Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients

Abstract

BackgroundNivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM.MethodsPatients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS.ResultsThree hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab. The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively. We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status. In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996). Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119).ConclusionImmunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.

An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery—the BUMPER study

“… 30 Moreover, patients receiving a combination of systemic and local therapies, namely surgery or radiosurgery, seem to have better outcomes than those who do not, regardless of the time point, that is, before or after systemic therapy initiation. 31 Patients with BRAFV600E/K-mutated melanoma also benefit from treatment with combined BRAF/MEK inhibitors, and if there is a continuous dependency on corticotherapy at the time of systemic therapy initiation, combined BRAF/MEK inhibitors is preferred to immunotherapy. 29 …”

Systemic Therapy of Metastatic Melanoma: On the Road to Cure

“…In a German retrospective trial [ 111 ], for example, data of 380 patients with MBM treated with nivolumab plus ipilimumab were analyzed. Further, 31% had symptomatic MBM.…”

The evolving role of neurosurgery for central nervous system metastases in the era of personalized cancer therapy

“…Results from this prospective cohort will clarify whether large steroid-requiring lesions indeed should be removed prior to immunotherapy. In turn, immunotherapy followed by surgery warrants also evaluation as some data suggest increased efficacy compared to immunotherapy alone [13]. Tumour resection, however, has to be considered in the context of the impact of postoperative recovery time after surgery and the risk of neurological sequelae with a decreased performance status which is a critical inclusion criterion in most trials.…”

“…With an increasing understanding of the individual cellular and molecular tumour targets available in a cancer, novel personalized treatment strategies are emerging [11]. Effective (targeted) medical and surgical therapies are available for subgroups of brain metastasis patients when targetable individual tumour-and patient-specific factors are present [12,13]. Accordingly, treatment of brain metastasis patients needs to be performed in the setting of multi-disciplinary care teams that can discuss and consider the full range of therapeutic options.…”