Patterns of disease control and survival in patients with melanoma brain metastases undergoing immune-checkpoint blockade.

OBJECTIVES: Immune-checkpoint blockers (ICBs) significantly prolong overall survival (OS) in patients with advanced melanoma. Limited data are available on the efficacy and clinical benefit in patients with melanoma brain metastases (MBMs). The aim of this study was to determine whether ICB is active in an unselected cohort treated of patients with known brain metastases and if disease control correlates with the survival. METHODS: A total of 385 patients with metastatic malignant melanoma treated with ICB as monotherapy between 2005 and 2017 in two tertiary referral centres were included. Patient records were searched for the development of brain metastases. Demographic and clinical data of all patients were collected retrospectively. RESULTS: We identified 177 patients with MBM who received ICBs (ipilimumab, nivolumab, pembrolizumab). Patients with and without brain metastases received similar ICB regimens. Prognosis was inferior in patients with brain metastases; patients with >1 brain metastasis showed even poorer survival. For extracranial (ec) metastases, disease control was associated with improved survival. However, when comparing patients with intracranial (ic) disease control during immunotherapy to patients with ic disease progression, no difference in OS could be observed. CONCLUSIONS: In our study, ec disease control was the dominant predictive factor for OS in both patients with or without melanoma brain metastases. These data indicate that clinical trials in melanoma patients with brain metastases should address end-points such as symptom control, quality of life or OS in addition to ic response rates.

Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis.

OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse events, with immune-related diarrhea and colitis (irColitis) being among the most frequent ones. While the majority of patients with irColitis respond well to corticosteroid treatment ± other immunomodulatory drugs such as infliximab, some patients do not show resolution of their symptoms. In the present study, we analysed the frequency of therapy-refractory irColitis, the underlying cause, and useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with metastatic malignant melanoma were treated with checkpoint inhibitors at the Department of Dermatology at the University Hospital Essen. All patients were identified for whom diarrhea and/or colitis was documented in the digital patient records. Patients who did not respond to standard immunosuppressive therapy within 2 weeks were classified as refractory. Demographic and clinical data of all patients were collected. RESULTS: We identified 41 patients with irColitis, the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%) were refractory to standard immunomodulatory treatment with corticosteroids and infliximab. Therapy-refractory cases tended to show more severe inflammation in colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005, in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during management of checkpoint inhibitor-induced colitis emphasises the need for repetitive diagnostic measures in treatment-refractory irColitis.