Focal radiation necrosis of the brain (fRNB) is a late adverse event that can occur following the treatment of benign or malignant brain lesions with stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS). Recent studies have shown that the incidence of fRNB is higher in cancer patients who received immune checkpoint inhibitors. The use of bevacizumab (BEV), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF), is an effective treatment for fRNB when given at a dose of 5–7.5 mg/kg every two weeks. In this single-center retrospective case series, we investigated the effectiveness of a low-dose regimen of BEV (400 mg loading dose followed by 100 mg every 4 weeks) in patients diagnosed with fRNB. A total of 13 patients were included in the study; twelve of them experienced improvement in their existing clinical symptoms, and all patients had a decrease in the volume of edema on MRI scans. No clinically significant treatment-related adverse effects were observed. Our preliminary findings suggest that this fixed low-dose regimen of BEV can be a well-tolerated and cost-effective alternative treatment option for patients diagnosed with fRNB, and it is deserving of further investigation.

Background: Patients with advanced melanoma who progress after treatment with immune checkpoint-inhibitors (ICI) and BRAF-/MEK-inhibitors (if BRAF ^V600 mutated) have no remaining effective treatment options. The presence of CD1c (BDCA-1)⁺ and CD141 (BDCA-3)⁺ myeloid dendritic cells (myDC) in the tumor microenvironment correlates with pre-existing immune recognition and responsiveness to immune checkpoint blockade. The synthetic saponin-based immune adjuvant AS01_B enhances adaptive immunity through the involvement of myDC. Methods: In this first-in-human phase I clinical trial, patients with metastatic melanoma refractory to ICI and BRAF-/MEK inhibitors (when indicated) were recruited. Patients received an intravenous administration of low-dose nivolumab (10 mg, every 2 weeks) plus an intratumoral (IT) administration of 10 mg ipilimumab and 50 µg (0.5 mL) AS01_B (every 2 weeks). All myDC, isolated from blood, were injected on day 2 into the same metastatic lesion. Tumor biopsies and blood samples were collected at baseline and repeatedly on treatment. Multiplex immunohistochemistry (mIHC) was performed on biopsy sections to characterize and quantify the IT and peritumoral immune cell composition. Results: Study treatment was feasible and well tolerated without the occurrence of unexpected adverse events in all eight patients. Four patients (50%) obtained a complete response (CR) in the injected lesions. Of these, two patients obtained an overall CR, and one patient a partial response. All responses are ongoing after more than 1 year of follow-up. One additional patient had a stable disease as best response. The disease control rate was 50%. Median progression-free survival and overall survival were 24.1 and 41.9 weeks, respectively. Baseline tumor biopsies from patients who responded to treatment had features of T-cell exclusion. During treatment, there was an increased T-cell infiltration, with a reduced mean distance between T cells and tumor cells. Peripheral blood immune cell composition did not significantly change during study treatment. Conclusions: Combining an intratumoral injection of CD1c (BDCA-1)⁺ and CD141 (BDCA-3)⁺ myDC with repeated IT administration of ipilimumab and AS01_B and systemic low-dose nivolumab is safe, feasible with promising early results, worthy of further clinical investigation. Trial registration number: ClinicalTrials.gov identifier NCT03707808.

