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Adverse events and high risk patient populations
The immune related adverse events (irAEs) of immunotherapies are important due to their unique
presentation and management compared to cytotoxic therapies. Due to the mechanism of “unleashing”
the immune system via up-regulation of T-cell activity, most toxicities are immune mediated and treated with
steroids and immune modulators. The unique mechanism of action of these drugs also raises concerns about
their use in certain patient populations as well, who may be at increased risk for adverse events. In general
toxicity rates are lower with immunotherapy in RM HNSCC; in most of the published trials, grade 3-4 adverse
events range from 9%-18% [12-15,17] by comparison, the standard therapy arm in CHECKMATE 141 had a grade
3-4 reaction rate of 35%, more consistent with what is seen in clinical practice with traditional therapies.

The most common adverse events are usually mild and include fatigue, nausea, rash, and decreased appetite.
Inflammatory processes such as colitis and pneumonitis are amongst the more common serious reactions;
rarely, hepatitis, cardiomyopathy, autoimmune cytopenias, and nephritis have been reported. Endocrinopathies
are also a recognized adverse event from these therapies, with hypothyroid the most common, necessitating
routine monitoring. Hyponatremia, hypophysitis, hyperglycemia, and even new development of type 1 diabetes
have all been reported with varying severities with the various checkpoint inhibitors.

Management of these reactions varies according to symptom and severity. Both the American Society for
Clinical Oncology (ASCO) and the Society for Immunotherapy of Cancer (SITC) have created consensus
practice guidelines to guide treatment, and have similar recommendations [28,29] . Grade 1 reactions can often
be managed symptomatically with supportive care; for grade 2, therapy should be held and prednisone
or equivalent started at 0.5-1 mg/kg, with either dose escalation or rapid taper depending on the patient’s
response. Therapy can be resumed when the reaction is ≤ grade 1 and the patient is off steroids. Grade 3
and 4 reactions necessitate stopping therapy and starting prednisone or equivalent at 1-2 mg/kg; once the
patient responds, a slow taper can be done over 4-6 weeks, with appropriate GI and infectious prophylaxis
depending on duration of steroid treatment. Generally, therapy can be resumed after resolution of symptoms
to ≤ grade 1, except for grade 4 reactions where immunotherapy should be permanently discontinued. In
patients with severe colitis that does not respond to steroids alone, the addition of infliximab, an anti-TNFa
antibody, has improved symptoms and can be weaned off steroids faster .
[30]
Endocrinopathies require management related to the specific derangement; holding immunotherapy is not
recommended unless the reaction is grade 3 or greater. The most common endocrinopathy that patients
develop is hypothyroidism necessitating replacement therapy, though hyperthyroidism and thyroiditis
can occur. If hypophysitis develops, patients should be screened for all possible complications including
hypogonadism, hypothyroidism, and hypoadrenergic complications. In hyperglycemia, insulin therapy is
generally preferred as these patients can develop type I diabetes and diabetic ketoacidosis; if these have been
ruled out, oral hyperglycemic therapy can be considered. Referral to endocrinology for co-management
is important in these patients to minimize long term impacts of these toxicities, and in some situations
patients can be optimized and allowed to continue on immunotherapy if they are responding well, even if
the reaction was initially grade 4.

Certain patient populations appear to be at increased risk for adverse events with the use of checkpoint
inhibitors. Others may require further study of the impact these therapies could have. Immunotherapy
adverse reactions mimic autoimmune phenomena, raising the question of how patients with pre-existing
autoimmune diseases may respond. There is retrospective data examining patients with these conditions who
go on to receive immunotherapy, especially with ipilumumab and melanoma. In these studies, exacerbations
of autoimmune diseases occurred in 38%-75% of patients; most were managed with corticosteroids or
immunosuppressive therapy and very few fatalities occurred [31-33] . Patients on immunosuppressive therapy
prior to treatment appeared to have lower rate of flare/adverse events , as did patients with neurologic or
[33]
gastrointestinal diseases as compared to arthritic or skin related autoimmune diseases . Similarly, post organ-
[21]