**5. Association of immunotherapy toxicities with efficacy in patients treated with immune checkpoint inhibitors**

After a comparison between patients with and without irAEs, it has been noticed that irAEs are associated with either improved efficacy of immunotherapy in terms of favorable response rates and prolonged survival or similar efficacy [27–29]. The interpretation of this finding is that the immune system is sufficiently activated to target patient's cancer and further cause irAEs [30].

In a retrospective analysis that assessed nivolumab efficacy in melanoma patients, treatment-related adverse events of any grade were associated with higher tumor objective response rate (ORR), but no progression-free survival benefit [31]. In patients receiving anti PD-1 or anti PD-L-1 medications an analysis was done on seven trials including 1747 patients on the association between adverse events and outcome, an increase in overall survival was seen in patients with reported adverse events compared to those with no related immune mediated adverse events [27]. It was also concluded in this trial that the relationship between outcome and reported adverse events did not seem to be due to the increased duration of exposure in responding patients [27]. Nevertheless, in a retrospective multicenter study, cumulative time-adjusted risk of disease progression and cumulative time-adjusted risk of death according to both the early-irAEs (≤12 months) and late-irAEs (>12 months) occurrence revealed no statistically significant differences [29].

While in case of high grade rare irAEs; grade 3 or more rare irAEs were associated with inferior overall survival and no impact on PFS [32].

From our point of view, more studies should be done to have a solid conclusion regarding the correlation between immunotherapy toxicities and their favorable impact on patients.

In this chapter we will discuss some of the rare or very rare irAEs including cutaneous irAEs, immune mediated Hypophysitis, hematological irAEs, ophthalmic irAEs, checkpoint inhibitor pneumonitis (CIP), neurologic irAEs, infectious irAEs and cardiac irAEs.

### **6. Cutaneous immune-related adverse events**

Cutaneous irAEs might affect more than half of patients receiving ICI [12]. They are considered the most common toxicity in patients receiving immunotherapy, and out of all irAEs, cutaneous toxicities usually manifest first [33, 34]. The most widely reported dermatological toxicities are inflammatory skin reaction, rash, pruritus, and vitiligo. Rates of cutaneous irAEs were mostly similar in patients receiving anti-PD-1 antibodies and those receiving anti- CTLA-4 antibodies [33]. Severe irAEs were reported more frequently with combination therapy of anti-PD-1 plus anti-CTLA-4 than with monotherapy with either class of agents [35].

The spectrum of irAEs can be categorized into auto-inflammatory and autoimmune responses. Auto-inflammatory side effects are usually nonspecific upregulations of the innate immune system. However, most of the cutaneous irAEs are autoimmune responses. Thus, they represent a more specific activation of adaptive immunity [33]. Cutaneous, autoimmune diseases occur more frequently with anti-PD-1/programmed cell death ligand 1 (PD-L1) than with anti-CTLA-4 therapy [32].

A pooled analysis of mucocutaneous irAEs revealed rare toxicities including urticaria, photosensitivity reactions, xerosis, stomatitis, changes in hair color, alopecia areata and hyperhidrosis [33]. Other reported cutaneous presentations included: ICI-induced dermatomyositis, drug response with eosinophilia and granulomatous, lichenoid, panniculitis-like and lupus-like reactions [36, 37]. For patients with psoriasis, episodes of exacerbation have been reported in patients receiving pembrolizumab, nivolumab or durvalumab [38]. In a single centre experience rare dermatological irAEs were reported as single cases of pemphigoid and bullous dermatitis respectively [32]. Other reported cutaneous irAEs that occurred rarely were vasculitis, neutrophilic dermatosis, erythema nodosum [39–41]. Keratoacanthoma specifically pembrolizumab induced keratoacanthoma type squamous cell carcinoma was reported with a description of eruptive or reactive morphologies [42]. Severe cutaneous irAEs are considered rare. They include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) [43–46].

### **7. Treatment of cutaneous immune-related adverse events**

The treatment of cutaneous irAEs follows the standard treatment of irAEs. Treatment of mild to moderate pruritis or maculopapular rash is topical emollient, oral antihistamine for pruritus, and topical steroids to affected areas. For moderate cutaneous toxicities, if unresponsive to topical steroids within 1 week, prednisone

*The Flip of the Coin of Personalized Cancer Immunotherapy: A Focused Review on Rare… DOI: http://dx.doi.org/10.5772/intechopen.107833*

0.5 mg/kg/day should be considered [38]. Treatment of severe cutaneous irAEs include the administration of topical and systemic steroids and dermatology consultation. For patients with severe pruritis, gabapentinoids and phototherapy can be considered, intravenous immunoglobulin (IVIG) can be given to severe cases of bullous dermatitis, TEN and SJS [5]. Conservative treatment with cryotherapy, intralesional steroids, electrodessication, curettage, and excision were done for patients having keratoacanthoma [42].

Grade 1 and 2 cutaneous irAEs do not require holding the ICI. However, Immunotherapy should be held in case of severe cutaneous toxicities. In case of severe or life-threatening bullous disease, SJS or TEN. ICI should be permanently discontinued [5]. ICI can be re-challenged if the patient's symptoms have resolved to ≤ grade 1. However, permanent discontinuation of immunotherapy should be warranted in the setting of severe or life-threatening bullous disease (grade 3–4), including all cases of SJS and TEN [5].

