Abstract CT230: Exploratory analyses of MGMT promoter methylation and PD-L1 expression from newly diagnosed glioblastoma patients in CheckMate 548 study suggest refinement in thresholds for predicting response to standard of care and nivolumab treatments
Authors: Hung Yu-Han , Chhibber Aparna , Lim Michael , Weller Michael , Reardon David A. , Omuro Antonio , Ligon Keith L. , Lako Ana , Forslund Ann 
Published: April 2024

CheckMate 548 (NCT02667587, CM548) is a phase III, randomized trial evaluating first line nivolumab (NIVO) in combination with standard of care (SOC) [surgical resection followed by radiotherapy and temozolomide (TMZ)] versus placebo plus SOC in patients with newly diagnosed glioblastoma (GBM) positive for promoter methylation of O6-methylguanine DNA methyltransferase (MGMT). MGMT promoter methylation status and PD-L1 expression predict better outcomes in GBM patients treated with TMZ and in patients treated with NIVO in other indications, respectively. However, the impact of varying levels of MGMT promoter methylation and PD-L1 expression on patient outcome in GBM remains unclear. In CM548, MGMT promoter methylation levels were quantified through a central lab assay (LapCorp) and PD-L1 expression was determined by percentage of detectable membrane staining of tumor cells. MGMT methylation and PD-L1 data were prospectively generated at the time of enrolment. Our analyses showed that increasing levels of MGMT promoter methylation level were associated with longer overall survival in patients treated with SOC alone (n = 349). However, no survival benefit was observed with increasing levels of MGMT methylation in patients treated with NIVO in combination with SOC (n = 353). In addition, our data showed a non-linear relationship between PD-L1 expression and overall survival across both arms. In patients with intermediate PD-L1 expression (≥5%, &lt;20%), longer survival was observed in the nivolumab + SOC arm compared to SOC alone. This benefit was not observed in patients with low (≥1%, &lt;5%) and high (&gt;20%) PD-L1 expression. Potential mechanisms driving these observed associations are currently explored using genomic data generated from patient samples. MGMT promoter methylation and PD-L1 expression are potential clinically relevant predictive biomarkers of response to treatments administered in the CM-548; however, the binary classification of positive/negative status of these markers does not fully capture their relationship with efficacy in CM548. Data generated from our exploratory analyses suggests that new, refined criteria are needed for better patient outcomes prediction.

Citation Format: Yu-Han Hung, Aparna Chhibber, Michael Lim, Michael Weller, David A. Reardon, Antonio Omuro, Keith L. Ligon, Ana Lako, Ann Forslund. Exploratory analyses of MGMT promoter methylation and PD-L1 expression from newly diagnosed glioblastoma patients in CheckMate 548 study suggest refinement in thresholds for predicting response to standard of care and nivolumab treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT230.