrinopathies, such as hypophysitis
  • Other immune-mediated adverse reactions, including ocular manifestations

In the event of any of these adverse events, ipilimumab should be discontinued and treatment initiated with systemic corticosteroids, i.e. prednis(ol)one or equivalent. Upon improvement, corticosteroids should be tapered gradually.

Vitiligo has been reported as an adverse effect of ipilimumab. Vitiligo has been thought to be a good prognostic factor in metastatic melanoma.

See also Cutaneous adverse effects of checkpoint inhibitors.

Dosage and administration of ipilimumab

The recommended dose of ipilimumab is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses [8].

For any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy, the scheduled dose of ipilimumab should be withheld. For patients with complete or partial resolution of adverse reactions (Grade 0–1), and who are receiving less than 7.5 mg prednisone or equivalent per day, ipilimumab should be resumed at a dose of 3 mg/kg every 3 weeks until administration of all 4 planned doses or 16 weeks from first dose, whichever occurs earlier.

Ipilimumab should be discontinued permanently for any of the following reasons:

  • Persistent moderate adverse reaction(s) or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.
  • Failure to complete full treatment course within 16 weeks from administration of first dose.
  • Severe or life-threatening adverse reactions such as colitis with abdominal pain, fever, ileus, or peritoneal signs, increase in stool frequency (7 or more over baseline), stool incontinence, need for intravenous hydration for more than 24 hours, gastrointestinal haemorrhage, and gastrointestinal perforation.
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limit of normal or total bilirubin >3 times the upper limit of normal.
  • Stevens-Johnson syndrome / toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations.
  • Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis
  • Severe immune-mediated reactions involving any organ system (eg, nephritis, pneumonitis, pancreatitis, non-infectious myocarditis).
  • Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy.

Contraindications to ipilimumab

None have been reported [8].

Drug interactions with ipilimumab

No formal drug-drug interaction studies have been conducted with ipilimumab.

Use of ipilimumab in specific populations

There are no adequate and well-controlled studies of ipilimumab in pregnant women. Ipilimumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (Pregnancy Category C) [1,8].

  • It is not known whether ipilimumab is secreted in human milk. Because of the potential adverse effects to the infant, a decision should be made whether to discontinue nursing or to discontinue ipilimumab, taking into account the importance of ipilimumab to the mother.
  • Safety and effectiveness of ipilimumab have not been established in children.
  • In clinical trials, no overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).
  • No formal studies of ipilimumab in patients with renal impairment have been conducted.
  • No formal studies of ipilimumab in patients with hepatic impairment have been conducted.
  • The genotoxic potential of ipilimumab has not been evaluated.
  • Fertility studies have not been performed with ipilimumab.
  • The carcinogenic potential of ipilimumab has not been evaluated in long-term animal studies.
  • It is unknown whether ipilimumab should be used before or after BRAF inhibitor therapy in patients suitable for both treatments.

Overdosage with ipilimumab

No data are currently available on overdosage with ipilimumab.

New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

If you are not based in New Zealand, we suggest you refer to your national drug approval agency for further information about medicines (eg, the Australian Therapeutic Goods Administration and the US Food and Drug Administration) or a national or state-approved formulary (eg, the New Zealand Formulary and New Zealand Formulary for Children and the British National Formulary and British National Formulary for Children).

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References

  1. Prescribing information for Yervoy
  2. Ajay V. Maker, Giao Q. Phan, Peter Attia, James C. Yang, Richard M. Sherry, Suzanne L. Topalian, et. al. Tumor Regression and Autoimmunity in Patients Treated With Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and Interleukin 2: A Phase I/II Study. Ann Surg Oncol 2005; 12: 1005–16. PubMed
  3. Hersh EM, O'Day SJ, Powderly J, Khan KD, Pavlick AC, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs 2011; 29: 489–98. PubMed
  4. F. Stephen Hodi, Steven J. O'Day, David F. McDermott, Robert W. Weber, Jeffrey A. Sosman, et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 2010; 363: 711–23. PubMed
  5. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2019; 381: 1535–46. PubMed
  6. Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI et al. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol 2020; 38: 567–75. PubMed
  7. Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol 2019; 20: 1239–51. PubMed
  8. New Zealand data sheet for Yervoy – Medsafe

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