Two early-phase studies and a retrospective analysis presented at the Society for Neuro-Oncology annual meeting highlight potential advances in treating brain metastases, glioblastoma, and leptomeningeal disease. The research focuses on novel approaches including targeted PI3K inhibition, tumor treating fields, and proton irradiation.
Paxalisib Shows Promise in PI3K-Mutant Brain Metastases
A phase I study indicated that the PI3K inhibitor paxalisib, combined with radiation therapy (RT), demonstrated early promise in patients with PI3K-mutant brain metastases. The study found that eight of 12 evaluable patients (66%) experienced intracranial responses (all partial) to the combination of paxalisib and RT. The results suggest a synergistic effect between targeted PI3K inhibition and brain RT in tumors that are often resistant to radiation.
"Concurrent daily administration of paxalisib with brain radiotherapy is safe and well tolerated at a maximum dose of 45 mg per day in advanced solid-tumor patients with brain metastases and PI3K pathway mutations," said Brandon Imber, MD, of Memorial Sloan Kettering Cancer Center. The study enrolled 21 patients, with 17 evaluable for safety and 12 treated at the maximum tolerated dose (MTD) of 45 mg/day. Two patients experienced dose-limiting toxicities at the 60-mg dose. Adverse events were mostly grade 1 or 2, with two patients experiencing grade 3 hyperglycemia and nausea. The study was supported by Kazia Therapeutics.
TTFields Improve Outcomes in Glioblastoma
Another study revealed that adding tumor treating fields (TTFields) to radiation and temozolomide significantly slowed glioblastoma progression and was associated with an almost 9-month improvement in median survival. The randomized trial showed that median progression-free survival (PFS) improved from 5.6 months with radiation and temozolomide alone to 9.9 months with the addition of TTFields (P = 0.049), representing a 47% reduction in the hazard for disease progression or death. Median overall survival (OS) also increased from 17 months to 25.9 months with TTFields, though this difference was not statistically significant (P = 0.515).
Rachel Grossman, MD, of Rambam Health Care Campus in Haifa, Israel, noted, "This study demonstrated promising initial outcomes for TTFields therapy as first-line treatment concomitant with chemoradiation." The study involved 46 patients with newly diagnosed glioblastoma. The addition of TTFields resulted in a 1-year PFS rate of 36% versus 19% for the control group (P = 0.1) and 2-year PFS rates of 21% and 5% (P = 0.07). Patients with at least 75% usage of TTFields had a 2-year OS of 78% versus 34% for the control arm (P = 0.01). The TTFields study was supported by Novocure.
Proton Irradiation for Leptomeningeal Disease
A retrospective analysis explored the role of proton craniospinal irradiation (CSI) for leptomeningeal metastases. The analysis of 45 patients who completed proton CSI showed a median OS of 13.7 months and a median PFS of 6.5 months. Patients with breast and lung cancer metastases drove the overall results, while those with other types of leptomeningeal metastases had a median OS of 3.9 months. Toxicity was predominantly grade 1/2, with the most common radiation-related side effects being nausea (76%), headache (51%), and fatigue (31%).
Keng Lam, MD, of City of Hope, stated that further study is needed to determine the optimal candidates and sequencing for proton craniospinal irradiation and the choice of sequential therapies. The most common primary tumor sites in the analysis were breast (53%) and lung (20%). About half the patients had active metastasis at diagnosis, and 80% were symptomatic, most commonly with headache (31%), cranial neuropathy (31%), and limb weakness/numbness (16%).
