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)

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2024-10, Vol.26 (Supplement_5), p.v76-v77
• Main 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
• Format: Article
• Language: English
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noae144.253

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)