Impact of Previous Local Treatment for Brain Metastases on Response to Molecular Targeted Therapy in BRAF-Mutant Melanoma Brain Metastasis: A Systematic Review and Meta-Analysis.

Background: Melanoma brain metastases (BMs) are associated with poor prognosis and are the main cause of mortality in melanoma patients. BRAF inhibitors have shown intracranial activity in both treatment-naïve and previously treated BM patients. We aimed to investigate if there was any difference in response of BRAF inhibitors in these two cohorts. Materials and Methods: Electronic database search included PubMed, Medline, and Cochrane library until March 2021 for studies with desired comparative outcomes. Outcomes of interest that were obtained for meta-analysis included intracranial response rate as the primary outcome and survival and safety outcomes as the secondary outcomes. Review Manager version 5.4 was used for data analysis. Results: Three studies comprising 410 BRAF-mutated melanoma patients with BMs were included according to eligibility criteria. The comparative cohort included patients with treatment-naïve BMs (TN cohort; n = 255) and those who had progressive disease after receiving local brain treatment for BMs (PT cohort; n = 155). Meta-analysis revealed that BRAF inhibitors (vemurafenib and dabrafenib) and BRAF/MEK inhibitor combination (dabrafenib and trametinib) induced significantly higher intracranial disease control (OR 0.58 [95% CI: 0.34, 0.97], p = 0.04) and a trend toward improved progression-free survival (PFS) (HR 1.22 [95% CI: 0.98, 1.52], p = 0.08) in the PT cohort as compared to the TN cohort. Overall survival was not significantly different between the cohorts (HR 1.16 [95% CI: 0.89, 1.51], p = 0.28). Subgroup analysis revealed that PFS was significantly improved (HR 1.67 [95% CI: 1.06, 2.62], p = 0.03), and a trend toward improved OS (HR 1.62 [95% CI: 0.95, 2.75], p = 0.08) was achieved in patients receiving BRAF/MEK inhibitor combination and patients with BRAFv600K mutation receiving dabrafenib alone. No increase in overall adverse events (AEs), grade 3/4 AEs, and severe adverse events (SAEs) was observed between the cohorts. Conclusions: BRAF inhibitors (plus MEK inhibitor) may achieve better intracranial disease stability in BRAF-mutant melanoma patients who have received previous local treatment for BMs. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/), identifier CRD42020185984.

Radiation Plus Anti-PD-1 Therapy for NSCLC Brain Metastases: A Retrospective Study.

BACKGROUND: Radiation therapy (RT) is the mainstay of brain metastases (BMs), and anti-PD-1 blockade has led to intracranial responses in non-small cell lung carcinoma (NSCLC) patients with BMs. OBJECTIVE: This study aimed to evaluate the efficacy and safety of adding anti-PD-1 blockade to RT in the management of NSCLC patients with BM in terms of survival outcome. MATERIALS AND METHODS: We retrospectively reviewed 70 NSCLC patients with BMs who were treated with whole brain radiation therapy (WBRT) between January 2016 and January 2021. Of the 70 patients, 29 additionally received anti-PD-1 therapy within 30 days of WBRT initiation. Baseline characteristics of the patients and efficacy outcomes such as progression-free survival (PFS) and overall survival (OS) were statistically compared using SPSS v26. Results were obtained using the Chi-square test/Fisher exact test, t-test, Kaplan-Meier, and Cox regression survival analyses. RESULTS: The median survival for the entire cohort was 24 months (95% CI, 19.5-28.5). The median survival times for WBRT alone and WBRT plus anti-PD-1 therapy cohorts were 20 months (95% CI, 11.6-28.3) and 27 months (95% CI, 19.5-28.5), respectively (p=0.035). There was no statistical difference in PFS for the treatment cohorts (median PFS for WBRT alone: 7 months vs. 12 months for WBRT plus anti-PD-1, p=0.247). In EGFR wild-type subgroup (n=31), both PFS (p=0.037) and OS (p=0.012) were significantly improved. Only the treatment group (WBRT plus anti-PD-1) was a significant predictor of OS on univariate and multivariate analyses (p=0.040). There were no significant differences in adverse events among the treatment groups. CONCLUSIONS: NSCLC patients with BM receiving additional anti-PD-1 therapy may derive better OS than WBRT alone without any increase in adverse events. Prospective well-designed studies are warranted to validate and elucidate the additive effects of the two modalities in this group of patients.

