Fadul, Camilo E.

Abstract Patients with brain metastases (BMETS) frequently emphasize the impact on quality of life (QOL) over prolongation of life at the time of making treatment decisions. Thus, it is critical to evaluate patient-reported health utility scores after treatment of BMETS. Stereotactic surgery (SRS) is becoming the most frequent treatment modality. The objective of this study was to determine the changes in the EuroQol- 5 Dimension (EQ-5D) in patients with BMETS treated with SRS. The NPA SRS Registry is a multi-institutional collaboration prospectively collecting information from patients undergoing SRS since 2017. We queried the registry for the results of the baseline and follow-up EQ-5D questionnaire, with a utility index score given based on the patient’s responses for five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The cohort included 522 cases treated with SRS between 2017 and 2023; 264 (47.8%), 197 (35.7%), and 91 (16.5%) had 1, 2-4, and 5-14 metastases, respectively. The mean EQ-5D score at the time of SRS was 0.551 (SD=0.443). At the last follow-up after SRS, 107 (34.0%) patients indicated improvement from their EQ-5D baseline while 51 (16.2%) were stable. The score decreased in 113 patients (35.9%) while 44 (13.9%) showed mixed changes (i.e., domain sub-scores both increased and decreased). For mobility, usual activities, pain/discomfort, and anxiety/depression domains patients experienced similar rates of improvement (21.0%-22.5%). In the self-care domain, 32 (10.2%) patients reported improvement, 232 (73.7%) reported no change and 89 (28.3%) had worsening scores. Our study provided the first longitudinal prospective real-world data using the EQ-5D, a health utility tool, in patients with BMETS treated with SRS. In more than half of the cases, the patients reported improved or stable EQ-5D scores over time after treatment. Factors independent of treatment that may prompt worsening QOL following SRS are being identified and will be presented.

PURPOSE Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

2502 Background: Patients with progressive or recurrent meningiomas have limited treatment options. Clinical trials of systemic therapies for meningiomas have failed to demonstrate benefit. FAK inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically-driven phase II study in recurrent or progressive grade I-III meningiomas. Methods: Eligible patients (pts) whose tumors screened positively for NF2 mutations were treated with GSK2256098 750mg po bid until progressive disease in 2 separate cohorts: grade I or II/III meningiomas. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; per study design, the trial would be declared positive if either endpoint was met. RR was evaluated across the overall cohort; PFS6 was evaluated within each subgroup. Historical benchmark data was obtained from Kaley et al. Neuro Oncol 2014. In the grade I group, 12 evaluable pts provided >79% power to detect a PFS6 rate >65% (vs. null hypothesis of 25%; alpha=0.014). In the grade II/III group, 24 evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha=0.02). The threshold for promising results for PFS6 was: 7+/12(grade I) and 8+/24(grade II/III) pts. For RR, 36 evaluable pts provided >94% power to detect RR >20% (vs. null 2.5%; alpha= 0.012). Results: Of 322 pts screened for all mutation cohorts of the study, 36 eligible and evaluable pts with NF2 mutations were enrolled. Across all grades, one pt had a partial response and 24 had stable disease as best response to treatment. In Grade I pts, the observed PFS6 rate was 83% (10/12 pts; 95% CI: 52-98%). In Grade II/III pts, the observed PFS6 rate was 33% (8/24 pts; 95% CI: 16-55%). The study met PFS6 efficacy endpoint both for the Grade I and the Grade II/III cohorts. Treatment was well tolerated. Only 7 patients had a maximum grade-3 adverse event that was at least possibly related to treatment; toxicities across these pts included: proteinuria (2), rash (1), pain (1), ALT (1), AST (1), cholecystitis (1), hypertriglyceridemia (1), apraxia (1), and lymphopenia (1) with no grade 4 or 5 events. Conclusions: GSK2256098 had excellent tolerability andresulted in an improved PFS6 rate in pts with recurrent or progressive NF2-mutated meningiomas. Trial endpoint was met. FAK inhibition warrants further evaluation in this patient population. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org Clinical trial information: NCT02523014 .