with nivolumab versus 88% of those having received everolimus. The most common treatment-related adverse events with nivolumab were fatigue (134 patients, 33%), nausea (57 patients, 14%), and pruritus (57 patients, 14%); among patients who received everolimus, the most common events were fatigue (134 patients, 34%), stomatitis (117 patients, 29%), and anemia (94 patients, 24%). Grade 3 or 4 treatment-related adverse events occurred in 19% and 37% of patient treated with nivolumab and everolimus, respectively; the most common grade 3 or grade 4 event was fatigue (10 patients, 2%) with nivolumab. 1 Treatment-related adverse events leading to treatment discontinuation occurred in 8% of patients treated with nivolumab and in 13% of patients treated with everolimus. No deaths from study-drug toxic effects were reported in the nivolumab group, and two deaths were reported in the everolimus group (one from septic shock and one from acute bowel ischemia). In a subsequent presentation the authors reported on the timing of onset and resolution of select AEs, addressing the unique nature of immune-mediated toxicties.2 While the median time to onset was <12wks for hepatic, skin, GI, renal irAEs, it tended to be later in immune endocrinopathies (median 16.4 weeks) and pneumonitis (median 17.4 weeks). Notably, the range of symptom onset was wide for each organ, several patients developing irAEs >100 weeks into treatment.2 Similarly, time to resolution of AE varied greatly across patients with some subject for all reported AEs requiring >1y until reported resolution. Importantly, the primary publication for Checkmate025 provided no details on the management of irAEs beyond the general rate of dose delays and treatment discontinuations. On the dose-randomized phase II study of nivolumab in metastatic RCC the rate of giving systemic corticosteroids for the management of AEs (regardless of causality) was 15-33% across three different dosing groups.3 This can be put in context with data from patients with advanced melanoma treated on clinical trials. Weber et al. reported on over 500 patients treated with single agent nivolumab across four trials.4 The authors found that the kinetics of onset and resolution of irAEs varied with distinct patterns across different organ systems, e.g. hepatic, skin and gastrointestinal toxicity emerging earlier, renal toxicity later. While many of these lingered for extended periods of time, no new-onset treatment related AEs were documented in patients 80 weeks or longer on therapy.4 Similarly, McDermott et al. recently presented long-term outcomes for RCC patients who received nivolumab on one other original phase I and phase II monotherapy studies. No new-onset irAEs across organ domains of interest (endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin) were recorded beyond 30 months from treatment start.5 Such data suggest that organ-specific immune toxifies can be delayed and in some patients persist for extended periods of time; however, they are unlikely to newly develop late in the course 40 Kidney Cancer Journal of those patients who have achieved extended benefit from therapy. In the above cited report for nivolumab-treated melanoma patients,4 24% of subjects received systemic immunomodulatory (IM) drugs to treat adverse effects. This was not associated with an apparent loss in treatment benefit, the objective response rate being 29.8% in IMtreated patients vs. 31.8% in others. In fact, adjusting for number of doses, response rate was higher in patients who experienced treatment related AEs in this dataset. These findings add to a growing body of safety data collected on studies performed in other diseases using this class of agents. Eigentler et al6 reviewed pooled data from pivotal trials, conducted not only in advanced RCC but also melanoma and non-small-cell lung cancer (NSCLC) as reported by the European Medicines Agency. The authors scrutinized incidence and kinetics of onset and resolution of immune-mediated ‘‘adverse events of specific interest” (AEOSI) for the two PD-1 inhibitors nivolumab and pembrolizumab. They found that the severity of AEOSI was generally mild to moderate (grade 1–2); the frequency of grade 3–4 adverse drug reactions was rarely >2% for any event term, the exception being grade 3 fatigue which was reported in >2% of patients in NSCLC and RCC. The onset of irAEs was highly variable across organ systems and underlying malignancies. On further analysis, the authors made recommendations for the diagnosis, monitoring and management of relevant dermatological, gastrointestinal, pulmonary, endocrine, renal and hepatic toxicities, including the use of topical and systemic corticosteroids as well as nonsteroidal immunosuppressants. Most Common Types of Immune-Related Adverse Events Dermatologic events. Dermatologic toxicity is among the most common adverse events and typically observed to have early onset; 10% of patients developed treatmentrelated rashes with nivolumab on CheckMate 025 with median onset at 8.4 weeks.2 With checkpoint blockade, the sign of an adverse event is most likely to emerge as a faintly erythematous rash. Reticular and maculopapular, it is generally observed on the trunk and extremities.6 The incidence of pruritus is similarly high (14% of patients on CheckMate 025), often presenting is an isolated symptom without rash. The initial approach for dermatologic toxic effects is supportive. Topical corticosteroid creams of medium to high potency can be used for rash.7 Cold compresses, oatmeal baths, and topical corticosteroids may be helpful in relieving symptoms of pruritus in addition to systemic antihistamines such as diphenhydramine hydrochloride and hydroxyzine hydrochloride. Oral or topical doxepin hydrochloride, a tricyclic antidepressant, has also been used with some success for pruritic symptoms as has oral aprepitant.7 Anti–CTLA-4 or anti–PD-1 therapy can be continued while managing grade 1 to 2 skin toxic effects. Severe rash (grade 3 or higher) should be treated with sys
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