P07.13.B A RANDOMIZED STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION FOR BRAIN METASTASIS FROM NON-SMALL CELL LUNG CANCER (LIMITLESS)

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2023-09, Vol.25 (Supplement_2), p.ii54-ii54
• Main Authors: Ahluwalia, M S, McDermott, M, Ozair, A, Khosla, A A, Sahgal, A, Mishra, M, Achrol, A, Woodworth, G, Lipsman, N
• Format: Article
• Language: English
• Subjects: POSTER PRESENTATIONS
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noad137.173

Abstract BACKGROUND The blood-brain barrier (BBB) limits the efficacy of systemic therapies for brain metastases (BM), for which non-small cell lung cancer (NSCLC) is the most common etiology. BBB disruption (BBBD) has been demonstrated, in preclinical models, to improve systemic drug delivery for BM. Low-intensity focused ultrasound (LIFU) results in non-invasive BBBD synergistically with intravenously (IV) administered microbubble oscillators. This randomized controlled trial (RCT) aims to determine the safety and efficacy of LIFU-mediated BBBD for NSCLC BM with immunotherapy. 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 2:1 ratio. Included patients have age ≥18 years, normal organ function, Karnofsky Performance Status ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting measurable disease criteria as per response assessment in neuro-oncology for BM (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). These patients undergo pre-treatment MRI brain, followed by IV administration of oscillating microbubbles for enhanced sonication. MR-guided BBBD is then performed using a 220 kHz LIFU device with real-time acoustic feedback for maintaining effective cavitation. Pembrolizumab is infused immediately thereafter, and a repeat MRI is done 24-48 hours later to confirm the closure of BBB each cycle. The primary study endpoint 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 subjects 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 subjects; 246 in the LIFU arm and 123 in the control arm. The secondary outcomes are the best objective response rate and median time-to-response per treatment arm. The exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life. RESULTS