### **8. Immune mediated hypophysitis**

It is not uncommon for patients receiving immunotherapy to suffer from endocrinopathies, the most common is hypothyroidism [4]. Central adrenal insufficiency and autoimmune diabetes mellitus are extremely rare adverse events related to ICI. Central adrenal insufficiency can be life threatening when it is severe as it is associated with severe electrolyte disturbance, dehydration, and hypoglycemia [7, 32, 34, 47, 48]. Another well-known endocrine irAE is hypophysitis. Hypophysitis is the inflammation of the pituitary gland (the anterior lobe of the hypophysis) [49].

Hypophysitis was known to be a rare condition, however, with ICI therapy it has become more common [50]. The incidence of hypophysitis was found to be more in patients receiving anti-CLTA-4 therapy as compared to patients receiving anti-PD-1 therapy [51]. It has been reported that hypophysitis occurs in up to 10% of patients receiving anti-CTLA-4 therapy [50, 51]. This might be because pituitary cells can express CTLA-4, thus, anti-CTLA-4 therapy can cause direct damage to the pituitary gland [52, 53]. Furthermore, the incidence of hypophysitis increases with combination ICI therapy compared to ICI monotherapy [50, 51]. Beside the type of ICI therapy, male gender is another risk factor for hypophysitis mainly with anti-CTLA-4 [54]. The onset of hypophysitis is typically 2–3 months after initiation of ICI therapy, however, it may occur even later, and it has been reported 19 months after initiation of therapy [55].

Hypophysitis is generally manifested with vague symptoms. These symptoms include mild fatigue, arthralgias, and behavioral changes. Severe headache and visual changes may also occur. Because the symptoms are non-specific, hypophysitis might be under-diagnosed [5, 20].

Since enlargement of the pituitary gland is rare, the diagnosis of hypophysitis is recommended to be based on clinical presentation and hormonal evaluation rather than imaging [56]. The main consequence of ICI Hypophysitis is deficiency in one or more pituitary hormones. The most reported deficiencies are central adrenal insufficiency, central hypothyroidism, and hypogonadotropic hypogonadism. Around 80% of patients with ICI-induced hypophysitis present with one or more of these deficiencies [52, 53, 55].

Hypophysitis grading depends on the severity of symptoms and can be divided into asymptomatic or mild, moderate but hemodynamically stable, and severe mass effect or severe hypoadrenalism. Hypophysitis is managed according to the symptoms and hormonal deficiency identified upon presentation. Asymptomatic and mild vague symptoms with no headache does not indicate an interruption of ICI therapy. In such patients, ICI therapy is continued with appropriate hormonal replacement therapy (HRT). On the other hand, patients with mild symptoms (no visual disturbance and no electrolyte imbalance) but hemodynamically stable are recommended to withhold ICI therapy. In addition, oral prednisolone might be initiated. Finally, for severe mass effect symptoms or severe hypoadrenalism, holding ICI therapy and starting IV prednisolone are recommended. In most cases, ICI therapy can be continued. However, most of the patients will require long-term HRT [5, 20, 57].

### **9. Hematological immune-related adverse events**

Hematological irAEs are considered rare in patients receiving ICIs, however, a variety of hematological related toxicities have been reported [58]. These include antibody-mediated hemolytic anemia, thrombotic thrombocytopenic purpura, acquired hemophilia A, autoimmune neutropenia, pancytopenia and autoimmune thrombocytopenia [59–64]. Interestingly, cross-reactions that provoke autoimmune thrombocytopenia after sequential treatment with nivolumab and ipilimumab have been described, this might indicate that the same or similar irAEs might re-emerge on subsequent treatment with a different class of agents [64].

A worth mentioning extremely rare adverse effect is hemophagocytic lymphohistiocytosis (HLH) as it is life threating with a high mortality rate and considered to be a serious complication [65]. Therefore, a patient presenting with severe inflammatory syndrome with associated fever, cytopenias and splenomegaly should prompt a full clinical work- up, including analysis of bone marrow aspirates and/or biopsy samples for the presence of hemophagocytic signs [65].

### **10. Ophthalmic immune-related adverse events**

Ophthalmic toxicity induced by ICI occur in less than 1% of patients treated with ICI therapy [66]. Ocular irAEs can be divided into ocular inflammation, orbital inflammation, and retinal and choroidal disease [67]. The most common ocular irAEs are dry eyes and uveitis. Dry eye syndrome could be severe enough to cause corneal perforation. Uveitis is a type of ocular inflammation and might be anterior, posterior, or panuveitis. Symptoms of uveitis include eye redness, pain, floaters, photophobia, and blurred vision [68]. In patient treated with ICI therapy, dry eye syndrome occurs at a rate of 1–24%. While the incidence of uveitis caused by ICI therapy is reported to range from less than 1% up to 6% [66, 69].

The risk factors of ocular toxicity induced by ICI agents include the type of ICI and the type of cancer [66]. Clinical cases reported that patients on anti-CTLA-4 agents showed higher incidence and severity of ophthalmic toxicity as compared to patients on PD-1/PDL1 inhibitors [67, 70]. Furthermore, ocular toxicity was found to occur more often in melanoma than other solid cancers. This can be explained by the fact of the presence of cross-reactivity between normal choroidal melanocytes and malignant melanoma [70].

Ocular toxicity should be properly recognized and accurately managed because untreated ocular toxicities may lead to vision loss [71, 72]. The treatment of ocular

toxicity depends on the severity of the side effect. Anterior uveitis is treated using topical corticosteroids. While more severe side effects such as ocular inflammation and orbital inflammation are indications for systemic corticosteroids. Artificial tears and other over-the-counter medication can be as symptomatic treatment when it is clinically indicated [5, 68].
