Hit and Miss for CDK4/6 Inhibitor in Recurrent Brain Cancer

HOUSTON — Progression-free survival for 6 months (PFS6) in recurrent/progressive high-grade meningioma improved more than threefold versus historical outcomes in patients who received the CDK4/6 inhibitor abemaciclib (Verzenio), a preliminary study showed.

The first 24 evaluable patients had a PFS6 of 54% as compared with a historical rate of 15%. After enrollment exceeded expectations, analysis of 35 evaluable patients showed a PFS6 of 49%. No objective responses were observed, but two-thirds of patients had stable disease.

Biomarker analyses showed that 14 of 24 patients with NF2 alterations met the PFS6 objective as compared with one of four patients with CDK variants and two of seven with both types of alterations, reported Priscilla Brastianos, MD, of Massachusetts General Hospital in Boston, at the Society for NeuroOncology (SNO) meeting.

“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,” said Brastianos. “Abemaciclib warrants further evaluation in patients with recurrent or progressive meningiomas.”

Accrual is ongoing in a study arm evaluating abemaciclib for meningiomas with AKT alterations, she added.

A second SNO report showed less favorable results when the CDK4/6 inhibitor was paired with an investigational ERK1/2 inhibitor for recurrent glioblastoma. The combination resulted in a median PFS of 2.7 months and median overall survival (OS) of 7.2 months, reported Shwetal Mehta, PhD, of the Ivy Brain Tumor Center in Phoenix.

The rationale for clinical evaluation of a CDK4/6 inhibitor in meningiomas has its origin in the recognition that loss of NF2 and CDKN2A/B are common findings in high-grade meningiomas and are associated with disease progression, Brastianos noted. In a preliminary study of patients with progressive brain metastases and CDK pathway alterations, the CDK4/6 inhibitor palbociclib (Ibrance) extended the PFS in more than half of patients.

The current study involved 36 patients (35 evaluable) with heavily pretreated recurrent glioblastoma and genetic alterations that could be targeted by the CDK4/6 inhibitor. The prespecified primary endpoint was PFS6 in the first 24 evaluable patients.

The trial had statistical power to detect a PFS6 ≥41.5%. The results showed that 14 of the 24 patients met the primary endpoint (95% CI 33-75%). The PFS6 in patients with NF2 alterations had a significantly higher PFS6 as compared with the patients who had CDK alterations or both types of alterations (P=0.036). The 35 evaluable patients had a median PFS of 7.6 months and 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 in two patients each. The grade 4 AEs consisted of elevated liver function tests and vomiting.

The phase 0/II glioblastoma study involved 42 patients with >30% ERK expression and CDKN2A/B deletion. Patients who met prespecified pharmacokinetic/pharmacodynamic thresholds and had gadolinium (Gd) non-enhancing tumor with evidence of pharmacokinetic response (defined by concentration of unbound drug) to both abemaciclib and the ERK inhibitor LY3214996 qualified for phase II.

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 and LY3214966 achieved the concentrations in three patients.

“Inadequate CNS penetration and tumor pharmacodynamic modulation by LY3214996 contributed to the unremarkable clinical efficacy profile of this drug combination,” Mehta stated. “Targeted ERK inhibition remains an unmet need in experimental glioblastoma therapy.”