Ipilimumab Therapy: Evaluating and Managing Immune-Related Adverse Events and Patterns of Clinical Response

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mmune-regulating cytotoxic T-lymphocyteassociated antigen-4 (CTLA-4) puts the brakes on activated immune cells as an “immune checkpoint molecule” that downregulates pathways of T-cell activation. Ipilimumab enhances the body’s immune response against tumors by blocking CTLA-4-mediated T-cell suppression. In this process, as clinical studies have consistently shown, an unusual spectrum of side effects and pattern of clinical response often emerges.^1-3

Consistent with its proposed mechanism of action, the majority of adverse events with ipilimumab are immune-related. In the pivotal trial showing improved survival with ipilimumab in patients with metastatic melanoma, immune-related adverse events (irAEs) most often affected the skin, liver, bowel, and endocrine system:³

• Rash/vitiligo/pruritus, 43.5% any grade and 1.5% grades 3-4
• Hepatitis/rise in liver enzymes, 3.8% any grade, 0% grades 3-4
• Diarrhea/colitis, 29.0% any grade, 7.6% grades 3-4
• Hypophysitis, thyroiditis, adrenal insufficiency, 7.6% any grade, 3.8% grades 3-4

Less commonly, ipilimumab-treated patients have experienced uveitis, conjunctivitis, neuropathy, myopathy, and nephritis.³ Although a preventive strategy for these adverse effects has not been identified, the irAEs have been responsive to interruption or discontinuation of the CTLA-4 blockade plus immunosuppressive drugs such as steroids or tumor necrosis factor-blocking antibodies.²

Ipilimumab was approved with a boxed warning in recognition that its use has the potential to result in severe or fatal immune-mediated adverse reactions related to T-cell activation.⁴ A Risk Evaluation and Mitigation Strategy (REMS) was developed by the drug’s maker in collaboration with the FDA, advising clinicians to:

• Permanently discontinue ipilimumab and initiate systemic high-dose corticosteroid therapy for identified severe immune-mediated reactions.
• Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose of ipilimumab.

Another unusual feature of ipilimumab relates to novel patterns of clinical response. In some instances after starting ipilimumab, there is an early period of disease progression before patients experience a disease response. In others cases, there is regression of initial tumors but development of additional smaller lesions.²

Interestingly, patients who experience irAEs may gain more benefit from ipilimumab therapy. However, serious adverse events are not required for a response to occur. Nor is the occurrence of irAEs a guarantee of clinical benefit from ipilimumab.^2,3

These unusual response patterns call for a new way to evaluate the benefits of ipilimumab and other immunotherapeutic agents. Accordingly, Wolchok et al5 proposed immune-related response criteria (irRC) that consider a patient’s “total tumor burden” and require confirmation of any suspected disease program by radiographic testing approximately four weeks after treatment. IrRC are currently being employed along with traditional response criteria (such as Response Evaluation Criteria In Solid Tumors [RECIST]) in clinical protocols for prospective validation of immunotherapeutic agents.^2,5

References:

1. Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer. 2007;7:95-106.

2. Postow MA, Wolchok JD. Ipilimumab: developmental history, clinical considerations, and future perspectives. The Melanoma Letter. 2012;30:1.

3. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.

4. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

5. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009; 15:7412-7420.