Background: Glioblastoma is the most common brain tumor accounting for 46.1% of all malignant brain tumors. Despite decades of research into its treatment, prognosis remains poor. A median overall survival (OS) of only 12-14 months indicates unmet need. We reviewed published literature to assess the clinical performance of various interventions in newly diagnosed GBM by MGMT methylation status. Methods: An SLR was conducted from database inception through October 29, 2018, in accordance with PRISMA guidelines. Embase, PubMed, and Cochrane Library were searched to identify studies evaluating newly diagnosed adult patients with GBM, and reporting data with consideration to MGMT methylation status. Outcomes of interest included OS, progression-free survival (PFS), response rates (RR) and safety. Conference proceedings from ASCO, ESMO, AANS, SNO, EANO and ISPOR were hand-searched (last 3 years). Results: A total of 19357 Abstracts and 4330 full-texts were screened. We identified 31 randomized controlled trials (RCTs) evaluating 1L therapies in patients with MGMT methylated (n=3), unmethylated (n=7), and mixed methylation status GBM with subgroup analysis (n=21) for both populations of interest. The methylation detection assays and cutoff points varied in trials. Of the 31 RCTs (n=9407 patients; range n=13-694), median OS ranged between 13.5 and 33.8 months in MGMT methylated and 10.0-15.4 months in unmethylated patients with combined radiotherapy/temozolomide (RT/TMZ). An incremental OS benefit was observed upon the addition of lomustine (median: 37.9 months) and losartan (27.8 months) to RT/TMZ in MGMT methylated patients. Treatment with tumor treating fields plus TMZ demonstrated a significant increase in OS, both in methylated (31.6 months) and unmethylated (16.9 months) patients versus TMZ alone. The addition of cilengitide to RT/TMZ showed a prolonged OS benefit (16.3 months) in MGMT unmethylated patients. Median PFS ranged between 6.5 and 10.3 months and 4.8-6.0 months for RT/TMZ in MGMT methylated and unmethylated patients, respectively. The SLR identified limited studies on RR (n=2) and safety (n=8) outcomes. Conclusions: Across the varied set of treatments evaluated, the median OS ranged from 7.7 to 37.9 months and 3.7-20.0 months in methylated and unmethylated patients, respectively. Although the introduction of limited treatments achieved some improvement, there still remains a continued need for effective, novel therapies to help improve outcomes.