Glioblastoma (GBM) is the most common adult brain cancer. Despite extensive treatment protocols comprised of maximal surgical resection and adjuvant chemo–radiation, all glioblastomas recur and are eventually fatal. Emerging as a novel investigation for GBM treatment, photodynamic therapy (PDT) is a light-based modality that offers spatially and temporally specific delivery of anti-cancer therapy with limited systemic toxicity, making it an attractive option to target GBM cells remaining beyond the margins of surgical resection. Prior PDT approaches in GBM have been predominantly based on 5-aminolevulinic acid (5-ALA), a systemically administered drug that is metabolized only in cancer cells, prompting the release of reactive oxygen species (ROS), inducing tumor cell death via apoptosis. Hence, this review sets out to provide an overview of current PDT strategies, specifically addressing both the potential and shortcomings of 5-ALA as the most implemented photosensitizer. Subsequently, the challenges that impede the clinical translation of PDT are thoroughly analyzed, considering relevant gaps in the current PDT literature, such as variable uptake of 5-ALA by tumor cells, insufficient tissue penetrance of visible light, and poor oxygen recovery in 5-ALA-based PDT. Finally, novel investigations with the potential to improve the clinical applicability of PDT are highlighted, including longitudinal PDT delivery, photoimmunotherapy, nanoparticle-linked photosensitizers, and near-infrared radiation. The review concludes with commentary on clinical trials currently furthering the field of PDT for GBM. Ultimately, through addressing barriers to clinical translation of PDT and proposing solutions, this review provides a path for optimizing PDT as a paradigm-shifting treatment for GBM.

INTRODUCTION Brain metastases from lung cancer (BMLC) are common and represent an aggressive form of disease. Numerous ongoing clinical trials are investigating targeted molecular therapies against epidermal growth factor receptor (EGFR), which have demonstrated blood-brain-barrier permeability and intracranial activity. However, there is limited real-world efficacy data on second and third-generation EGFR tyrosine kinase inhibitors (TKI), Afatinib and Osimertinib, for the treatment of BMLC. This study provides a real-world assessment to evaluate the impact of these agents on overall survival (OS) at the population-level. METHODS This retrospective cohort study queried data from TriNetX, a multi-institutional de-identified database, aggregating data from 90 U.S. healthcare organizations. Three cohorts were established, consisting of patients with BMLC treated with 1) Osimertinib, 2) Afatinib, or 3) Neither Osimertinib nor Afatinib. Cohorts 1 and 3, as well as cohorts 2 and 3, were propensity matched on demographics and comorbidities. Median overall survival (OS) was compared via Kaplan Meier analyses, using log-rank tests and Cox proportional hazards ratios (HR). RESULTS After matching, we identified 1,990 BMLC patients treated with Osimertinib (cohort 1) and 1,990 treated without Afatinib and Osimertinib (cohort 3). Median OS was 21.2 months and 13.5 months for the two cohorts, respectively (p < 0.0001; HR [95% CI], 0.69 [0.63-0.77]). Furthermore, we identified 685 BMLC patients treated with Afatinib (cohort 2) and 685 treated without Afatinib and Osimertinib (cohort 3) after matching. Median OS was 19.0 months and 11.5 months, respectively (p < 0.0185; HR [95% CI], 0.83 [0.71-0.97]). CONCLUSION Afatinib and Osimertinib demonstrated a significant survival benefit for patients with BMLC, with comparable, if not better, results to other therapeutic options. These findings suggest strong intracranial efficacy of these agents, while indicating a greater generalizability of the results. Further prospective studies are warranted to better understand their potential role in the BMLC treatment paradigm.

INTRODUCTION Mounting evidence demonstrates the therapeutic promise of immunotherapies (ITs) for brain metastases (BM). However, there is concern that stringent eligibility criteria in these clinical studies have selected against patients with comorbid conditions. As a result, it remains unclear if these results are truly applicable to the general population, particularly in individuals with end-stage renal disease (ESRD) on dialysis. Therefore, we sought to determine the impact of concomitant dialysis treatment and IT on overall survival (OS) of patients with BM. METHODS Data were collected from TriNetX (TriNetX, Inc., Cambridge, MA), a global research network that aggregates clinical data from 92 healthcare organizations. Independent variables included ‘secondary malignant neoplasm of brain’, ‘ipilimumab’, ‘pembrolizumab’, ‘ESRD’, ‘dependence on renal dialysis’, and ‘dialysis services and procedures’. Patients with BM receiving IT were dichotomized by dialysis use. Cohorts were propensity matched on age, gender, and race. Kaplan-Meier analyses and log rank tests were conducted to assess overall survival (OS) and survival probability over a five-year period. RESULTS Of the 14,368 confirmed BM patients treated with IT, 95 (0.6%) began dialysis within three months of IT initiation. Propensity matching established 95 patients in each cohort. The dialyzed cohort had a median OS of 277 days with a survival probability of 11.6%, compared to the non-dialyzed group with a median OS of 419 days and survival probability of 40.29% (p=0.109; hazard ratio 1.422, 95% confidence interval, 0.923-2.191, p=0.891). A separate comparison cohort was created to compare ESRD diagnosis with or without dialysis (n=56 and n=106 respectively). The comparison cohorts did not show a difference in median OS and survival probability (p=0.49). CONCLUSION Despite their health complexities, individuals with ESRD, with or without dependence on dialysis, may nonetheless derive a similar survival benefit from ITs. Therefore, we advocate for greater inclusion of patients with advanced comorbidities in clinical trials to assess for real-world safety and efficacy outcomes.

