Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center.

Ipilimumab is a standard treatment for metastatic melanoma, but immune-related adverse events (irAEs) are common and can be severe. We reviewed our large, contemporary experience with ipilimumab treatment outside of clinical trials to determine the frequency of use of systemic corticosteroid or anti-tumor necrosis factor α (anti-TNFα) therapy and the effect of these therapies on overall survival (OS) and time to treatment failure (TTF). We reviewed retrospectively the medical records of patients with melanoma who had received treatment between April 2011 and July 2013 with ipilimumab at the standard dose of 3 mg/kg. We collected data on patient demographics, previous and subsequent treatments, number of ipilimumab doses, irAEs and how they were treated, and overall survival. Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNFα therapy. Defining TTF as either starting a new treatment or death, estimated median TTF was 5.7 months. Twelve percent of patients experienced long-term disease control without receiving additional antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids. IrAEs are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy. Practitioners and patients should be prepared to treat irAEs and should understand that such treatment does not affect OS or TTF.

Horvat TZ ，Adel NG ，Dang TO ，Momtaz P ，Postow MA ，Callahan MK ，Carvajal RD ，Dickson MA ，D'Angelo SP ，Woo KM ，Panageas KS ，Wolchok JD ，Chapman PB ... -  《-》

Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: Analysis of 60 Japanese patients.

Due to resistance and immune-related adverse events (irAE) some melanoma patients require ipilimumab after nivolumab therapy. However, little is known about the result of this switching. Investigate the outcome of ipilimumab switching in Japanese patients. We retrospectively collected 60 patients who were treated with ipilimumab after nivolumab from 9 institutes in Japan. Information of the primary tumor, treatment, response, irAE), and survival was collected. In our cohort, acral lentiginous and mucosal melanoma accounted for 53% of the cases. The most common reason for initiating ipilimumab was disease progression (93%). Median interval from the last nivolumab administration to first ipilimumab administration was 29days. Only 38% of patients completed 4 injections of ipilimumab. The best overall response was 3.6%. IrAE occurred in 78% of patients and 70% of those were of grade 3/4 (G3/4) and 31% of patients experienced 2 or more irAEs. An within interval of 28days or less between the last nivolumab administration and ipilimumab administration was correlated with the development of G3/4 pyrexia and 3 or more irAEs, but irAE occurrence did not affect survival. Multivariate analysis showed that endocrine irAE (relative risk=0.22, P=0.015) and skin irAE (relative risk=2.78, P=0.048) were significant factors associated with survival. In our study, the response ratio to ipilimumab after nivolumab was unsatisfactory and associated with a high frequency of severe irAEs. As there are few second-line treatment options for patients with BRAF wild-type advanced melanoma after nivolumab failure, patients should be closely monitored if ipilimumab is initiated.

Fujisawa Y ，Yoshino K ，Otsuka A ，Funakoshi T ，Uchi H ，Fujimura T ，Matsushita S ，Hata H ，Okuhira H ，Tanaka R ，Nagai K ，Ishida Y ，Nakamura Y ，Furudate S ，Yamamura K ，Imafuku K ，Yamamoto Y ... -  《-》

Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity.

Programmed cell death protein 1 (PD-1) inhibitors are a common treatment strategy for metastatic melanoma and other tumour entities. Clinical trials usually exclude patients with preexisting autoimmune diseases, thus experience with PD-1 inhibitor (PD-1i) in this patient population is limited. Metastatic melanoma patients with preexisting autoimmune disorders or previous ipilimumab-triggered immune-related adverse events (irAE) undergoing treatment with PD-1i from seven German skin cancer centres were evaluated retrospectively with regard to flare of the preexisting autoimmunity and development of new, not preexisting irAE as well as response to PD-1i therapy. In total, 41 patients had either preexisting autoimmunity (n=19, group A, including two patients with additional ipilimumab-triggered autoimmune colitis) or ipilimumab-triggered irAE (n=22, group B). At PD-1i therapy initiation, six patients in group A and two patients in group B required immunosuppressive therapy. In group A, a flare of preexisting autoimmune disorders was seen in 42% of patients, new irAE in 16%. In group B, 4.5% of patients showed a flare of ipilimumab-triggered irAE and 23% new irAE. All flares of preexisting autoimmune disorders or irAE were managed by immunosuppressive and/or symptomatic therapy and did not require termination of PD-1i therapy. tumour responses (32% in group A and 45% in group B) were unrelated to occurrence of autoimmunity. While preexisting autoimmunity commonly showed a flare during PD-1i therapy, a flare of ipilimumab-triggered irAE was rare. Response rates were above 30% and unrelated to irAE. PD-1i therapy can be considered in patients with autoimmune disorders depending on severity and activity of autoimmunity.

Gutzmer R ，Koop A ，Meier F ，Hassel JC ，Terheyden P ，Zimmer L ，Heinzerling L ，Ugurel S ，Pföhler C ，Gesierich A ，Livingstone E ，Satzger I ，Kähler KC ，German Dermatooncology Group (DeCOG) ... -  《-》

Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis.

The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood. E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034). Occurrence of grades 1-2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1-2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1-2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1-2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1-2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3-4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3-4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1-2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found. Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3-4 irAEs.

Tarhini AA ，Kang N ，Lee SJ ，Hodi FS ，Cohen GI ，Hamid O ，Hutchins LF ，Sosman JA ，Kluger HM ，Eroglu Z ，Koon HB ，Lawrence DP ，Kendra KL ，Minor DR ，Lee CB ，Albertini MR ，Flaherty LE ，Petrella TM ，Streicher H ，Sondak VK ，Kirkwood JM ... -  《Journal for ImmunoTherapy of Cancer》

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.

Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients. Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified. One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths. In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.

Menzies AM ，Johnson DB ，Ramanujam S ，Atkinson VG ，Wong ANM ，Park JJ ，McQuade JL ，Shoushtari AN ，Tsai KK ，Eroglu Z ，Klein O ，Hassel JC ，Sosman JA ，Guminski A ，Sullivan RJ ，Ribas A ，Carlino MS ，Davies MA ，Sandhu SK ，Long GV ... -  《-》