- Immune checkpoint inhibitors (ICPi) have revolutionized the treatment of many different types of cancers.
- The immune checkpoint proteins — cytotoxic T lymphocyte-associated 4 (CTLA-4), and programmed cell death protein 1 (PD-1) — are receptors expressed on the surface of cytotoxic T-cells. They control immune response pathways that can be coopted to help cancer cells evade cytotoxic T-cell-mediated death. ICPis disrupt this signaling.
- Despite the often durable clinical benefits of immune checkpoint blockade therapy, its use is associated with a spectrum of side effects that is quite different from other systemic therapies such as cytotoxic chemotherapy.
FDA-approved ICPi Agents (as of January 2018)
|PD-L1||urothelial cancers, non-small cell lung cancer (NSCLC)|
|PD-L1||Merkel cell carcinoma, urothelial carcinoma|
|CTLA-4||advanced melanoma (± nivolumab)|
|PD-1||melanoma, metastatic NSCLC, head and neck squamous cancers, urothelial carcinoma, gastric adenocarcinoma and mismatch repair deficient solid tumors, classical Hodgkin lymphoma, hepatocellular carcinoma, renal cell carcinoma|
|PD-1||melanoma, metastatic NSCLC, head and neck squamous cancers, urothelial carcinoma, gastric adenocarcinoma and mismatch repair deficient solid tumors, classical Hodgkin lymphoma|
Figure 1. Distribution of Grade I–II and Grade III–V irAEs
Fig. 1. Adapted from European Journal of Cancer, Vol 54, J.M. Michot et al, Immune-Related Adverse Events With Immune Checkpoint Blockade: A Comprehensive Review, 139-149, Copyright 2016, with permission from Elsevier. Distribution of (A) grade I–II and (B) grade III–V irAEs for all tumour types in the main clinical trials with anti-CTLA4, anti-PD-1 or anti-PD-L1 antibodies as single therapies. The values quoted are the median (range) irAE rates for the set of clinical trials as a whole.
The following are general recommendations that should be followed irrespective of affected organs. For organ-specific management, please see Tables 1–10.
It is recommended that clinicians manage toxicities as follows:
- Patient and family caregivers should receive timely and up-to-date education about immunotherapies, their mechanism of action, and the clinical profile of possible irAEs prior to initiating therapy and throughout treatment and survivorship.
- There should be a high level of suspicion that new symptoms are treatment related.
- In general, ICPi therapy should be continued with close monitoring for Grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities.
- Hold ICPis for most grade 2 toxicities and consider resuming when symptoms and/or laboratory values revert to Grade 1 or less. Corticosteroids (initial dose of 0.5 to 1 mg/kg/d of prednisone or equivalent) may be administered.
- Hold ICPis for Grade 3 toxicities and initiate high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone IV 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. If symptoms do not improve with 48 to 72 hours of high-dose corticosteroid, infliximab may be offered for some toxicities.
- When symptoms and/or laboratory values revert to Grade 1 or less, rechallenging with ICPis may be offered; however, caution is advised, especially in those patients with early-onset irAEs. Dose adjustments are not recommended.
- In general, Grade 4 toxicities warrant permanent discontinuation of ICPis, with the exception of endocrinopathies that have been controlled by hormone replacement.
Commonly Conducted Testing at Baseline Prior to ICPi Therapya
Physical examination including performance score, weight, body mass index (BMI), heart rate, and blood pressure
Comprehensive history including autoimmune, organ-specific disease, endocrinopathy, neuropathy, and infectious disease
Questioning of general health including appetite, bowel habits, asthenia. Preexisting symptoms involving bowel movements, dyspnea, cough, rash, headaches, arthralgia should be noted.
Complete blood count (CBC) + differential test
Complete metabolic panel that may include serum electrolytes (Na, K, Ca, CO2), liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALKP], γ-glutamyl transferase [GGT]), creatinine, creatine kinase [CK], total bilirubin
Lactate dehydrogenase (LDH) and aldolase
Thyroid-stimulating hormone (TSH), free thyroxine (T4)
Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels in males or estrogen in premenopausal females with fatigue, loss of libido, and mood changes
Surveillance for latent tuberculosis
Virology including HIV, hepatitis C virus (HCV) and hepatitis B virus (HBV), Epstein-Barr virus (EBV), cytomegalovirus (CMV)
Spirometry/ diffusing capacity of lung for carbon monoxide (DLCO)
Computed tomography (CT)
a Other testing may also be necessary based on patient’s history and preexisting comorbidities and/or risk factors.