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 ... -  《-》

Systematic review and meta-analysis efficacy and safety of immune checkpoint inhibitors in advanced melanoma patients with anti-PD-1 progression: a systematic review and meta-analysis.

More than half of melanoma patients taking first-line anti-PD-1 therapy either express transient or no response at all. The efficacy and safety of secondary treatments for these patients are still not well established. Here, we evaluate the efficacy and safety of different melanoma FDA-approved ICI modalities used in post-anti-PD-1 refractory settings. We searched the PubMed database and the ASCO meetings library for studies on advanced melanoma patients with cancer progression on anti-PD-1 therapy and were then treated with ipilimumab, nivolumab/ipilimumab combination, or retreated with anti-PD-1. Primary and secondary endpoints were efficacy and toxicity, respectively. Pooled estimates for each treatment group were obtained using a random or fixed effects model according to detected heterogeneity. Fourteen studies, of which 10 on ipilimumab, 2 on anti-PD-1 treatment, and 6 on combination therapies, were included, involving a total of 1460 patients. Twelve studies reported objective response rates (ORRs) and nine of them reported immune-related adverse events (irAEs). As for ORR, patients experienced a response that was inferior compared to the same therapy in treatment -naïve patients, with combination therapy having the best ORR of a pooled 23.08% (95% CI: 16.75% to 30.03%), followed by ipilimumab with a pooled ORR of 8.19% (95% CI: 5.78% to 10.92%). Survival data were also inferior in the ipilimumab cohort (mOS: 5.1 to 7.4 months) compared to ipilimumab in anti-PD-1 naive patients. As for grade 3/4 irAE occurrence, the ipilimumab cohort showed an estimate of 43.77% (95% CI 22.55% to 66.19%). Our findings provide the best current evidence that patients who progress on anti-PD-1 can still respond to different ICI modalities (ipilimumab with or without nivolumab, and retreatment or continuation beyond progression with anti-PD-1) with tolerable grade 3/4 irAEs. However, more prospective clinical trials are needed to confirm these results.

Alrabadi NN ，Abushukair HM ，Ababneh OE ，Syaj SS ，Al-Horani SS ，Qarqash AA ，Darabseh OA ，Al-Sous MM ，Al-Aomar SR ，Ahmed YB ，Haddad R ，Al Qarqaz FA ... -  《-》

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 ... -  《-》

Efficacy of PD-1-based immunotherapy after radiologic progression on targeted therapy in stage IV melanoma.

Targeted therapy (TT) is an effective treatment for advanced BRAFV600-mutated melanoma, but most patients eventually acquire resistance and progress. Here, we evaluated the outcome of second-line immune checkpoint blockade (ICB) after progression on dual BRAF and MEK inhibition. Patients with metastatic melanoma progressing on combined BRAF + MEK inhibition and receiving second-line ICB between 2015 and 2019 in 9 tertiary referral centres were enrolled. Demographic and clinical data and blood counts of all patients were collected retrospectively. We identified 99 patients with stage IV melanoma receiving ICB (nivolumab, pembrolizumab [n = 39] or ipilimumab plus nivolumab [n = 60]) after progression on combined TT. The median progression-free survival was similar in the PD-1 and ipilimumab plus nivolumab group (2.6 months [95% confidence interval {CI}, 2.0-3.1] vs. 2.0 [95% CI, 1.4-2.6], p = 0.15). The objective response rate was 18.0% in the PD-1 and 15.0% in the ipilimumab plus nivolumab group (p = 0.70). The disease control rate was 25.7% for monotherapy and 18.3% for combined ICB (p = 0.39). The median overall survival was 8.4 months (95% CI, 5.1-11.7) for patients receiving PD-1 monotherapy and 7.2 months (95% CI, 5.2-9.1) for patients receiving ipilimumab plus nivolumab (p = 0.86). The latter was associated with a higher rate of treatment-related adverse events (AEs). No significant association of laboratory values or clinicopathological characteristics with response to second-line ICB was observed. PD-1 monotherapy and combined ipilimumab plus nivolumab show similar activity and outcome in patients with melanoma resistant to BRAF + MEK inhibition. However, combined ipilimumab plus nivolumab was associated with a higher rate of treatment-related AEs compared with monotherapy.

Kreft S ，Gesierich A ，Eigentler T ，Franklin C ，Valpione S ，Ugurel S ，Utikal J ，Haferkamp S ，Blank C ，Larkin J ，Garbe C ，Schadendorf D ，Lorigan P ，Schilling B ... -  《-》

Investigation of clinical factors associated with longer overall survival in advanced melanoma patients treated with sequential ipilimumab.

Melanoma is one of the most serious form of skin cancer. Nowadays, ipilimumab is used for advanced melanoma refractory to first-line anti-programmed death 1 (PD-1) antibodies. Thirty patients (male : female ratio, 18:12; median age, 60.5 years) sequentially treated with ipilimumab after anti-PD-1 antibody (nivolumab or pembrolizumab), while 58 (male : female ratio, 27:31; median age, 66.5 years) with anti-PD-1 antibody only. The kind of therapy and schedules were as follows: nivolumab, 2 mg/kg at 3-week intervals or at 3 mg/kg every 2 week; pembrolizumab, 2 mg/kg every 3 weeks; ipilimumab, 3 mg/kg at 3-week intervals for four doses. The sequential therapy was selected for the patients with disease progression and/or recovered from severe (immune-related [ir]) adverse events (AE) after PD-1 blockade monotherapy. We evaluated multiple parameters and analyzed their relevance to overall survival (OS). The best objective response rate was 6.7% in sequential ipilimumab treatment. Median OS was 163 days (range, 16-489). Baseline absolute lymphocyte count (ALC) and performance status (PS) before sequential ipilimumab were associated with OS in univariate analyses. Baseline PS and irAE within 6 weeks after ipilimumab administration showed significant differences on multivariate analysis. Prior to first-line PD-1 blockade, these parameters were not associated with OS. The other factors (i.e. age, sex, number of doses, absolute neutrophil counts, neutrophil : lymphocyte ratio, lactate dehydrogenase and C-reactive protein) were not associated with OS. [Correction added on 17 April 2019, after first online publication: 'not related to OS' has been amended to 'not associated with OS'.] Ipilimumab as sequential therapy did not appear to improve OS and was associated with more severe irAE than PD-1 blockade monotherapy. We need to carefully consider treating patients with poor PS and low ALC.

Muto Y ，Kitano S ，Tsutsumida A ，Namikawa K ，Takahashi A ，Nakamura Y ，Yamanaka T ，Yamamoto N ，Yamazaki N ... -  《-》