Recognizing and Managing Immune-Specific Adverse Events

The world of oncology has been abuzz with the rapid advent of immuno-oncologic (I-O) agents either recently approved by the U.S. Food and Drug Administration (FDA) or in the development pipeline. While immuno-modulating agents such as interleukin-2 (IL-2) and interferon (IFN) have been used in the treatment of some solid malignancies for years, their use has generally been limited to cancers considered immunogenic, i.e., melanoma and kidney cancers.1

The last decade has seen incredible growth in the understanding of how host environments, malignancies, and the immune system interact. With this understanding has come the development and approval of new agents that have the potential to redefine how cancer care is approached and delivered. Discoveries such as the enhancement of the immune response and increase in anti-tumor activity through manipulating regulatory interactions between immune and cancer cells have led to a new class of immuno-oncologic agents: the checkpoint inhibitors.

The currently approved checkpoint inhibitors are monoclonal antibodies that target the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death/programmed death ligand (PD-1/PD-L1) pathways. These classes are both regulators of T-cell activity. To date, one CTLA-4 checkpoint inhibitor and two PD-1 checkpoint inhibitors have received FDA approval:

  • Ipilimumab [Yervoy] binds to the CTLA-4 on T cells and is indicated for the treatment of unresectable of metastatic melanoma;2
  • Pembrolizumab (Keytruda) targets the PD-1 receptor on T cells and is indicated for the treatment of unresectable of metastatic melanoma;3
  • Nivolumab (Opdivo) targets the PD-1 receptor on T cells and is indicated for the treatment of unresectable of metastatic melanoma, metastatic squamous non-small cell lung cancer (NSCLC) and non-squamous NSCLC.4

Numerous other checkpoint inhibitors, including PD-L1 inhibitors, are under clinical development for a variety of indications.

For many patients, the use of the checkpoint inhibitors has been associated with significant and durable clinical responses. However, the side effects noted with these agents are different than those seen with traditional chemotherapy, and these have been categorized as immune-related adverse events (irAEs) or immune-mediated adverse reactions. As I-O agents continue to emerge as mainstream cancer treatments, learning how to monitor and manage these side effects will be critical to optimizing patient health.

Unique Mechanisms, Unique Side Effects

While interactions between the immune system and tumors are complex and still not fully understood, the mechanism of action associated with checkpoint inhibitors explains some of their unique adverse side effects noted with these agents. Both CTLA-4 and PD-1/PD-L1 are normally involved in maintaining an appropriate immune response through down-regulation as well as prevention of inappropriate activity against self-antigens.5

Tumor cells have been shown to have the ability to exploit the CTLA-4 and PD-1/PD-L1 pathways and, in effect, up-regulate inhibitory immune pathways.6Blocking these interactions with CTLA-4 and PD-1 checkpoint inhibitors leads to increased T-cell proliferation and activity in addition to pro-inflammatory reactions; however, in addition to targeting tumor cells, this activity can target normal tissues as well, resulting in side effects that are autoimmune in nature.7

“If you take off the brakes on the immune system, you lower the bar on the immune tolerance that we all have to have to avoid autoimmune toxicities.”
— Interview with John M. Kirkwood, MD, May 2015

Indeed, data from clinical trials indicate most of the adverse events experienced by patients receiving checkpoint inhibitors are autoimmune in nature and usually occur during the first three months of therapy, although some may occur after the final dose.8,9 Although the toxicities associated with checkpoint inhibitors follow a predictable pattern of onset, toxicities associated with ipilimumab appear to be dose related, whereas those with the nivolumab and pembrolizumab do not (Figure 1).9,10

Pattern of Toxicity Onset Seen with the Checkpoint Inhibitors9,10
Figure 1. Pattern of Toxicity Onset Seen with the Checkpoint Inhibitors

The Types of Side Effects Seen with Checkpoint Inhibitors

The types of irAEs observed may also vary with tumor type. The most commonly observed (≥20%) adverse events in clinical trials, as well as specific immune-mediated adverse reactions noted in each agent’s Product Information, are presented in Tables 1 and 2, respectively.2-4 Overall, the PD-1 inhibitors appeared to be better tolerated in clinical trials than the CTLA-4 inhibitors; Grade 3 and 4 toxicities occurred in 10-15%, 12%, and 11% of patients receiving ipilimumab, pembrolizumab, and nivolumab, respectively.11

The types of irAEs also vary with the type of checkpoint inhibitor. For example, PD-1 inhibitors are associated with higher rates of pneumonitis; conversely, diarrhea/colitis is a more common complaint in patients receiving therapy with a CTLA-4 inhibitor.2-4

While many of the irAEs are Grade 1 or 2, irAEs may progress and become severe and life-threatening; thus patients should be routinely assessed at baseline and before each dose for signs and symptoms of irAEs as well as changes in clinical chemistries (blood counts, metabolic panels, liver, and thyroid function tests).7,12

Percentage of Select Adverse Events Reported in =20% of Patients and Corresponding Percentage with Grades = 32-4
Table 1. Percentage of Select Adverse Events Reported in ≥20% of Patients and Corresponding Percentage with Grades ≥ 32-4

Recognizing irAEs When They Develop

The FDA requires manufacturers of the three checkpoint inhibitors to develop FDA-approved Risk Evaluation and Mitigation Strategies (REMS) to assist clinicians in monitoring, recognizing, and managing treatment-related adverse events. Each REM includes a management guide that provides detailed checklists for healthcare personnel to use for patient education, monitoring, and treatment decisions. While not exhaustive, many of the signs and symptoms associated with specific checkpoint inhibitor-related adverse events are summarized in Table 3.

