# Laser interstitial thermal therapy and adjuvant pembrolizumab in recurrent high-grade astrocytoma: a Phase 1/randomized Phase 2b trial

## TL;DR

Combining laser therapy with pembrolizumab improved survival and immune response in patients with recurrent high-grade brain tumors.

## Contribution

Demonstrated that LITT followed by pembrolizumab is safe and effective in overcoming immunosuppression in rHGA.

## Key findings

- LITT + PEM improved median overall survival to 11.8 months compared to 5.2 months with NLS + PEM.
- Treatment activated immune cells and showed better progression-free survival with LITT + PEM.
- The combination was well tolerated and generated antitumor immunity in rHGA patients.

## Abstract

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.

Immune checkpoint inhibitors (ICIs) have shown limited efficacy in recurrent high-grade astrocytoma (rHGA). Here the authors report the results of a Phase 1/randomized Phase 2b trial of laser interstitial thermal therapy followed by anti-PD1 pembrolizumab in patients with rHGA.