A multicenter, randomized, controlled, pivotal trial of microbubble-enhanced transcranial focused ultrasound for patients with NSCLC brain metastases (LIMITLESS).
Background: The efficacy of systemic therapies for brain metastases (BM) is hindered by the blood-brain barrier (BBB) and brain-tumor barrier. Transcranial low-intensity focused ultrasound combined with IV microbubble oscillators (MB-FUS), allows for localized, controlled, non-invasive and temporary BBB opening, which has been shown to enhance tumor drug delivery of systemic therapies, as well as impro efficacy of immunotherapies. Non-small cell lung cancer (NSCLC) is the most common cause of BM, and this randomized controlled trial (RCT) aims to evaluate the safety and efficacy of MB-FUS-mediated BBB opening combined with standard of care (SOC) systemic therapy versus systemic therapy alone for patients with NSCLC BM. Methods: LIMITLESS is prospective, multicenter, parallel-arm, RCT, ongoing at up to 30 centers, that randomizes patients with NSCLC BM, in a 2:1 ratio to either: (i) Arm 1: MR-guided MB-FUS plus all FDA approved on-label use of immune checkpoint inhibitors (ICIs) with or without chemotherapy regimen (SOC systemic therapy), or (ii) Arm 2: SOC systemic therapy alone. Included patients are ≥18 years aged, with normal organ function, KPS ≥70, and have ≥0.5 cm size 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 MB-FUS. Patients undergo pre-treatment brain MRI, followed by IV administration of microbubbles for enhanced sonication effects. BBB opening is performed using a transcranial 220 kHz device with 1024-element phased array transducer with real-time acoustic feedback-based power control for maintaining effective microbubble activation. 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 MB-FUS arm versus 30% in the control arm for a total sample size of N = 96, 64 participants in MB-FUS and 32 in 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 MB-FUS 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. Patient enrollment commenced in 2022 and is ongoing (ClinicalTrials.Gov Registration: NCT05317858).
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Author Details
Manmeet Ahluwalia
Miami Cancer Institute, Baptist Health South Florida, Miami, FL
Abstract Details
Meeting
2025 ASCO Annual Meeting
Session Type
Poster Session
Session Title
Central Nervous System Tumors
Track
Central Nervous System Tumors
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