Percentage of Select Immune-mediated Adverse Events Occurring in Patients Receiving Treatment with Checkpoint Inhibitors
Table 2. Percentage of Select Immune-mediated Adverse Events Occurring in Patients Receiving Treatment with Checkpoint Inhibitors

Management of irAEs

Once it has been determined a patient is experiencing an irAE, the severity of the toxicity needs to be assessed, since severity determines the management strategy. Management often includes involving specialists and may include symptomatic treatment, withholding or discontinuing checkpoint inhibitor treatment, hormone-replacement therapy when applicable, and in the case of moderate-severe irAEs, the addition of corticosteroid or alternative immuno-suppressive therapy.7

In many cases, appropriate corticosteroid treatment has been shown to be successful in resolving immune-mediated toxicities, while preserving the antitumor response.5,7,10 Broadly speaking:

  • Grade 1 (mild) events are usually managed through symptomatic relief while continuing checkpoint inhibitor therapy, although consideration may be given to withholding checkpoint inhibitor therapy until symptoms have improved;
  • Patients presenting with Grade 2 (moderate) irAEs can generally receive symptomatic support while low-dose corticosteroid treatment is initiated; checkpoint inhibitor treatment is withheld. Treatment with steroids usually continues until symptoms are resolved or improved to grade 1 (mild) and which time corticosteroid therapy is appropriately tapered and checkpoint inhibitor therapy is resumed;
  • Patients experiencing Grade 3 or 4 (severe or life-threatening) irAEs receive therapy with corticosteroids at a higher dose as well; however, treatment with the checkpoint inhibitor is permanently discontinued even with improvement of symptoms and corticosteroid tapering. In some situations, patients whose Grade 3-4 symptoms persist or worsen may receive treatment with a non-corticosteroid immunosuppressive medication;
  • In the event of immune-mediated endocrinopathies, patients may receive replacement therapy with the appropriate hormone;
  • When patients fail to improve or worsen, they should receive treatment according to the next higher grade level. 7,10,13-15

     

    Possible irAEs and Associated Signs and Symptoms
    Table 3. Possible irAEs and Associated Signs and Symptoms

The REMS guides provide algorithms that detail immediate management as well as follow-up treatment for patients presenting with varying grades of irAEs. While management approaches are similar between the three checkpoint inhibitors, differences do exist. Each individual guide provides specific guidance. 13-15

Conclusion

As immuno-oncologic agents continue to be developed and enter the community clinical care setting, it is clear that there will be an ongoing learning curve. Due to their different mechanisms of action, the checkpoint inhibitors elicit not only distinct clinical responses, but also unique adverse events that differ from those seen with the more familiar cytotoxic agents.

While many of the irAEs are mild-moderate in nature, severe and life-threatening irAEs do occur. Fortunately, through increasing patient and clinician awareness, prompt identification, and appropriate management, many of these adverse events can be reversed; and if identified in the early stages, may allow patients to resume checkpoint inhibitor therapy once irAEs are resolved.

Key Takeaways

  • The immunotherapy checkpoint inhibitors have a different mechanism of action from cytotoxic agents; as such, they have a different adverse event profile.
  • Educate patients and caregivers on signs and symptoms of irAEs and stress the importance of early identification and reporting.
  • Perform baseline assessments.
  • Monitor patients for signs/symptoms and lab changes that may indicate irAEs at every visit.
  • Initiate prompt and appropriate treatment and dose modification based on irAE grade.

References

  1. Amin A, White RD. High-Dose Interleukin-2: Is It Still Indicated for Melanoma and RCC in an Era of Targeted Therapies? Oncology 2013;27(7):12.
  2. Yervoy (ipilimumab) Prescribing Information.
  3. Keytruda Prescribing Information.
  4. Opdivo Product Information.
  5. Amos SM, Duong CP, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011;118(3):499-509.
  6. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer. 2012;12(4):252-264.
  7. Berman D, Korman A, Peck R, Feltquate D, Lonberg N, Canetta R. The development of immunomodulatory monoclonal antibodies as a new therapeutic modality for cancer: the Bristol-Myers Squibb experience.Pharmacol Ther. 2015;148:132-153.
  8. Andrews S, Holden R. Characteristics and management of immunerelated adverse effects associated with ipilimumab, a new immunotherapy for metastatic melanoma. Cancer Manag Res. 2012;4:299-307.
  9. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of Immunotherapy for the Practitioner. J Clin Oncol. 2015;33(18):2092-2099.
  10. Tarhini A. Immune-mediated adverse events associated with ipilimumab ctla-4 blockade therapy: the underlying mechanisms and clinical management.Scientifica (Cairo). 2013;2013:857519.
  11. Haanen JB, Thienen H, Blank CU. Toxicity patterns with immunomodulating antibodies and their combinations. Semin Oncol. 2015;42(3):423-428.
  12. ESMO. Managing the Side Effects of Novel Cancer Immunotherapeutics 2014. http://www.esmo.org/Oncology-News/Managing-the-Side-Effects-of-Novel-Cancer-Immunotherapeutics. Accessed Sept 17, 2015.
  13. Squibb B-M. Yervoy: Immune-mediated Adverse Reaction Management Guide. 2011. https://www.hcp.yervoy.com/pdf/rems-management-guide.pdf. Accessed Sept 20, 2015.
  14. Squibb B-M. Immune-Mediated Adverse Reactions Management Guide. 2015.http://www.opdivohcp.bmscustomerconnect.com/servlet/servlet.FileDownload?file=00Pi000000GL6RoEAL. Accessed Sept 20, 2015.
  15. Merck. A Guide to Monitoring Patients During Treatment with Keytruda. 2014.https://www.keytruda.com/static/pdf/adverse-reaction-management-tool.pdf. Accessed Sept 21, 2015.

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