Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study

Abstract

Background Radiotherapy may synergize with programmed death 1 (PD-1)/PD-1 ligand (PD-L1) blockade. The purpose of this study was to determine the recommended Phase II dose, safety/tolerability, and preliminary efficacy of combining pembrolizumab, an anti-PD-1 monoclonal antibody, with hypofractionated stereotactic irradiation (HFSRT) and bevacizumab in patients with recurrent high grade gliomas (HGGs). Methods Eligible subjects with recurrent glioblastoma or anaplastic astrocytoma were treated with pembrolizumab (100 or 200 mg based on dose level Q3W) concurrently with HFSRT (30 Gy in 5 fractions) and bevacizumab 10 mg/kg Q2W. Results Thirty two patients were enrolled (bevacizumab naïve, n = 24; bevacizumab resistant, n = 8). The most common treatment-related adverse events (TRAEs) were proteinuria (40.6%), fatigue (25%), increased alanine aminotransferase (25%), and hypertension (25%). TRAEs leading to discontinuation occurred in 1 patient who experienced a grade 3 elevation of aspartate aminotransferase. In the bevacizumab naïve cohort, twenty patients (83%) had a complete response (CR) or partial response (PR). The median overall survival (OS) and progression-free survival (PFS) were 13.45 months (95% CI: 9.46-18.46) and 7.92 months (95% CI: 6.31-12.45), respectively. In the bevacizumab resistant cohort, PR was achieved in 5 patients (62%). Median OS was 9.3 months (95% CI: 8.97-18.86) with a median PFS of 6.54 months (95% CI: 5.95-18.86). The majority of patients (20/26 pts; 77%) had tumor-cell/tumor-microenvironment PD-L1 expression <1%. Conclusions The combination of HFSRT with pembrolizumab and bevacizumab in patients with recurrent HGG is generally safe and well tolerated. These findings merit further investigation of HFSRT with immunotherapy in HGGs.

Checkpoint Inhibitors as High-Grade Gliomas Treatment: State of the Art and Future Perspectives

“…Treatment was well tolerated, with only one discontinuation due to grade 3 transaminases elevation. ORR in the bevacizumab naïve and bevacizumab resistant cohorts was 83% and 62.5%, respectively [ 40 ]. Median PFS was 7.92 and 6.54 months, and median OS was 13.45 and 9.3 months in bevacizumab naïve and bevacizumab resistant patients, respectively [ 40 ].…”

“…ORR in the bevacizumab naïve and bevacizumab resistant cohorts was 83% and 62.5%, respectively [ 40 ]. Median PFS was 7.92 and 6.54 months, and median OS was 13.45 and 9.3 months in bevacizumab naïve and bevacizumab resistant patients, respectively [ 40 ]. In a phase I/II clinical trial evaluating the combination of HFSRT with durvalumab for recurrent GBM (NCT02866747), one dose-limiting-toxicity (DLT) was reported among six patients (grade 3 immune-related vestibular neuritis).…”

Intermittent radiotherapy as alternative treatment for recurrent high grade glioma: A modelling study based on longitudinal tumor measurements

“…Patients with recurrent HGG included in this modelling study (n=16) were treated at the Moffitt Cancer Center, FL between August 2015 and March 2018 as part of a phase I clinical trial (NCT02313272, 05/12/2014) 8 . All patients provided written consent and the treatment protocol was approved by the institutional review board (IRB study #: Pro00014674 and # 00000971).…”

“…This study demonstrated safety in terms of adversarial side effects for this particular protocol. Although efficacy was not the primary endpoint, the response results were promising; yet median time to progression remained below one year 8 . In this trial, HFSRT was given in doses with maximum log cell kill intent over one week (consistent with current practice and trials for recurrent HGG re-irradiation studies 9 ).…”

“…Inevitably, HGG tumors develop resistance to these systemic therapies. In our recent phase 1 clinical trial (NCT02313272, 05/12/2014) recurrent HGG patients were treated with a combination of hypofractionated stereotactic radiotherapy (HFSRT; ≥ 6 Gy x 5 fractions), bevacizumab (antibody against vascular endothelial growth factor (VEGF)) and pembrolizumab (anti PD1 antibody) 8 . This study demonstrated safety in terms of adversarial side effects for this particular protocol.…”