Immunotherapy and immune-related adverse events

The rise of the checkpoint blockade has been celebrated as the breakthrough of the year 2011. There is a wide diversity of checkpoint-inhibiting antibodies: anti-CTLA-4 (cytotoxic T‑lymphocyte-associated Protein 4; Yervoy® ipilimumab [1]), anti-PD‑1 (programmed cell death Protein 1; Opdivo® nivolumab [2, 3]; Keytruda® pembrolizumab [4]) or anti-PD-L1 directed against the ligand of PD‑1 (programmed death ligand 1; Bavencio® avelumab [5], Tecentriq® atezolizumab [6], Imfinzi® durvalumab [7]), all of which received approval from the US Food and Drug Administration (FDA) and some from the European Medicines Agency (EMA) for treatment of diverse entities of malignancies (metastatic melanoma, metastatic Merkel cell carcinoma, squamous and nonsquamous lung cancer, bladder cancer, metastatic renal cell cancer, therapy-resistant Hodgkin’s lymphoma, head and neck cancer, hepatic cell cancer, mismatch repair-deficient/microsatellite instability-high solid tumors). While these have to be mentioned, the brevity of this overview precludes their discussion.

Treatment of metastatic melanoma and both entities of lung cancer (squamous and nonsquamous cell carcinoma) mainly contributed to the success of ICIs as part of current treatment protocols. While in many cases sustained antitumor response directly correlates with clinical benefit, it may be associated with a wide spectrum of adverse events (presented at the American Association for Cancer Research 2017 Annual Meeting in Washington and commented by Julie Brahmer: Abstract No.: CT077, on 3 April 2017; Checkmate 209-003 ph1b study: 5a OS for the overall study population: 16%, 95% CI 10–23. Survival was seen across PD-L1 expression levels and tumor histologies, but with the bias of not being randomized, blinded or controlled). The reported AEs mainly differ from all known side-effects generated by cytotoxic therapies (chemotherapy, radiotherapy) or antibodies or combinations of them. A wide range of organ systems can be affected (skin, gastrointestinal tract, lungs, endocrine, nervous: peripheral as well as central, ocular, cardiovascular system). The occurring inflammatory reactions strongly resemble autoimmune disorders. While severity is generally mild, even life-threatening complications have been detected. There are some differences between anti-CTLA-4 and anti-PD1/-PDL1 antibodies, especially in grading and duration of occurrence of ir-AEs [8, 9]. There is no direct correlation to drug administration, with infusion related reactions (IRR) documented in very rare cases, namely fewer than 1% of patients. ir-AEs occur even after treatment has been suspended for weeks or even months and this has to be kept in mind when managing patients receiving IO (immuno-oncology) treatment [8].

Recognition is the first step to successful treatment

Many very interesting reviews provide extensive information and elaborate this topic in a concise manner [10,11,12].

Successful management of ir-AEs irrespective of the affected organ systems demands that the patient, family caregivers and the patient’s GP (general practitioner) be kept abreast of the latest IO developments. All of these persons need to be informed about the IO concept and the clinical profile of possible AEs before the concept is initiated, and their information level should be maintained throughout the treatment period. The aim is to generate a “sound” but high level of suspicion for the fact that new symptoms occurring during and even after treatment start may be primarily related to ICI treatment. Grading of toxicities follows CTCAE version 5.0 (National Cancer Institute: Common Terminology Criteria for Adverse Events [CTCAE] 5.0.).

Recommended management of ir-AEs

An increasing number of treatment approaches using ICIs require early recognition of symptoms in connection with changes in laboratory results. Every new symptom must be viewed in connection with the treatment and regarded as an ir-AE until proven otherwise. Diagnostic tools (laboratory results, body scans) are helpful in excluding ir-AEs. Identifying patients at higher risk for ir-AEs demands prompt and aggressive reaction. Recent data suggest that patients suffering from autoimmune diseases are eligible for checkpoint inhibition although they are currently excluded from all trials. There are ways to treat them safely while remaining more alert for unexpected adverse events, although they are still seriously underrepresented [13] and could form a group of high-risk patients. Indeed, such patients do not show a higher incidence of ir-AEs despite having active disease. Hence, treatment-specific risk factors are defined by IO/IO combinations and by the checkpoint inhibitor itself due to differences in incidence and severity of ir-AEs between anti-CTLA-4 [1], anti-PD1 [2,3,4], and anti-PDL1 antibodies [6, 7].

A heightened awareness for early recognition and treatment helps to mitigate the severity of ir-AEs.

Organ-specific recommendations for ir-AEs

In most cases (with some exceptions) ir-AEs grade 2 can be managed by promptly interrupting treatment and providing supportive care. Questionnaires or standardized assessments assist in early recognition. New symptoms or changes in a patient’s health indicate early onset of ir-AEs. Giving patients wallet cards containing detailed information about symptoms and the patient’s immunotherapy history (documented ir-AEs with grading) ensures that all care providers (GPs but also emergency department staff) have additional information to handle the situation and avoid morbidity and ultimately even mortality.

