P14.02.B A MULTICENTER, RANDOMIZED, CONTROLLED TRIAL OF FOCUSED-ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER DISRUPTION PLUS SYSTEMIC PEMBROLIZUMAB FOR PATIENTS WITH NSCLC BRAIN METASTASES (LIMITLESS)
Authors: Ahluwalia M S , Ozair A , Sahni K S , Sanai N , Sahgal A , McDermott M W , Nwaogu K , Dye L , Woodworth G F , Lipsman N 
Published: October 2024

Abstract

BACKGROUND
The efficacy of systemic therapies for brain metastases (BM) is hindered by the blood-brain barrier (BBB), whose disruption is associated with improved systemic drug delivery. Low-intensity focused ultrasound (LIFU), combined with IV microbubble oscillators, leads to non-invasive disruption of BBB. This can potentially enhance intracranial drug delivery of systemically administered immune checkpoint inhibitors like pembrolizumab. Given that non-small lung cancer (NSCLC) remains the most common etiology behind BM, this randomized controlled trial (RCT) aims to evaluate the safety and efficacy of LIFU-mediated BBB disruption combined with systemic pembrolizumab for NSCLC BM.

MATERIAL AND METHODS
LIMITLESS is an ongoing, prospective, multicenter, parallel-arm, open-label RCT that randomizes patients with NSCLC BM on pembrolizumab monotherapy prescribed as per standard-of-care to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in a 2:1 ratio. Included patients have age ≥18 years, normal organ function, KPS ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting measurable disease criteria as per RANO-BM. Patients on both arms receive standard-of-care therapy, while those on arm 1 also undergo LIFU before each dose of pembrolizumab (200 mg IV every 3 weeks). Patients undergo pre-treatment brain MRI, followed by IV administration of microbubbles for enhanced sonication effects. MR-guided BBB disruption is then performed using a transcranial 220 kHz LIFU device with real-time acoustic feedback-based power control for maintaining effective microbubble activation. Pembrolizumab is infused immediately after the sonication, and a repeat MRI is done 24-48 hours later to assessment to treatment effects. The primary study outcome is the overall objective response rate (ORR) at 6 months as assessed using RANO-BM criteria. Using a Bayesian design for power analysis, a superior ORR of 60% is assumed for the LIFU arm versus 30% in the control arm for a total sample size of N = 96, 64 participants in LIFU and 32 in the control arm, for 80% power using a two-sided chi-square test with an alpha of 0.05. For the upper-bound estimate, ORR of 45% in the LIFU arm and 30% in the control arm, the study needs N = 369 participants: 246 in LIFU arm and 123 in control arm. The secondary outcomes are best objective response rate and median time-to-response per treatment arm. Exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life.

RESULTS
Patient enrollment commenced in 2022 and is ongoing.

CONCLUSION
Findings from this trial will be critical to overcoming the historic challenges presented by the BBB to efficacious CNS drug delivery (ClinicalTrials.Gov Registration: NCT05317858).