Tocilizumab, atezolizumab, and stereotactic radiotherapy in recurrent glioblastoma: primary analysis of safety and efficacy of a phase 2 trial, NRG Oncology-BN010.
Abstract
Background
Preclinical data suggest that fractionated stereotactic radiotherapy (FSRT) may sensitize immunologically-cold tumors to immune checkpoint inhibition by stimulating neoantigen release and that inhibition of interleukin-6 (IL-6) permits immunosuppressive tumor-associated macrophages to become immunostimulatory. This study aimed to test the safety and efficacy of the combination of tocilizumab (anti-IL6R), atezolizumab [anti-programmed death-ligand 1 (PD-L1)], and FSRT in patients with recurrent glioblastoma (rGBM).
Methods
A multicenter, single-arm, phase 2 trial was conducted with a safety run-in phase followed by a Simon's two-stage design. Patients received the combination of tocilizumab and atezolizumab administered on 28-day treatment cycles until disease progression, unacceptable toxicity, or for up to 2 years. FSRT (24 Gy in 3 fractions) was initiated 3-7 days following cycle 1 of systemic therapy. The primary endpoint was objective response rate (ORR) by modified Response Assessment in Neuro-Oncology (mRANO) criteria. The window for assessment of the primary endpoint was 6 months from time of enrollment. The two-stage design was used for the primary endpoint analysis to discriminate between true response rates of no more than 10% (null hypothesis) and at least 30% (alternative hypothesis). Secondary endpoints included the rates and severity of adverse events (AEs), progression-free survival (PFS), and overall survival (OS).
Results
Forty-one patients were eligible and evaluable. The safety run-in (n=12) established Dose Level 3 (combination of tocilizumab 8 mg/kg, FSRT, and atezolizumab 1680 mg) as the maximum tolerated dose, which was subsequently evaluated in the Simon's two-stage design (n=29). The study did not meet its primary endpoint (ORR 3.4%, 95% CI: 0.1% - 17.8%). Median PFS was 3.2 months (95% CI: 2.0 - 4.0), and median OS was 10.2 months (95% CI: 6.6 - 13.6).
Conclusions
These findings suggest that the combination of tocilizumab, atezolizumab, and FSRT was safe and well tolerated in patients with rGBM but did not achieve the pre-specified efficacy outcome.