Preliminary results from a study on recurrent/progressive high-grade meningioma indicate that the CDK4/6 inhibitor abemaciclib (Verzenio) significantly improved progression-free survival at 6 months (PFS6) compared to historical outcomes. However, a separate trial combining abemaciclib with the investigational ERK1/2 inhibitor LY3214996 yielded less favorable results in recurrent glioblastoma.
Abemaciclib Monotherapy in Meningioma
The initial analysis of 24 evaluable patients with recurrent/progressive high-grade meningioma treated with abemaciclib showed a PFS6 of 54%, compared to a historical rate of 15%. Expanding the analysis to 35 evaluable patients, the PFS6 was 49%. While no objective responses were observed, two-thirds of patients experienced stable disease.
According to Dr. Priscilla Brastianos of Massachusetts General Hospital in Boston, biomarker analyses revealed that 14 of 24 patients with NF2 alterations met the PFS6 objective, compared to one of four patients with CDK variants and two of seven with both types of alterations. (P =0.036)
"Abemaciclib had excellent tolerability and resulted in an improved PFS6 rate compared to historical controls in patients with recurrent or progressive high-grade meningiomas harboring NF2 or CDK pathway alterations," Brastianos stated. She added that abemaciclib merits further evaluation in patients with recurrent or progressive meningiomas, with ongoing accrual in a study arm evaluating abemaciclib for meningiomas with AKT alterations.
The rationale for using a CDK4/6 inhibitor in meningiomas stems from the frequent loss of NF2 and CDKN2A/B in high-grade meningiomas, which is associated with disease progression. Previous research has suggested the potential of CDK4/6 inhibitors in this setting.
The study involved 36 patients (35 evaluable) with heavily pretreated recurrent glioblastoma and genetic alterations that could be targeted by the CDK4/6 inhibitor. The trial was designed to detect a PFS6 ≥41.5%. Results indicated that 14 of the 24 patients met the primary endpoint (95% CI 33-75%). The 35 evaluable patients had a median PFS of 7.6 months and an estimated 6-month overall survival of 88%.
Among all 36 patients, grade 3 adverse events (AEs) occurred in eight patients and grade 4 AEs in two. The most common grade 3 AEs were anemia, neutropenia, fatigue, and diarrhea (two patients each). The grade 4 AEs included elevated liver function tests and vomiting.
Abemaciclib and ERK Inhibitor Combination in Glioblastoma
A separate study presented at SNO explored the combination of abemaciclib and the investigational ERK1/2 inhibitor LY3214996 in recurrent glioblastoma. This phase 0/II trial involved 42 patients with >30% ERK expression and CDKN2A/B deletion. The combination resulted in a median PFS of 2.7 months and a median overall survival (OS) of 7.2 months.
To qualify for phase II, patients needed to meet prespecified pharmacokinetic/pharmacodynamic thresholds and have gadolinium (Gd) non-enhancing tumor with evidence of pharmacokinetic response to both abemaciclib and LY3214996. Only nine of 40 evaluable patients exceeded the pharmacokinetic thresholds for phase II. Abemaciclib achieved pharmacologically relevant concentrations in Gd non-enhancing tumor tissue in seven patients, while LY3214966 achieved the concentrations in three patients.
Dr. Shwetal Mehta of the Ivy Brain Tumor Center in Phoenix concluded that "Inadequate CNS penetration and tumor pharmacodynamic modulation by LY3214996 contributed to the unremarkable clinical efficacy profile of this drug combination." Mehta emphasized that "Targeted ERK inhibition remains an unmet need in experimental glioblastoma therapy."
