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21 de janeiro de 2019
Brain metastasis represents one of the most devastating complications in advanced systemic cancers. The treatment of patients with brain metastasis remains an ongoing challenge. Historically, the major treatment approaches for brain metastases included surgery, radiation therapy (as whole brain radiation therapy and stereotactic radiosurgery) and chemotherapy. However, as genomic studies have revealed a number of clinically actionable mutations and we gain further insight in the molecular characteristics and the immune microenvironment of brain metastases, more and more therapeutic agents targeting molecular signaling pathways and immune responses in brain metastases are emerging. In recent years, immunotherapy has dramatically changed the landscape of treatment of patients with brain metastases. To date, immune checkpoint inhibitors such as ipilimumab targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) as well as pembrolizumab and nivolumab targeting programmed cell death protein 1 (PD-1) are available for the treatment of patients with brain metastases. In a double-blinded phase-III trial in patients with unresectable stage III or IV melanoma, the CTLA-4-inhibitor ipilimumab was shown to improve overall survival (OS) (median 10.1 months), compared to treatment with the peptide vaccine gp100 alone (median OS 6.4 months, hazard ratio, 0.66; p=0.003). No difference in OS was observed between patients receiving ipilimumab alone and a combination of ipilimumab and gp100 (median OS 10 months, hazard ratio for death with ipilimumab plus gp100, 1.04; P=0.76).(1) Studies following these promising results included an open-label phase-II trial and two trials of the Italian Network for Tumor Biotherapy, NIBIT-1 and NIBIT2. The open-label phase-II trial by Margolin et al. investigated the response to treatment with ipilimumab in patients with neurologically asymptomatic melanoma brain metastases without corticosteroid treatment (cohort A) and neurologically symptomatic patients with melanoma brain metastases on a stable dose of corticosteroids (cohort B). After 12 weeks, systemic disease control was achieved in 18% of cohort A and in 5% of patients in cohort B. Intracranial response to treatment was achieved in 24% patients of cohort A and in 10% of cohort B.(2) In the open-label, single-arm phase-II trial NIBIT-1, patients with measurable, locally advanced, unresectable stage III or stage IV melanoma were included and received a combination therapy of ipilimumab and fotemustine. Intracranial disease control was achieved in 50% of participating patients with melanoma brain metastases. Median brain progression-free survival (PFS) in these patients was three months.(3) The authors subsequently published the three-year followup results of this study, revealing that patients with brain metastases treated with this combination had a median OS of 12.7 months.(4) These results set the foundation for the open-label, triple arm phase-III trial NIBIT-2, which aims to evaluate the OS of patients with melanoma brain metastases receiving either fotemustine only, a combination of ipilimumab and fotemustine or the combination of ipilimumab and nivolumab, which is currently recruiting participants (NCT02460068). The PD-1 inhibitors pembrolizumab and nivolumab are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced nonsmall cell lung cancer (NSCLC), melanoma and renal cell carcinoma (RCC). An early analysis of an ongoing phase-II trial on pembrolizumab