In the case of grade 1 toxicities, watchful continuation of the IO treatment is generally appropriate. However, without complete resolution of symptoms or deterioration to grade 2 or worse immunosuppressive treatment must be started at 0.5 to 1 mg/kg/day prednisone or equivalent corticosteroid combined with tapered discontinuation of treatment. Such tapering of systemic corticosteroids over 4–6 weeks is performed contingent on resolution of the individual’s immune-related reaction. Grade 3 or 4 ir-AEs involve some substantial differences concerning the affected organ system. These differences are discussed in the subsequent part of this article and summarized in Table 1 (pointing out the management of severe adverse events = CTCAE ≥ grade 3 in defined organ toxicities).

Table 1 Management of ir-AEs in patients treated with ICIs/overview of the most relevant (S)AEs (severe adverse events) focused on severe adverse events (CTCAE 5.0 ≥ 3). (Adapted from [10]; based on expert consensus based recommendations with benefits outweighing harms—strength of recommendations is moderate)
Full size table

Skin toxicities

In the case of failure of high-dose corticosteroid treatment (up to 2 mg/kg/day) an additional immunosuppressive therapy regimen is available: rituximab 375 mg/m2 is recommended instead of high-dose corticosteroids for bullous dermatoses and cyclosporine with or without IVIG (intravenous immunoglobulin) for severe or steroid-resistant cases of SCARs (severe cutaneous adverse reactions) including SJS (Stevens–Johnson syndrome), TEN (toxic epidermal necrolysis), acute generalized exanthematous pustulosis, and DRESS (drug reaction with eosinophilia and systemic syndrome)/DIHS (drug-induced hypersensitivity syndrome).

Enterocolitis

Furthermore, grade 3 or 4 enterocolitis is mainly documented in IO/IO combination approaches (anti-CTLA-4 plus anti-PD-1 antibodies) illustrated in checkmate 063 in advanced melanoma in up to 13% of patients [14]. However, even the sole administration of ICIs results in severe colitis in fewer than <1% of patients, as shown in checkmate 037 and checkmate 066 (both melanoma trials using nivolumab) [15] and checkmate 017 in SQ-NSCLC (nivolumab) [3] and mentioned in treatment with anti-CTLA-4 antibody. This correlates with long-lasting responses persisting even after discontinuation of IO therapy [16]. In the case of grade 3 or 4 ir-AEs early administration of infliximab 5–10 mg/kg must be weighed if there is no response. Therefore, screening laboratory work (like HIV, hepatitis A & B, blood quantiferon for tuberculosis) must be routinely done in patients at high risk in order to be prepared to start infliximab, if and when necessary. Administration of vedolizumab (anti-integrin antibody) is an option in patients who are refractory to infliximab and/or contraindicated for TNF-alpha blockade. Nonsteroidal anti-inflammatory drugs (NSAIDs) are reported to be associated with an increase in ICI-induced enterocolitis [17].

Hepatitis

Hepatitis (grade 3: AST/ALT 5–20 × ULN and/or total bilirubin 3‑10 × ULN) needs a second immunosuppressive agent like mycophenolate mofetil 1 g bid, which should be started if no improvement is assessed after 3 days.

Pneumonitis

Worsening to grade 3 ir-AE always demands permanent discontinuation of ICI, escalated prednisone 1–2 mg/kg/day IV and, if no improvement is observed, the addition of infliximab, MMF or IVIG over 5 days or cyclophosphamide. In life-threatening grade 4 pneumonitis urgent intervention is needed with empirical antibiotics and bronchoscopy with BAL ± transbronchial biopsy if there are any doubts concerning the diagnosis. Less severe pneumonitis (grades 1–2) can be treated with oral prednisone 1–2 mg/kg/day whenever the patient is clinically stable and eligible for regular outpatient visits.

Endocrinopathies

In many cases, endocrine dysfunction (hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis) can be adequately treated on a symptomatic basis except in patients with diabetes, where such treatment could trigger a life-threatening situation as T1DM (type 1 diabetes mellitus) with ketoacidosis demands a strict work-up and insulin substitution.

Cranial MRI (with or without contrast) is indicated for complaints associated with vision changes, severe headaches and multiple endocrine abnormalities (including alterations in diverse electrolytes) in order to exclude hypophysitis [4].

Nervous system toxicities

Neurologic disorders like myasthenia gravis, Guillain–Barré syndrome, peripheral neuropathy, autonomic neuropathy, aseptic meningitis, encephalitis and transverse myelitis are treated with 1–2 mg/kg/day prednisone (grade 3) and, if there is no steroid response, IVIGs or plasmaphereses are ultimately alternative options.

Myocarditis

Cardiovascular complications (myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and vasculitis) require primary administration of corticosteroids. Furthermore, if grading deteriorates (grade 3 or 4) and/or there is no response to corticosteroid, treatment must be adapted by adding mycophenolate mofetil, infliximab or ATG (antithymocyte globulin).

Future aspects and remarks

In the context of ir-AEs, which vary in grading and duration of occurrence, manifestation always correlates with progression-free survival (documented in ongoing and already completed IO studies). Taking into account the fact that responders are primarily long responders, oncologists should maintain a sound awareness for the possibility of evolving immune-related adverse events of diverse grading [10] in order to be able to react promptly and correctly to keep their patients on ICI therapy as long as possible. Therefore, as so often in life, good timing can make all the difference.