TY - JOUR
T1 - Laser interstitial thermal therapy and adjuvant pembrolizumab in recurrent high-grade astrocytoma
T2 - a Phase 1/randomized Phase 2b trial
AU - Campian, Jian L.
AU - Le, Son B.
AU - Ghiaseddin, Ashley
AU - Butt, Omar H.
AU - Manektalia, Harshit
AU - Chen, Dongjiang
AU - Xu, Yifei
AU - Liu, Jingxia
AU - Rahman, Maryam
AU - Thai, Nathan
AU - Leidig, William A.
AU - Johanns, Tanner
AU - Ansstas, George
AU - Zhou, Alice Y.
AU - Pugazenthi, Sangami
AU - Dunn, Gavin P.
AU - Huang, Jiayi
AU - Chheda, Milan G.
AU - Kim, Albert H.
AU - Leuthardt, Eric C.
AU - Tran, David D.
N1 - Publisher Copyright:
© The Author(s) 2026.
PY - 2026/12
Y1 - 2026/12
N2 - Immune checkpoint inhibitors (ICIs) show minimal efficacy in recurrent high-grade astrocytoma (rHGA). Laser interstitial thermal therapy (LITT), a minimally invasive cytoreductive approach, may prime rHGA for ICI response. A phase 1/randomized phase 2b trial (ClinicalTrials.gov: NCT02311582) was designed to test pembrolizumab in combination with LITT in patients with rHGA. Nine patients were enrolled in the phase I dose-escalation lead-in study. No dose-limiting toxicities were observed and 200 mg of pembrolizumab every three weeks was determined as the recommended phase 2 dose. The phase 2b study was initially designed to randomize (up to 45) patients 1:1 to either LITT followed by pembrolizumab (LITT + PEM) or non-LITT surgery followed by pembrolizumab (NLS + PEM). Phase 2’s primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), safety, and immune signature. After 21 patients, based on an independent Data and Safety Monitoring Committee request of unscheduled interim review of accumulating efficacy data, randomization stopped as benefit from NLS + PEM appeared limited, and the subsequent 24 patients received LITT + PEM. The pre-specified study endpoints were achieved. Among 39 per-protocol patients, LITT + PEM (n = 33) improved median OS (11.8 versus 5.2 months) and 18-month survival (42% versus 0%) compared to NLS + PEM (n = 6) (hazard ratio [HR] 0.17; 95% confidence interval [CI], 0.06–0.49; P = 0.0002). Median PFS was longer in LITT + PEM (4.5 versus 1.6 months; HR 0.21; 95% CI, 0.08–0.56; P = 0.0006). In an intent-to-treat sensitivity analysis (n = 21), OS (HR 0.29; 95% CI, 0.10–0.88) and PFS (HR 0.30; 95% CI, 0.10–0.87) again favored LITT + PEM (n = 13). Treatment was well tolerated. LITT activated non-classical monocytes, and pembrolizumab unleashed CD8⁺ T cell proliferation, clonal expansion, and coordinated memory T-cell responses. Overall, LITT + PEM is safe and may overcome rHGA immunosuppression to generate antitumor immunity.
AB - Immune checkpoint inhibitors (ICIs) show minimal efficacy in recurrent high-grade astrocytoma (rHGA). Laser interstitial thermal therapy (LITT), a minimally invasive cytoreductive approach, may prime rHGA for ICI response. A phase 1/randomized phase 2b trial (ClinicalTrials.gov: NCT02311582) was designed to test pembrolizumab in combination with LITT in patients with rHGA. Nine patients were enrolled in the phase I dose-escalation lead-in study. No dose-limiting toxicities were observed and 200 mg of pembrolizumab every three weeks was determined as the recommended phase 2 dose. The phase 2b study was initially designed to randomize (up to 45) patients 1:1 to either LITT followed by pembrolizumab (LITT + PEM) or non-LITT surgery followed by pembrolizumab (NLS + PEM). Phase 2’s primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), safety, and immune signature. After 21 patients, based on an independent Data and Safety Monitoring Committee request of unscheduled interim review of accumulating efficacy data, randomization stopped as benefit from NLS + PEM appeared limited, and the subsequent 24 patients received LITT + PEM. The pre-specified study endpoints were achieved. Among 39 per-protocol patients, LITT + PEM (n = 33) improved median OS (11.8 versus 5.2 months) and 18-month survival (42% versus 0%) compared to NLS + PEM (n = 6) (hazard ratio [HR] 0.17; 95% confidence interval [CI], 0.06–0.49; P = 0.0002). Median PFS was longer in LITT + PEM (4.5 versus 1.6 months; HR 0.21; 95% CI, 0.08–0.56; P = 0.0006). In an intent-to-treat sensitivity analysis (n = 21), OS (HR 0.29; 95% CI, 0.10–0.88) and PFS (HR 0.30; 95% CI, 0.10–0.87) again favored LITT + PEM (n = 13). Treatment was well tolerated. LITT activated non-classical monocytes, and pembrolizumab unleashed CD8⁺ T cell proliferation, clonal expansion, and coordinated memory T-cell responses. Overall, LITT + PEM is safe and may overcome rHGA immunosuppression to generate antitumor immunity.
UR - https://www.scopus.com/pages/publications/105031479452
U2 - 10.1038/s41467-026-69522-w
DO - 10.1038/s41467-026-69522-w
M3 - Article
C2 - 41748622
AN - SCOPUS:105031479452
SN - 2041-1723
VL - 17
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1763
ER -