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》

Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609.

Tarhini AA ，Lee SJ ，Hodi FS ，Rao UNM ，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 ... -  《-》

Corticosteroids and other immunosuppressants for immune-related adverse events and checkpoint inhibitor effectiveness in melanoma.

Verheijden RJ ，Burgers FH ，Janssen JC ，Putker AE ，Veenstra SPGR ，Hospers GAP ，Aarts MJB ，Hehenkamp KW ，Doornebosch VLE ，Verhaert M ，van den Berkmortel FWPJ ，Chatzidionysiou K ，Llobell A ，Barros M ，Maria ATJ ，Takeji A ，García Morillo JS ，Lidar M ，van Eijs MJM ，Blank CU ，Aspeslagh S ，Piersma D ，Kapiteijn E ，Labots M ，Boers-Sonderen MJ ，van der Veldt AAM ，Haanen JBAG ，May AM ，Suijkerbuijk KPM ... -  《-》

Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy but frequently cause immune-related adverse events (irAEs). Description of late-onset and duration of irAEs in the literature is often incomplete. To investigate reporting and incidence of late-onset and long-lasting irAEs, we reviewed all registration trials leading to ICI's approval by the US FDA and/or EMA up to December 2019. We analysed real-world data from all lung cancer (LC) and melanoma (Mel) patients treated with approved ICIs at the University Hospital of Lausanne (CHUV) from 2011 to 2019. To account for the immortal time bias, we used a time-dependent analysis to assess the potential association between irAEs and overall survival (OS). Duration of irAEs and proportion of patients with ongoing toxicities at data cut-off were not specified in 56/62 (90%) publications of ICIs registration trials. In our real-world analysis, including 437 patients (217 LC, 220 Mel), 229 (52.4%) experienced at least one grade ≥2 toxicity, for a total of 318 reported irAEs, of which 112 (35.2%) were long-lasting (≥6 months) and about 40% were ongoing at a median follow-up of 369 days [194-695] or patient death. The cumulative probability of irAE onset from treatment initiation was 42.8%, 51.0% and 57.3% at 6, 12 and 24 months, respectively. The rate of ongoing toxicity from the time of first toxicity onset was 42.8%, 38.4% and 35.7% at 6, 12 and 24 months. Time-dependent analysis showed no significant association between the incidence of irAEs and OS in both cohorts (log Rank p = 0.67 and 0.19 for LC and Mel, respectively). Late-onset and long-lasting irAEs are underreported but common events during ICIs therapy. Time-dependent survival analysis is advocated to assess their impact on OS. Real-world evidence is warranted to fully capture and characterise late-onset and long-lasting irAEs in order to implement appropriate strategies for patient surveillance and follow-up.

Ghisoni E ，Wicky A ，Bouchaab H ，Imbimbo M ，Delyon J ，Gautron Moura B ，Gérard CL ，Latifyan S ，Özdemir BC ，Caikovski M ，Pradervand S ，Tavazzi E ，Gatta R ，Marandino L ，Valabrega G ，Aglietta M ，Obeid M ，Homicsko K ，Mederos Alfonso NN ，Zimmermann S ，Coukos G ，Peters S ，Cuendet MA ，Di Maio M ，Michielin O ... -  《-》

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 ... -  《-》