Outcomes for Patients With MGMT Methylated GBM Favorable Over MGMT Unmethylated

Manmeet Ahluwalia, MD, FASCO

The outcomes of patients with newly diagnosed glioblastoma (GBM) treated with ibrutinib (Imbruvica) 420 mg in combination with temozolomide and radiotherapy are promising and compare favorably with historical controls of patients with MGMT methylated tumors.¹

The safety and tolerability of this novel combination was investigated in a nonrandomized, prospective, phase 1 study (EQUILIBRIUM; NCT03535350) of 26 patients with newly diagnosed GBM. Findings from the study were presented by Manmeet Ahluwalia, MD, FASCO, in June 2023 at 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

Multiple cohorts of patients were included in the study. Specifically, 15 patients (58%) had MGMT methylated GBM, and 11 patients (42%) had unmethylated tumors.

Seventeen patients in the study were treated with ibrutinib plus temozolomide and radiotherapy, while 9 were treated with ibrutinib plus radiotherapy alone. For 22 patients in the study, EGFR amplification status was available, and 8 patients (36%) showed EGFR amplification. The EGFR non-amplified cohort included 14 patients.

“What we found out was that ibrutinib with radiation was fairly toxic, which came to us as a huge surprise. But ibrutinib along with temozolomide and radiation was well-tolerated at the 420 mg dose,” said Ahluwalia. “We did see also very promising efficacy, especially in the MGMT methylated glioblastoma cohort.”

Cancer cell: © vitanovski - stock.adobe.com

The median overall survival (OS) observed in the MGMT methylated population was 26.0 months (95% CI, 22.0 to not assessed [NA]). In comparison, among patients with MGMT unmethylated tumors, the median OS observed was 14.0 months (95% CI, 8.54-NA).

Among patients treated with ibrutinib, temozolomide, and radiotherapy, the median OS was 26.0 months (95% CI, 21.8 months to NA) compared with 10.6 months (95% CI, 8.54 months to NA), in the MGMT unmethylated population. Finally, in the EGFR amplified cohort, the median OS was 29.5 months (95% CI, 21.9-NA) vs 21.8 months (95% CI, 16.6 months to NA).

For safety, patients who received ibrutinib with radiotherapy experienced dose-limiting toxicities. The maximum-tolerated dose (MTD) of ibrutinib was determined to be 420 mg daily.

Patients in the EQUILIBRIUM study all had newly diagnosed GBM with a Karnofsky performance score of 70% or higher, and adequate organ function.² Treatment with ibrutinib in the study was approached using a 3+3 design by which dosing starting at 420 mg daily and escalated to 560 mg daily. Ibrutinib could also be deescalated to 280 mg daily.

The primary objective of the study was determining the MTD of ibrutinib in combination with temozolomide 75 mg/m2 and radiotherapy 60 Gy over 6 weeks. The secondary objectives of the study included determining safety, OS, and progression-free survival.

“At the current time, we are investigating further the genomic biomarkers which can help us pick on the patients that derive the highest benefit from combination of ibrutinib along with temozolomide, and radiation in glioblastoma,” said Ahluwalia. “Currently, we are also looking at genomic profiling of all our patients who were treated on the study to see if we can find a biomarker that predicts for benefit with this agent. Based on that, talks are ongoing around whether to launch the next phase of research.”

According to Ahluwalia’s presentation at ASCO, a phase 2 study of ibrutinib used in combination with temozolomide and radiotherapy for the treatment of newly diagnosed GBM is planned.

REFERENCES:

1. Ahluwalia MS, Ozair A, Khosla AA, et al. Phase I study of BTK inhibitor ibrutinib with temozolomide and radiation in newly-diagnosed glioblastoma (EQUILIBRIUM): Final trial report. J Clin Oncol. 2023;41(16).2067. doi:10.1200/JCO.2023.41.16_suppl.2067

2. Ibrutinib with radiation and temozolomide in patients with newly diagnosed glioblastoma. ClinicalTrials.gov. Updated August 21, 2023. Accessed October 6, 2023. https://tinyurl.com/2p9fvr5d