Innovative tailored management of melanoma brain metastases

The occurrence of brain metastases (BM) in solid tumors is steadily increasing with the highest incidence being reported in melanoma (28.2%), lung (26.8%), renal (10.8%), and breast cancer (7.6%). The prognosis and survival of patients with BM remains poor and available prognostic factors are of limited clinical value. Therapeutic options (i.e., surgical resection, whole-brain radiation therapy, stereotactic radiosurgery) for patients with BM are largely palliative, while chemotherapy is uncommonly utilized due to its acknowledged limitation in effectively crossing the blood-brain barrier (BBB). Notably, until recently, patients with BM were systematically excluded from pivotal clinical trials with immune checkpoint blocking (ICB) mAbs because of their poor prognosis and to the prevailing dogma that the BBB would prevent effector immune cells from trafficking into the brain. However, recent insights on the immune landscape of the CNS, as well as of the brain tumor microenvironment, are shedding light on the immune-biology of BM. Along this line, we showed in the phase II, NIBIT-M1, study that the anti-CTLA-4 ipilimumab, combined with the alkylating drug fotemustine, appears to be an active therapeutic strategy in melanoma patients with asymptomatic BM, meriting further investigation (Di Giacomo AM et al, Lancet Oncol 2012). More recent results from two phase II studies reported that co-targeting of CTLA-4 and PD-1 induced objective intracranial tumor responses in approximately 50% of melanoma patients (Tawbi HA et al, N Engl J Med 2018, Long GV et al, Ann Oncol 2019), providing initial support for the efficacy of ipilimumab plus nivolumab in this hard-to-treat patient population. Furthermore, our phase III NIBIT-M2 study, demonstrated the efficacy of ipilimumab plus nivolumab on the overall and long-term survival of melanoma patients with untreated BM, with a 4-year overall-survival (OS) rate of 41% (Di Giacomo AM et al, Clin Cancer Res 2021). The NIBIT-M2 study, is a phase III, randomized, multicenter study that treated 76 melanoma patients with active, untreated and asymptomatic BM, randomly assigned to the 3 study Arms: 23 to fotemustine (Arm A), 26 to ipilimumab plus fotemustine (Arm B), and 27 to ipilimumab plus nivolumab (Arm C). The 7-year results of this study provide the longest evidence with a 43% OS rate, preserving the health-related quality of life (HRQoL) (Di Giacomo AM et al, Eur J Cancer 2024). Despite these unprecedented results, a significant proportion of melanoma patients with BM do not benefit from ICB therapy; thus, novel prognostic and predictive biomarkers are needed to improve their comprehensive clinical management. Along this line, blood-based biomarkers readily available and easy measurable, offering a unique opportunity to explore the systemic anti-cancer immunity of patients before and throughout the treatment course. In this scenario our project will exploit the availability of sera samples from melanoma patients with BM, enrolled in NIBIT-M2 study, which will be characterized by multi-omics and phenotypic analyses to identify novel biomarkers of response to ICB therapy. To this end, sera, plasma and PBMCs were collected at different timepoints (w1, w4, w7, w12 and w24) from a total of 60 treated patients. Initial studies aim to characterize peripheral circulating pro-inflammatory cytokines that can affect tumor response to ICB therapy. In detail, we are analyzing levels of tumor necrosis factor-alpha, interferon-gamma, interleukin-6, and monocyte chemotactic protein 2, selected for their potential predictive role, by ELLA™ platform, which allows to perform automated immunoassay by using specific microfluidic cartridges for the target of interest. The immunoassays are ongoing on serum samples derived from responder and non-responder patients of the 3 study arms, collected at baseline (n=60) and during treatment at different time points (week 4, n=28 and week 12, n=28). Results from these translational studies will allow identify new predictive biomarkers that will be utilized to select patients with BM who are the best candidates to ICB therapy.