Soluble B7-CD28 Family Inhibitory Immune Checkpoint Proteins and Anti-Cancer Immunotherapy.

Co-inhibitory B7-CD28 family member proteins negatively regulate T cell responses and are extensively involved in tumor immune evasion. Blockade of classical CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) and PD-1 (programmed cell death protein-1) checkpoint pathways have become the cornerstone of anti-cancer immunotherapy. New inhibitory checkpoint proteins such as B7-H3, B7-H4, and BTLA (B and T lymphocyte attenuator) are being discovered and investigated for their potential in anti-cancer immunotherapy. In addition, soluble forms of these molecules also exist in sera of healthy individuals and elevated levels are found in chronic infections, autoimmune diseases, and cancers. Soluble forms are generated by proteolytic shedding or alternative splicing. Elevated circulating levels of these inhibitory soluble checkpoint molecules in cancer have been correlated with advance stage, metastatic status, and prognosis which underscore their broader involvement in immune regulation. In addition to their potential as biomarker, understanding their mechanism of production, biological activity, and pathological interactions may also pave the way for their clinical use as a therapeutic target. Here we review these aspects of soluble checkpoint molecules and elucidate on their potential for anti-cancer immunotherapy.

Bevacizumab Treatment of Radiation-Induced Brain Necrosis: A Systematic Review.

BACKGROUND: Radiation brain necrosis (RBN) is a serious complication in patients receiving radiotherapy for intracranial disease. Many studies have investigated the efficacy and safety of bevacizumab in patients with RBN. In the present study, we systematically reviewed the medical literature for studies reporting the efficacy and safety of bevacizumab, as well as for studies comparing bevacizumab with corticosteroids. MATERIALS AND METHODS: We searched PubMed, Cochrane library, EMBASE, and ClinicalTrials.gov from their inception through 1 March, 2020 for studies that evaluated the efficacy and safety of bevacizumab in patients with RBN. Two investigators independently performed the study selection, data extraction, and data synthesis. RESULTS: Overall, the present systematic review included 12 studies (eight retrospective, two prospective, and two randomized control trials [RCTs]) involving 236 patients with RBN treated who were treated with bevacizumab. The two RCTs also had control arms comprising patients with RBN who were treated with corticosteroids/placebo (n=57). Radiographic responses were recorded in 84.7% (200/236) of patients, and radiographic progression was observed in 15.3% (36/236). Clinical improvement was observed in 91% (n=127) of responding patients among seven studies (n=113). All 12 studies reported volume reduction on T1 gadolinium enhancement MRI (median: 50%, range: 26%-80%) and/or T2 FLAIR MRI images (median: 59%, range: 48%-74%). In total, 46 responding patients (34%) had recurrence. The two RCTs revealed significantly improved radiographic response in patients treated with bevacizumab (Levin et al.: p = 0.0013; Xu et al.: p < 0.001). Both also showed clinical improvement (Levin et al.: NA; Xu et al.: p = 0.039) and significant reduction in edema volume on both T1 gadolinium enhancement MRI (Levin et al.: p=0.0058; Xu et al.: p=0.027) and T2 FLAIR MRI (Levin et al.: p=0.0149; Xu et al.: p < 0.001). Neurocognitive improvement was significantly better after 2 months of treatment in patients receiving bevacizumab than in those given corticosteroids, as assessed by the MoCA scale (p = 0.028). The recurrence rate and side effects of the treatments showed no significant differences. CONCLUSIONS: Patients with RBN respond to bevacizumab, which can improve clinical outcomes and cognitive function. Bevacizumab appears to be more efficacious than corticosteroid-based treatment. The safety profile was comparable to that of the corticosteroids.

Bevacizumab for radiation necrosis following radiotherapy of brain metastatic disease: a systematic review & meta-analysis.