Ipilimumab plus nivolumab (COMBO) is the standard treatment in patients with asymptomatic melanoma brain metastases (MBM). We report a retrospective study aiming to assess the outcome of patients with MBM treated with COMBO with or without sequential/concomitant stereotactic radiotherapy (SRT). MBM patients treated with COMBO with or without SRT have been retrieved: demographics, steroid treatment, Central Nervous System [CNS]-related symptoms, BRAF status, radiotherapy (yes/no and timing) or surgery, number of MBM, maximum diameter of metastasis, overall response rate (ORR), progression-free (PFS) and overall survival (OS) have been analyzed. 453 patients were included: 190 received COMBO alone, 107 received COMBO and concomitant SRT, 156 COMBO and sequential SRT, respectively. At multivariable analysis the line of treatment [> 1st vs 1st: HR 2.60 (1.93-3.50)], sequential SRT vs no radiotherapy [HR 0.45 (0.32-0.64)], concomitant SRT vs no radiotherapy [HR 0.48 (0.33-0.69)], steroids [HR 1.56 (1.17-2.08)], age [HR 1.01 (1.00-1.02)] and number of MBM [≥ 3 vs 1 HR 1.55 (1.11-2.17)), 2 vs 1 HR 1.53 (1.02-2.31)] at baseline were associated with OS. There was no significant difference between patients who received concomitant vs sequential SRT. At a median follow-up of 29 months, the median-OS in the overall population was 17.8 months while in those who received SRT was 27.3 (15.3-39.4) for patients receiving sequential radiotherapy and 22.2 (12.7-31.7) for those receiving radiotherapy concomitantly to COMBO. The incidence of radionecrosis was 10.3 %. Toxicities were consistent with previous studies. Our results suggest a better OS in patients who receive SRT plus COMBO, regardless of timing of SRT. Prospective studies are needed to validate our findings.

Background: Antibodies that inhibit the programmed cell death protein 1 (PD-1) receptor offer a significant survival benefit, potentially cure (i.e., durable disease-free survival following treatment discontinuation), a substantial proportion of patients with advanced melanoma. Most patients however fail to respond to such treatment or acquire resistance. Previously, we reported that baseline total metabolic tumour volume (TMTV) determined by whole-body [${}^{18}$F]FDG PET/CT was independently correlated with survival and able to predict the futility of treatment. Manual delineation of [${}^{18}$F]FDG-avid lesions is however labour intensive and not suitable for routine use. A predictive survival model is proposed based on automated analysis of baseline, whole-body [${}^{18}$F]FDG images. Methods: Lesions were segmented on [${}^{18}$F]FDG PET/CT using a deep-learning approach and derived features were investigated through Kaplan–Meier survival estimates with univariate logrank test and Cox regression analyses. Selected parameters were evaluated in multivariate Cox survival regressors. Results: In the development set of 69 patients, overall survival prediction based on TMTV, lactate dehydrogenase levels and presence of brain metastases achieved an area under the curve of 0.78 at one year, 0.70 at two years. No statistically significant difference was observed with respect to using manually segmented lesions. Internal validation on 31 patients yielded scores of 0.76 for one year and 0.74 for two years. Conclusions: Automatically extracted TMTV based on whole-body [${}^{18}$F]FDG PET/CT can aid in building predictive models that can support therapeutic decisions in patients treated with immune-checkpoint blockade.

Clonal MAPK-pathway activating mutations in the MAP2K1 (MEK1) gene are present in approximately 9% of cutaneous melanomas. These mutations are divided into three classes: RAF-dependent, RAF-regulated, RAF-independent. Cell lines with class-2 or RAF-regulated MAP2K1-mutations are most responsive to MEK-inhibitors. We present a patient with a class-2 MAP2K1-mutant stage IV-M1d melanoma who experienced extra- and intracranial progressive disease following treatment with immune-checkpoint inhibitors. The patient was treated with the MEK-inhibitor trametinib (2 mg OD) to which a low-dose of dabrafenib (50 mg BID) was added to mitigate skin-toxicity. Following documentation of a partial response (PR), she developed one new, and increase in volume of two pre-existing brain metastases that were treated with stereotactic radiosurgery (SRS) while continuing trametinib and dabrafenib. Thereafter, a deep partial radiologic and metabolic response both extra-and intra-cranially was achieved and is ongoing 88 weeks after initiating trametinib. She experienced no grade > 2 adverse events. Focal post-radiation necrosis at site of an irradiated brain metastasis developed 9 months after SRS and is successfully being treated with low-dose bevacizumab. This is the first published case of a durable intracranial disease control with the MEK-inhibitor trametinib of a stage IV-M1d class-2 MAP2K1-mutant melanoma. This illustrates the utility of NGS profiles that include class-1/2 MAP2K1-mutations in patients with melanoma and other malignancies to provide valuable information on a potentially active individualized treatment option. A prospective clinical trial that further evaluates the efficacy of MEK-inhibitor therapies in MAP2K1-mutated tumors is justified.