New Guidelines for Treating Checkpoint Inhibitor Toxicities

Roxanne Nelson, RN, BSN

February 14, 2018

The introduction of immune checkpoint inhibitors has dramatically changed the treatment of a number of cancer types, but these drugs are quite different from those that have been used before, and clinicians are having to manage with a whole new spectrum of adverse effects.

To help with this, the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have jointly developed new guidelines for assessing and managing these side effects. The guidelines were published February 14 in the Journal of Clinical Oncology and online at NCCN.org.

"With rapidly increasing use of immune checkpoint inhibitors, it is imperative that clinicians are knowledgeable about their unique toxicity profiles," said Clifford A. Hudis, MD, FASCO, FACP, who is also the chief executive officer of ASCO, in a statement.

"Some people will brush their symptoms aside, but any unusual symptom should be reported to the doctor," said Julie Brahmer, MD, chair of the expert panel that developed the guidelines, in a statement.

"These guidelines will help all providers who care for patients treated with immune checkpoint inhibitors — not just oncologists but also emergency room and primary care doctors — assess and manage these side effects," she added.

Many Drugs, Many Indications

A growing number of immune checkpoint inhibitors have received approval by the US Food and Drug Administration for an ever increasing number of indications. The drugs include ipilimumab (Yervoy, Bristol-Myers Squibb), nivolumab (Opdivo, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck Sharp Dohme), atezolizumab (Tecentriq, Genentech), durvalumab (Imfinzi, AstraZeneca), and avelumab (Bavencio, EMD Serono).

Approved indications include melanoma, metastatic non–small cell lung cancer, head and neck squamous cancers, urothelial carcinoma, mismatch repair–deficient solid tumors, Hodgkin's lymphoma, renal cell carcinoma, urothelial cancers, and Merkel cell carcinoma.

Adverse effects with these agents can affect a wide range of organs. The most common ones affect the skin, the gastrointestinal tract, the lungs, endocrine organs (thyroid, adrenal gland, pituitary gland), and musculoskeletal, renal, nervous, hematologic, cardiovascular, and ocular systems.

The growing use of these agents, along with increasing recognition of the wide range of adverse events — which have been fatal in severe cases — highlighted the need for guidance, the authors write.

To develop the guidelines, ASCO and the NCCN convened multidisciplinary panels that included experts from a wide range of medical disciplines, along with participants from nursing and patient advocacy organizations.

The panel based the recommendations on a systematic review of literature and an informal consensus process. ASCO and the NCCN emphasize that these guidelines pertain only to immune checkpoint inhibitors, not other types of immunotherapy.

The NCCN plans to update its guidelines continuously as data evolve. It notes that it plans to include the toxicities associated with CAR T-cell therapies later this year.

Key General Recommendations

The guidelines note that these general recommendations should be followed irrespective of affected organs. It is recommended that clinicians manage toxicities as follows:

  • Patients and their families should receive timely and up-to-date education about immunotherapies, the mechanism of action, and information about related adverse effects prior to initiating treatment and throughout therapy and survivorship.

  • When new symptoms develop, there should be a high level of suspicion that they are treatment related.

  • Therapy can generally be continued with close monitoring for grade 1 toxicities, with the exception of neurologic and some hematologic toxicities.

  • Treatment should be halted for most grade 2 toxicities and held until symptoms and/or laboratory values revert to effects of grade 1 or less. Corticosteroids (initial dose of 0.5 to 1 mg/kg/d of prednisone or equivalent) may be administered.

  • The drugs should be stopped for grade 3 toxicities, and high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone IV 1-2 mg/kg/d) should be initiated. Corticosteroids should be tapered over a period of at least 4 to 6 weeks; if symptoms do not improve after 48 to 72 hours of treatment with high-dose corticosteroids, infliximab may be offered for some toxicities.

  • When symptoms and/or laboratory values revert to effects of grade 1 or less, a treatment rechallenge may be offered, although caution is advised, especially for patients who experience adverse events early in therapy. Dose adjustments are not recommended.

  • Grade 4 toxicities will generally warrant permanent discontinuation of the drug, except for endocrinopathies that have been controlled by hormone replacement.

The guidelines also provide detailed recommendations for managing the specific toxicities that have been observed in each system of the body.

These include skin reactions, such as inflammatory dermatitis and bullous dermatosis; gastrointestinal toxicities, such as colitis and hepatitis; lung toxicities, such as pneumonitis; endocrine toxicities, such as primary hypothyroidism, hyperthyroidism, primary adrenal insufficiency, hypophysitis, and diabetes; musculoskeletal toxicities, such as inflammatory arthritis, myositis, and polymyalgia-like syndrome; renal toxicities, such as nephritis; nervous system toxicities, such as myasthenia gravis, Guillain-Barré syndrome, autonomic neuropathy, peripheral neuropathy, aseptic meningitis, encephalitis, and transverse myelitis; hematologic toxicities, such as autoimmune hemolytic anemia, acquired thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, aplastic anemia, lymphopenia, immune thrombocytopenia and acquired hemophilia; cardiovascular toxicities, such as myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and vasculitis, and venous thromboembolism; and ocular toxicities, such as uveitis/iritris, episcleritis, and blepharitis.

The guidelines also emphasize that patients should be educated about immune checkpoint inhibitors. They stress the importance of patients' reporting changes in how they feel to the physician, because such changes may be early signs of an adverse reaction.

The Oncology Nursing Society has produced immunotherapy wallet cards for patients to carry. The cards detail symptoms to watch for and how to notify their healthcare provider. They may also be useful for healthcare providers (eg, emergency department staff) who care for patients with a history of immunotherapy, the authors note.

Copies of the immunotherapy wallet card and more information can be obtained by e-mailing clinical@ons.org.

The authors' relevant financial relationships are listed in the published guidelines.

J Clin Oncol. Published online February 14, 2018.

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