BACKGROUND: Radiotherapy is the mainstay of brain metastasis (BM) management. Radiation necrosis (RN) is a serious complication of radiotherapy. Bevacizumab (BV), an anti-vascular endothelial growth factor monoclonal antibody, has been increasingly used for RN treatment. We systematically reviewed the medical literature for studies reporting the efficacy and safety of bevacizumab for treatment of RN in BM patients. MATERIALS AND METHODS: PubMed, Medline, EMBASE, and Cochrane library were searched with various search keywords such as "bevacizumab" OR "anti-VEGF monoclonal antibody" AND "radiation necrosis" OR "radiation-induced brain necrosis" OR "RN" OR "RBN" AND "Brain metastases" OR "BM" until 1st Aug 2020. Studies reporting the efficacy and safety of BV treatment for BM patients with RN were retrieved. Study selection and data extraction were carried out by independent investigators. Open Meta Analyst software was used as a random effects model for meta-analysis to obtain mean reduction rates. RESULTS: Two prospective, seven retrospective, and three case report studies involving 89 patients with RN treated with BV were included in this systematic review and meta-analysis. In total, 83 (93%) patients had a recorded radiographic response to BV therapy, and six (6.7%) had experienced progressive disease. Seven studies (n = 73) reported mean volume reductions on gadolinium-enhanced T1 (mean: 47.03%, +/- 24.4) and T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI images (mean: 61.9%, +/- 23.3). Pooling together the T1 and T2 MRI reduction rates by random effects model revealed a mean of 48.58 (95% CI: 38.32-58.85) for T1 reduction rate and 62.017 (95% CI: 52.235-71.799) for T2W imaging studies. Eighty-five patients presented with neurological symptoms. After BV treatment, nine (10%) had stable symptoms, 39 (48%) had improved, and 34 (40%) patients had complete resolution of their symptoms. Individual patient data was available for 54 patients. Dexamethasone discontinuation or reduction in dosage was observed in 30 (97%) of 31 patients who had recorded dosage before and after BV treatment. Side effects were mild. CONCLUSIONS: Bevacizumab presents a promising treatment strategy for patients with RN and brain metastatic disease. Radiographic response and clinical improvement was observed without any serious adverse events. Further class I evidence would be required to establish a bevacizumab recommendation in this group of patients.

Soluble PD-1: Predictive, Prognostic, and Therapeutic Value for Cancer Immunotherapy.

Programmed death protein 1 (PD-1) interaction with PD-L1 deliver immunosuppressive environment for tumor growth, and its blockade with directed monoclonal antibodies (anti-PD-1/anti-PD-L1) has shown remarkable clinical outcome. Lately, their soluble counterparts, sPD-1 and sPD-L1, have been detected in plasma, and elevated levels have been associated with advanced disease, clinical stages, and worst prognosis for cancer patients. Elevated plasma levels of sPD-L1 have been correlated with worst prognosis in several studies and has displayed a persistent outlook. On the other hand, sPD-1 levels have been inconsistent in their predictive and prognostic ability. Pretherapeutic higher sPD-1 plasma levels have shown to predict advanced disease state and to a lesser extent worst prognosis. Any increase in sPD-1 plasma level post therapeutically have been correlated with improved survival for various cancers. In vitro and in vivo studies have shown sPD-1 ability to bind PD-L1 and PD-L2 and block PD-1/PD-L1 interaction. Local delivery of sPD-1 in cancer tumor microenvironment through local gene therapy have demonstrated an increase in tumor specific CD8+ T cell immunity and tumor growth reduction. It had also exhibited enhancement of T cell immunity induced by vaccination and other gene therapeutic agents. Furthermore, it may also lessen the inhibitory effect of circulating sPD-L1 and enhance the effects of mAb-based immunotherapy. In this review, we highlight various aspects of sPD-1 role in cancer prediction, prognosis, and anti-cancer immunity, as well as, its therapeutic value for local gene therapy or systemic immunotherapy in blocking the PD-1 and PD-L1 checkpoint interactions.

Lapatinib Plus Local Radiation Therapy for Brain Metastases From HER-2 Positive Breast Cancer Patients and Role of Trastuzumab: A Systematic Review and Meta-Analysis.

