Phase 1b Study of Neoadjuvant Anti-PD-1 Immunotherapy and Stereotactic Radiation in Recurrent Glioblastoma: Feasibility and Preliminary Survival Outcomes

Introduction: Recurrent glioblastoma (rGBM) remains a challenging disease with limited treatment options and poor survival. Neoadjuvant immune checkpoint blockade with anti-PD-1 therapy has demonstrated increased anti-tumor immune response and potentially improved survival. Stereotactic Radiation Therapy (SRT) has the potential to work synergistically with anti-PD-1 agents. This phase 1b study evaluates the feasibility and safety of neoadjuvant pembrolizumab and SRT in patients with rGBM who are planning to undergo surgical resection.

Methods: Six patients with rGBM were enrolled in this phase 1b/II prospective, single-arm trial. Treatment included neoadjuvant pembrolizumab (400 mg, Day 0), SRT on Day 7 (8GyX3), and surgical resection within 10–28 days. Patients then received adjuvant pembrolizumab (400 mg every 6 weeks) until disease progression or toxicity. Feasibility was assessed by the proportion of patients undergoing surgery within 28 days of PD-1 inhibitor administration. Safety was evaluated by treatment-related adverse events (AEs) per CTCAE v5.0. The trial would halt if Grade ≥3 AEs exceeded 40% or >30% of surgeries were delayed. Future analyses will explore tumor heterogeneity, immune response, and treatment resistance via single-cell sequencing, flow cytometry, and ELISA assays.

Results: Five patients exhibited Grade 1–2 AEs, while one patient experienced a Grade 3 AE; no Grade 4 or 5 events occurred. The most frequent AEs were fatigue (n=4), headache (n=3), nausea (n=2), and rash (n=2). The Grade 3 AE was vasogenic edema requiring admission, likely related to disease progression but categorized as possibly related to pembrolizumab. The median OS was 7.6 months (range:0.34–19.6 months), and the median PFS was 2.7 months (range:0.5–4.9 months). At the end of the Phase 1b, stopping criteria were not met, and the trial has since proceeded to Phase II and is currently accruing patients.

Conclusion : Neoadjuvant anti-PD-1 therapy combined with SRT appears to be safe and feasible in patients with rGBM.