CTIM-11. LASER INTERSTITIAL THERMAL THERAPY PLUS PEMBROLIZUMAB PROLONGS SURVIVAL AND ELICITS ROBUST ANTI-TUMOR IMMUNITY IN RECURRENT, REFRACTORY HIGH-GRADE ASTROCYTOMA: A PHASE 1/RANDOMIZED PHASE 2B TRIAL

Abstract Immune checkpoint inhibitors (ICIs) have limited benefit in recurrent high-grade astrocytoma (rHGA), largely because the blood–brain barrier and a profoundly immunosuppressive tumor microenvironment prevent T cells from infiltrating. Laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive procedure that can “heat up” these otherwise “cold” tumors and sensitize them to ICIs. In this tri-institutional Phase 1/randomized Phase 2 trial (NCT02311582), bevacizumab- and immunotherapy-naïve rHGA patients were initially randomized 1:1 to either LITT followed by pembrolizumab (LITT+PEM) or non-LITT surgery (biopsy or resection) followed by pembrolizumab (NLS+PEM). Phase 2 participants enrolled at a second recurrence—with several already at a third recurrence—underscoring the advanced disease stage of this cohort. After 21 patients, randomization was halted when contemporaneous evidence showed limited benefit from adjuvant ICIs alone, and the remaining 24 patients received only LITT+PEM. In the 21-patient intent-to-treat cohort, LITT+PEM extended median OS to 21.3 months with 54% alive at 18 months (OS18) versus 6.7 months with 12.5% OS18 with NLS+PEM (HR 0.29; 95% CI, 0.01–0.88; p=0.021). Median PFS was 7.8 versus 2.2 months (HR 0.3; 95% CI, 0.10–0.87; p=0.020). Among 39 per-protocol patients, LITT+PEM yielded a median OS of 11.8 months with 42% OS18 versus 5.2 months with 0% OS18 for NLS+PEM (HR 0.17; 95% CI, 0.06–0.49; p=0.0002), and a median PFS of 4.5 versus 1.6 months (HR 0.21; 95% CI, 0.08–0.56; p=0.0006). The combination was well tolerated. Immune profiling revealed that LITT triggers early activation of non-classical monocytes—a change associated with improved survival—while subsequent pembrolizumab unleashes robust CD8⁺ T cell proliferation and clonal expansion. Long-term LITT+PEM survivors developed coordinated memory T-cell responses, whereas shorter-surviving patients exhibited stagnant memory pools and exhausted phenotypes. Together, these results demonstrate that LITT plus pembrolizumab is safe, overcomes rHGA’s immunosuppressive barrier, and mobilizes robust anti-tumor immunity.