BACKGROUND: Intracranial activity of lapatinib has been demonstrated in several studies in patients with human epidermal growth factor receptor-2 positive breast cancers (HER-2+ BC). Stereotactic radiosurgery (SRS) has been increasingly used as the local therapy for brain metastases in breast cancer patients. Increased objective response rate was observed for lapatinib plus whole brain radiotherapy (WBRT) is such patients with high toxicity. OBJECTIVE: We seek to obtain clinical evidence of synergistic efficacy of lapatinib in combination with radiation therapy, in particular, SRS. MATERIALS AND METHODS: We carried out a comprehensive research using the following databases: PubMed; Medline; EMBASE; Cochrane library. These databases were searched until 10 June 2020. PRISMA guidelines were followed step by step for carrying out this systematic review and meta-analysis. Review Manager v 5.4 software was used for statistical evaluation of data. RESULTS: Overall 6 studies with 843 HER-2 positive breast cancer patients (442 HER-2 amplified disease, 399 luminal B disease) were included in this systematic review and meta-analysis. A total 279 patients had received lapatinib in addition to HER-2 antibody (trastuzumab) plus/minus chemoradiotherapy, while 610 patients had received trastuzumab-based management or only chemoradiotherapy. Lapatinib-based management of BM was associated with significant increase in overall survival (HR 0.63 [0.52, 0.77], p < 0.00001). Combination of the two (trastuzumab plus lapatinib) was associated with increased survival advantage compared to each agent alone (0.55 [0.32, 0.92], p = 0.02). SRS in combination with lapatinib was associated with increased local control (HR 0.47 [0.33, 0.66], p = 0.0001). Ever use of lapatinib with SRS was associated an increased survival as reported in two studies (Shireen et al.: 27.3 vs. 19.5 months, p = 0.03; Kim et al.: 33.3 vs. 23.6 months, p = 0.009). Kim et al. also revealed significant increase in intracranial activity with concurrent lapatinib reporting 57% complete response compared to 38% (p < 0.001) and lower progressive disease rate of 11 vs. 19% (p < 0.001). Risk of radiation necrosis was decreased with lapatinib use. CONCLUSIONS: Lapatinib has shown intracranial activity and yielded better survival for HER-2+ BC patients with BMs. SRS in combination with ever use of lapatinib had better local control and were associated with better survival. Radiation necrosis risk was reduced with the use of lapatinib.

Impact of Tyrosine Kinase Inhibitors (TKIs) Combined With Radiation Therapy for the Management of Brain Metastases From Renal Cell Carcinoma.

Background: Targeted therapy has transformed the outcome for patients with metastatic renal cell carcinoma. Their efficacy and safety have also been demonstrated in brain metastatic RCC. Preclinical evidence suggests synergism of radiation and tyrosine kinase inhibitors. Consequently, several studies have compared their efficacy in the treatment of RCC brain metastases to the era of brain management with surgery/radiation only. Objectives: We seek to systematically review and meta-analyze the results of those studies that involved comparative intervention groups of brain management; TKIs, and never used TKIs. Methods and Materials: Online databases (PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov) were searched for comparative studies. Overall survival as the primary outcome of interest, and local brain control, distant control, and adverse events as secondary outcomes of interest were recorded for meta-analysis. Hazard ratios were pooled together using Review Manager 5.3. Fixed effects or random effects model were adopted according to the level of heterogeneity. Subgroup analysis included studies that involved SRS as the local treatment of management. Results: Overall 7 studies (n = 897) were included for meta-analysis. TKI use was associated with better survival (HR 0.60 [0.52, 0.69], p < 0.00001) and local brain control (HR 0.34 [0.11, 0.98], p = 0.05). SRS subgroup also revealed significantly better survival (HR 0.61 [0.44, 0.83], p = 0.002) and local brain control (HR 0.19 [0.08, 0.45], p = 0.0002). Distant brain control (HR 0.95 [0.67, 1.35], p = 0.79) and brain progression free survival were unaffected (HR 0.94 [0.56, 1.56], p = 0.80). Only one study (n = 376) reported significantly greater 12-months cumulative incidence of radiation necrosis with TKI use within 30 days of SRS (10.9 vs. 6.4%, p = 0.04). Conclusions: TKIs use in combination with SRS is safe and effective for treating RCC brain metastases. Larger randomized controlled trials are warranted to validate the results.

Tumor Primary Site and Histology Subtypes Role in Radiotherapeutic Management of Brain Metastases.

