Impact of the development of immune related adverse events in metastatic melanoma treated with PD -1 inhibitors

Abstract

Some clinical trials have described improved outcomes in patients who develop immune-related adverse events (irAEs) while receiving immune checkpoint inhibitors for advanced melanoma. It is unknown if this effect would be seen in a real-world population. This is a single-center retrospective analysis of all patients receiving singleagent PD-1 inhibitor for unresectable stage III or stage IV melanoma between 2012 and 2018. The majority of patients had cutaneous melanoma and were elderly (put in median and range). Totally 33.3% were BRAF mutated and 66.7% had PD-1 inhibitor as first-line treatment for metastatic disease. Also, 22% of patients had brain metastases at presentation. Of the 87 patients included in this analysis, 48 (55%) developed at least one irAE. Dermatologic toxicities were the most common irAE. The median time to develop any irAE was 12 weeks. Only one patient died of immune-related toxicity. Overall survival in the population of patients that had an irAE was significantly greater than those that did not have any toxicity (21.1 vs. 7.5 months; P < 0.001). The development of endocrine toxicity had the strongest correlation with survival as did patient with grade 1 (NCI V.5) toxicity. The development of multiple toxicities did not correlate with survival. In patients with multiple toxicities, the type of irAE that presented initially did not impact the outcome. These findings add to the growing body of literature suggesting an association between irAEs and immune-checkpoint inhibitor efficacy while suggesting that this benefit may depend on the type of toxicity and severity. Melanoma Res 31: 258

Patients with melanoma treated with immune checkpoint inhibitors who had non-thyroid endocrine and skin immune-related adverse events have better prognosis: A systematic review and meta-analysis

“…Of the included studies, 46 were retrospective ( 13 – 17 , 32 , 34 , 35 , 39 , 41 , 43 – 52 , 54 , 55 , 57 , 59 – 72 , 74 – 78 , 82 – 85 ), 13 were prospective ( 18 , 33 , 36 – 38 , 40 , 53 , 56 , 58 , 73 , 79 – 81 ) (including four studies that extracted data from clinical trials ( 18 , 33 , 73 , 79 )), and one included both retrospective and prospective data ( 42 ). All included studies assessed the relationship between the presence of irAEs and prognosis (12 of them examined the effect of irAE grades ( 14 , 37 , 45 , 57 , 58 , 68 , 71 , 73 , 76 , 82 , 84 , 85 )), 18 studies assessed endocrine irAEs (any, thyroiditis, or hypophysitis) ( 32 , 34 , 44 , 46 – 48 , 51 , 55 , 56 , 60 , 68 – 70 , 73 , 76 , 78 , 81 , 85 ), five assessed pulmonary irAEs ( 32 , 34 , 46 ...…”

“…Twenty studies assessed the association between the occurrence of skin irAEs and OS in patients with melanoma ( 32 , 34 , 38 , 42 , 46 – 48 , 51 , 53 , 54 , 56 , 62 – 64 , 73 , 74 , 76 , 79 , 81 , 85 ), while12 assessed the association with PFS ( 32 , 34 , 38 , 42 , 47 , 54 , 62 , 64 , 76 , 79 , 81 , 85 ). Pooled analysis showed that, among patients with melanoma treated with ICIs, those who had skin irAEs had a significant advantage in OS (pooled HR, 0.59; 95%CI, 0.41–0.85; P = 0.004; I 2 = 68%) and PFS (pooled HR, 0.43; 95%CI, 0.36–0.52; P < 0.00001; I 2 = 50%) compared with patients who did not have skin irAEs ( Figure 7 ).…”

“…Identifying reliable biomarkers of response to ICIs has been the focus of intensive research since the initiation of ICI use in the treatment of malignancies ( 87 ). Early clinical observations in the era of novel immunotherapeutics have hinted at a potential association between irAEs and patient survival, but the results remain controversial ( 23 , 32 , 51 , 57 , 71 ). Previous studies have focused on the association between the occurrence of irAEs and efficacy and survival in all patients with cancer or lung cancer ( 19 , 88 , 89 ), while there was a lack of systematic review on the association between the occurrence of irAEs and survival in patients with melanoma.…”

Association of Immune-Related Adverse Events, Hospitalization, and Therapy Resumption With Survival Among Patients With Metastatic Melanoma Receiving Single-Agent or Combination Immunotherapy

“…Retrospective data and meta-analyses for single-agent ICB across multiple tumor sites have largely observed improved objective response rates, progression-free survival, and OS among patients who develop irAEs. [7][8][9][10][11] In metastatic melanoma, the association of irAEs with outcomes has been more variable. 7,12,13 One proposed explanation may be immortal time bias, in particular in early studies.…”

Association between Immune-Related Adverse Events and Survival in 319 Stage IV Melanoma Patients Treated with PD-1-Based Immunotherapy: An Approach Based on Clinical Chemistry

“…In an adjuvant setting, and for melanoma patients, Eggermont et al were also able to demonstrate a correlation between irAEs and an improvement in recurrence-free survival (RFS) [ 8 ]. In contrast to reports based on data from clinical studies, this relationship has not been studied as intensively in real-world data [ 23 ]. This work describes the association of the occurrence of immune-related adverse events and improved survival in melanoma using real-world data.…”