Monoclonal antibodies targeting the immune checkpoint proteins cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown significant efficacy in the treatment of multiple tumour types. Ipilimumab (anti-CTLA-4), pembrolizumab and nivolumab (anti-PD-1), as well as atezolizumab and durvalumab (anti-PD-L1), are lead examples of these agents. The trade-off for clinical activity of immune checkpoint inhibitors (ICPIs) is the potential for immune-related adverse events (irAEs). These are well-recognized complications of ICPIs and are also a significant cause of discontinuation of therapy and patient morbidity. The onset of irAEs is largely unpredictable in timing and may affect any organ in the body; there is currently a lack of clinical phenotype or biomarkers that reliably predict those who are destined to develop irAEs. Examples of irAEs range from mild reactions such as pruritus and skin rash, generally manageable on an outpatient basis, to more severe and clinically significant toxicities such as colitis, hepatitis and pneumonitis, which may lead to prolonged hospitalization. Furthermore, potentially fatal fulminant myocarditis and neurotoxicities may occur. All irAEs should be graded according to the Common Terminology Criteria for Adverse Events. Most toxicities are reversible with prompt institution of corticosteroids. Patients who develop immune-related endocrinopathies such as hypothyroidism, hypopituitarism and diabetes, however, are likely to require hormone replacement therapies indefinitely.
Rates of irAEs: agent, dosage, regimen and pre-existing autoimmunity
The expected rates of irAEs may be related to agent and dosage, and whether the ICPI is given as a combination regimen.
Ipilimumab was the first ICPI with proven efficacy for treatment of advanced cancer in the context of melanoma1,2 and subsequently also in the adjuvant setting.3 Ipilimumab dosed at 3 mg/kg for four doses every 3 weeks for the treatment of advanced melanoma has a drug-related toxicity rate of ~80%;1 grades 3–4 irAEs were seen in ~30% of patients.2 In the adjuvant setting, where ipilimumab was dosed at 10 mg/kg for four doses every 3 weeks, then every 3 months for up to 3 years, irAE rates of all grades were ~90%, and ~40% were grades 3–4.3,4 A previous phase III study comparing ipilimumab dosed at 10 mg/kg vs 3 mg/kg for four doses every 3 weeks,4 as well as a dose-ranging phase II study, supported the finding of increasing toxicities with escalating doses.5 It is worthwhile noting that ipilimumab has been superseded both as standard initial therapy for advanced disease and in the adjuvant setting for the treatment of melanoma.
Treatment with single-agent anti-PD-1/anti-PD-L1 is generally well tolerated, and this is consistent across tumour types and approved treatment settings. Anti-PD-1 agents have been evaluated in phase III studies for advanced melanoma,6 renal cell carcinoma,7 non-small-cell lung carcinoma (NSCLC)8 and recurrent squamous cell carcinoma of the head and neck9 in the advanced setting. Rates of grades ...