At the (ASCO) 2023 conference, Dr. Manmeet Singh Ahluwalla discussed, researchers presented the final trial report on a phase 1 study called EQUILIBRIUM. The study investigated the combination of a BTK inhibitor called Ibrutinib, along with Temozolomide and radiation therapy, in patients with newly diagnosed glioblastoma tumors.
Glioblastoma is a type of brain tumor that has historically had poor prognosis, with patients typically surviving only 14 to 16 months on average, despite advancements in surgery, radiation, and medical therapy. The use of Temozolomide has shown limited benefits in patients with an unmethylated MGMT phenotype, which led to a shift in recent years when Temozolomide was omitted in upfront treatments for these patients.
In the EQUILIBRIUM trial, two treatment arms were designed. Patients with unmethylated MGMT glioblastoma received Ibrutinib in combination with radiation alone, while those with methylated MGMT glioblastoma received Ibrutinib with radiation and Temozolomide, considering the latter’s six-month benefit in these patients.
The trial revealed that Ibrutinib with radiation alone was associated with significant toxicity at both dose levels of 20 milligrams and 280 milligrams. However, when Ibrutinib was combined with radiation and Temozolomide at a dose of 420 milligrams, it was found to be safe, alongside standard doses of Temozolomide (75 milligrams per square meter) and radiation, for patients with unmethylated MGMT glioblastoma.
Moreover, the study demonstrated promising outcomes for patients with unmethylated MGMT glioblastoma who received Ibrutinib, radiation, and Temozolomide, with a median survival of 26 months. This result appears to be an improvement compared to the traditional benchmarks of 18 to 20 months seen in patients with unmethylated MGMT glioblastoma.
Based on these findings, discussions are underway with the pharmaceutical company to initiate a phase 2 trial. The proposed trial would evaluate the combination of Ibrutinib, Temozolomide (at standard doses of 75 milligrams per square meter daily for 6 weeks), and radiation (at standard doses) using a dose level of 420 milligrams of Ibrutinib. This novel therapeutic approach holds promise for patients with glioblastoma.
Additionally, the trial showed that patients with EGFR alterations had even better outcomes. Preclinical evidence suggests that Ibrutinib may be particularly beneficial for patients with EGFR alterations. In this subgroup, the median survival reached approximately 28 months, surpassing the 26-month survival observed in the entire cohort.
In conclusion, the EQUILIBRIUM trial presented encouraging results for the treatment of glioblastoma. The study’s findings support the initiation of a phase 2 trial to further investigate the combination therapy of Ibrutinib, Temozolomide, and radiation, potentially offering a novel therapeutic option for patients with this devastating disease. The trial also highlighted the potential benefit of Ibrutinib in patients with EGFR alterations.