Early Promise for PI3K Inhibitor in Brain Metastases

HOUSTON — Two-thirds of patients with PI3K-mutant brain metastases responded to the maximum tolerated dose (MTD) of the small-molecule inhibitor paxalisib plus radiation therapy (RT), a small phase I study showed.

Eight of 12 evaluable patients had intracranial responses (all partial) to the dual-modality treatment, supporting the hypothesis that targeted PI3K inhibition has synergy with brain RT in tumors that are often resistant to radiation. The remaining four patients had stable disease, reported Brandon Imber, MD, of Memorial Sloan Kettering Cancer Center in New York City, at the Society for NeuroOncology annual meeting.

“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,” he said. “The results established proof-of-principle for molecularly selected, rational combination studies in radiation oncology to assess safety and ultimately efficacy.”

By way of background, Imber noted that partial or whole-brain RT remains standard of care for brain metastases and leptomeningeal carcinomatosis. PI3K-mutated metastases have an increased likelihood of local failure with RT. He and his colleagues hypothesized that combining paxalisib, a brain-penetrant PI3K/mTOR inhibitor, with RT might improve outcomes in patients with PI3K-mutant brain metastases.

The investigators in this dose-escalation study enrolled a total of 21 patients, 17 of whom were evaluable for safety and 12 treated with the MTD of 45 mg/day. Two of the 17 patients had dose-limiting toxicities at the 60-mg dose of paxalisib. Overall, five patients had grade 1 adverse events, four had grade 2 events, and two had grade 3 events (hyperglycemia and nausea).

Imber said future studies should include validation of circulating tumor DNA for patient enrollment and post-treatment monitoring, a longer duration of PI3K inhibition, and the evaluation of neoadjuvant, adjuvant, and maintenance therapy, including use of complementary systemic agents.

Promising Results With TTFields in Glioblastoma

Glioblastoma progression slowed substantially with the addition of tumor treating fields (TTFields) to radiation and temozolomide, and TTFields was associated with a median survival improvement of almost 9 months, a randomized trial showed.

Median progression-free survival (PFS) improved significantly, from 5.6 months with radiation and temozolomide to 9.9 months with the addition of TTFields, representing a 47% reduction in the hazard for disease progression or death with the electric-field therapy (P=0.049). Median overall survival (OS) numerically increased from 17 months to 25.9 months when patients received TTFields plus standard treatment (P=0.515).

“This study demonstrated promising initial outcomes for TTFields therapy as first-line treatment concomitant with chemoradiation,” said Rachel Grossman, MD, of Rambam Health Care Campus in Haifa, Israel. “The ongoing phase III TRIDENT trial will provide more robust information about the effects of TTFields therapy when provided with chemoradiation.”

TTFields therapy employs low-energy electrical fields to produce an anti-mitotic effect in cancer cells. The currently available devices have approved indications in glioblastoma, mesothelioma, and non-small cell lung cancer.

Grossman reported findings from a randomized trial comparing temozolomide and RT with or without TTFields in patients with newly diagnosed glioblastoma. The primary endpoint was 12-month PFS, and secondary endpoints included OS and median PFS. The study involved 46 patients who had a median age of 62.

The addition of TTFields to upfront therapy 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).

Median OS favored the TTFields group, but the difference was not significant (HR 0.80, 95% CI 0.413-1.558). Patients who had at least 75% usage of TTFields had a 2-year OS of 78% versus 34% for the control arm (P=0.01).

Adverse events were primarily dermatologic, consistent with previous experience with the transdermally administered therapy.

Proton Irradiation for Leptomeningeal Disease

The potential role of proton craniospinal irradiation (CSI) for leptomeningeal metastases continues to evolve, a small retrospective analysis suggested.

Patients who received the treatment had a median OS of 13.7 months and a median PFS of 6.5 months. The overall results were driven by those in breast and lung cancer metastases, as patients with other types of leptomeningeal metastases had a median OS of 3.9 months, reported Keng Lam, MD, of City of Hope in Duarte, California.

The results were consistent with those of a small randomized phase II study that showed a median OS of 9.9 months and median PFS of 7.5 months in patients with leptomeningeal metastases treated with proton CSI. The outcomes were significantly better than results with standard photon involved-field radiotherapy.

“Further study is indicated to determine the optimal candidates for photon craniospinal irradiation, sequencing of photon craniospinal irradiation, and choice of sequential therapies,” said Lam, who was at the University of Texas MD Anderson Cancer Center in Houston during the study period (December 2020 to January 2024).

The retrospective analysis included 45 patients who completed proton CSI for leptomeningeal disease confirmed by imaging and/or cerebrospinal fluid cytology. The most common primary tumor sites were breast (53%) and lung (20%). About half the patients had active metastasis at diagnosis, and 80% were symptomatic, most commonly headache (31%), cranial neuropathy (31%), and limb weakness/numbness (16%).

Toxicity was predominantly grade 1/2, said Lam. The most common radiation-related side effects were nausea (76%), headache (51%), and fatigue (31%).

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