Randomized controlled trials have failed to report any survival advantage for WBRT combined with SRS in the management of brain metastases, despite the enhanced local and distant control in comparison to each treatment alone. Literature review have revealed important role of primary histology of the tumor when dealing with brain metastases. NSCLC responds better to combined approach even when there was only single brain metastasis present while breast cancer has registered better survival with SRS alone probably due to better response of primary tumor to advancement in surgical and chemotherapeutic agents. Furthermore, mutation status (EGFR/ALK) in lung cancer and receptor status (ER/PR/HER2) in breast cancer also exhibit diversity in their response to radiotherapy. Radioresistant tumors like renal cell carcinoma and melanoma brain metastases have achieved better results when treated with SRS alone. Secondly, single brain metastasis may benefit from local and distant brain control achieved with combined treatment. These diverse outcomes suggest a primary histology-based analysis of the radiotherapy regimens (WBRT, SRS, or their combination) would more ideally establish the role of radiotherapy in the management of brain metastases. Molecularly targeted therapeutic and immunotherapeutic agents have revealed synergism with radiation therapy particularly SRS in treating cancer patients with brain metastases. Clinical updates in this regard have also been reviewed.

NK Cell-Based Immune Checkpoint Inhibition.

Immunotherapy, with an increasing number of therapeutic dimensions, is becoming an important mode of treatment for cancer patients. The inhibition of immune checkpoints, which are the source of immune escape for various cancers, is one such immunotherapeutic dimension. It has mainly been aimed at T cells in the past, but NK cells are a newly emerging target. Simultaneously, the number of checkpoints identified has been increasing in recent times. In addition to the classical NK cell receptors KIRs, LIRs, and NKG2A, several other immune checkpoints have also been shown to cause dysfunction of NK cells in various cancers and chronic infections. These checkpoints include the revolutionized CTLA-4, PD-1, and recently identified B7-H3, as well as LAG-3, TIGIT & CD96, TIM-3, and the most recently acknowledged checkpoint-members of the Siglecs family (Siglec-7/9), CD200 and CD47. An interesting dimension of immune checkpoints is their candidacy for dual-checkpoint inhibition, resulting in therapeutic synergism. Furthermore, the combination of immune checkpoint inhibition with other NK cell cytotoxicity restoration strategies could also strengthen its efficacy as an antitumor therapy. Here, we have undertaken a comprehensive review of the literature to date regarding NK cell-based immune checkpoints.

Efficacy of BRAF Inhibitors in Combination With Stereotactic Radiosurgery for the Treatment of Melanoma Brain Metastases: A Systematic Review and Meta-Analysis.

BACKGROUND: BRAF inhibitors have improved the outcome for patients with BRAF mutant metastatic melanoma and have shown intracranial responses in melanoma brain metastases. Stereotactic radiosurgery (SRS) is being used as a local treatment for melanoma brain metastasis (MBM) with better local control and survival. We searched for studies comparing the combination of two treatments with SRS alone to detect any clinical evidence of synergism. MATERIALS AND METHODS: PubMed, EMBASE, Medline, and Cochrane library were searched until May 2020 for studies with desired comparative outcomes. Outcomes of interest that were obtained for meta-analysis included survival as the primary, and local control as the secondary outcome. RESULTS: A total of eight studies involving 976 patients with MBM were selected. Survival was significantly improved for patients receiving BRAF inhibitor plus SRS in comparison to SRS alone as assessed from the time of SRS induction (SRS survival: hazard ratio [HR] 0.67 [0.58-0.79], p <0.00001), from the time of brain metastasis diagnosis (BM survival: HR 0.65 [0.54, 0.78], p < 0.00001), or from the time of primary diagnosis (PD survival: HR 0.74 [0.57-0.95], p = 0.02). Dual therapy was also associated with improved local control, indicating an additive effect of the two treatments (HR 0.53 [0.31-0.93], p=0.03). Intracranial hemorrhage was higher in patients receiving BRAF inhibitors plus SRS than in those receiving SRS alone (OR, 3.16 [1.43-6.96], p = 0.004). CONCLUSIONS: BRAF inhibitors in conjunction with SRS as local treatment appear to be efficacious. Local brain control and survival improved in patients with MBM receiving dual therapy. Safety assessment would need to be elucidated further as the incidence of intracranial hemorrhage was increased.