INTRODUCTION: Melanoma brain metastases (BM) are common and are historically associated with poor prognosis. In the early 2010s, the treatment paradigm for malignant metastatic melanoma shifted with the introduction of immunotherapy (IT). Recent studies suggest that IT provides survival benefits for patients with BM from melanoma primary. The goal of this study was to validate these findings in a large population cohort. METHODS: Data were collected from the Surveillance, Epidemiology and End Results (SEER) database, version 8.3.4 (22 March 2017). Three cohorts were created based on the FDA approval date of IT: ipilimumab (2011), nivolumab (2014), and nivolumab plus ipilimumab (2015) for use in metastatic melanomas. Respectively, the cohorts are defined as the pre-IT era cohort (2010), early-IT era cohort (2011-2015) and late-IT era cohort (2016-2018). One-year overall survival (OS), 2-year OS, and median OS were assessed using a Kaplan-Meier analysis and log rank tests. RESULTS: 1,893 patients were included in this analysis (190 in the pre-IT era, 1,021 in the early-IT era, and 682 in the late-IT era) that had histologically confirmed melanoma with secondary BM at diagnosis. Median OS was significantly increased across the pre-, early-, and late-IT era cohorts, respectively, with the largest increase occurring between the early-IT and late-IT eras (1-year OS: 20.6% vs. 17.0% vs. 38.2%, 2-year OS: 10.5% vs. 14.2% vs. 27.1%, and median OS: 5 vs. 6 vs. 8 months, p < 0.001 by log-rank test). CONCLUSION: The introduction of IT for malignant melanomas has significantly improved the survival outcomes of melanoma patients with brain metastasis. Novel treatment paradigms involving IT with other adjuvant therapies need to be explored to further improve intracranial activity in melanoma patients.

INTRODUCTION Melanoma brain metastases (MBM) are often associated with poor prognosis. Over the last decade, the treatment paradigm for malignant melanoma shifted with the introduction of immunotherapies (ITs), including ipilimumab (ipi) and nivolumab (nivo). Recent clinical trials suggest that IT offers a survival benefit in MBM and may suffice as the sole intervention in those with small, asymptomatic lesions. Secondary trial analyses suggest IT may reduce rates of BM. The goal of this study was to assess the potential impact of IT in reducing prevalence of MBM in a real-world population-level analysis. METHODS A retrospective query of TriNetX, a database that collates clinical data from 92 healthcare organizations, was performed. Melanoma patients without brain metastases at diagnosis were stratified as: 1) ipi and nivo (dual-IT), 2) ipi alone (single-IT), or 3) no IT treatment (no-IT). A new diagnosis of MBM, from one month of initiating IT to any time after, was compared among cohorts. Median overall survival (OS) of MBM patients were calculated and compared using Kaplan Meier analysis and log-rank tests. RESULTS 732,555 melanoma patients were included (717,408 no IT, 4,585 dual-IT, 4,101 single-IT). Mean ages at MBM diagnosis were 66.9, 61.5, and 63.2 years, respectively. MBM prevalence was 1.5%, 9.6%, and 15.6%, for the respective cohorts (p < 0.0001). Dual-IT was associated with a lower rate of MBM compared to single-IT (OR [95%CI], 0.64 [0.61-0.77]). After propensity score matching for age, sex, and comorbidities, median OS were not statistically different between the no-IT, dual-IT, and single-IT cohorts (347, 400, 414 days) for MBM patients. CONCLUSION This analysis of real-world data suggests that dual-IT for malignant melanomas decreased the incidence of MBMs compared to single-IT. However, survival outcomes remain comparable once patients succumb to the MBM diagnosis. Prospective studies are underway to look at MBM prevalence given various dual-IT.