A Comparative Retrospective Study of Immunotherapy RANO Versus Standard RANO Criteria in Glioblastoma Patients Receiving Immune Checkpoint Inhibitor Therapy

Xin Chen,Mary Jane Lim-Fat,Lu Gao,Annie Bryant,David A Reardon,Zaiyi Liu,Angie Li,Camden P Bay,Geoffrey S Young,Lei Qin,J Bryan Iorgulescu,Nityanand Miskin,Xiaoyin Xu

doi:10.3389/fonc.2021.679331

Abstract

ObjectivesReal-time assessment of treatment response in glioblastoma (GBM) patients on immune checkpoint blockade (ICB) remains challenging because inflammatory effects of therapy may mimic progressive disease, and the temporal evolution of these inflammatory findings is poorly understood. We compare GBM patient response during ICB as assessed with the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) and the standard Response Assessment in Neuro-Oncology (RANO) radiological criteria.Methods49 GBM patients (seven newly diagnosed and 42 recurrent) treated with ICBs at a single institution were identified. Tumor burden was quantified on serial MR scans according to RANO criteria during ICB. Radiographic response assessment by iRANO and RANO were compared.Results82% (40/49) of patients received anti–PD-1, 16% (8/49) received anti-PD-L1, and 2% (1/49) received anti-PD-1 and anti-CTLA4 treatment. Change in tumor burden and best overall response ranged from −100 to +557% (median: +48%). 12% (6/49) of patients were classified as concordant non-progressors by both RANO and iRANO (best response: one CR, one PR, and four SD). Another12% (6/49) had discordant assessments: 15% (6/41) of RANO grade progressive disease (PD) patients had iRANO grade of progressive disease unconfirmed (PDU). The final classification of these discordant patients was pseudoprogression (PsP) in three of six, PD in two of six, and PDU in one of six who went off study before the iRANO assessment of PDU. iRANO delayed diagnosis of PD by 42 and 93 days in the two PD patients. 76% (37/49) patients were classified as concordant PD by both RANO and iRANO. 12% (6/49) of all patients were classified as PsP, starting at a median of 12 weeks (range, 4–30 weeks) after ICB initiation.ConclusionsStandard RANO and iRANO have high concordance for assessing PD in patients within 6 months of ICB initiation. iRANO was beneficial in 6% (3/49) cases later proven to be PsP, but delayed confirmation of PD by <3 months in 4% (2/49). PsP occurred in 12% of patients, starting at up to 7 months after initiation of ICB. Further study to define the utility of modified RANO compared with iRANO in ICB GBM patients is needed.

Highlights

Patients with glioblastoma (GBM), the most common primary malignant brain tumor in adults, face a poor prognosis, limited effective treatment options, and early clinical deterioration [1]
We report direct comparison of response assessment in neuro-oncology (RANO) and immunotherapy RANO (iRANO) assessments of immune checkpoint blockade (ICB) response and describe the patterns of response in a retrospective cohort of 49 GBM patients treated with ICB
One patient voluntarily withdrew from the study and was lost to follow-up

Summary

Introduction

Patients with glioblastoma (GBM), the most common primary malignant brain tumor in adults, face a poor prognosis, limited effective treatment options, and early clinical deterioration [1]. Immune checkpoint inhibitors targeting cytotoxic T lymphocyte-4 (CTLA-4; ipilimumab), programmed cell death protein 1 (PD-1; pembrolizumab, nivolumab, and cemiplimab), and programmed cell death ligand (PD-L1; durvalumab, atezolizumab, and avelumab) have obtained approval from the US Food and Drug Administration and become part of the standard of care for melanoma, non-small cell lung cancer, and other solid tumors based on impressive responses and prolonged OS in a minority of patients, some with very advanced disease [5,6,7,8,9,10,11]. Neoadjuvant use of both pembrolizumab [14] and nivolumab [15] has shown immunomodulatory effects, Abbreviations: GBM, glioblastoma; OS, overall survival; ICB, immune checkpoint blockade; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed death receptor 1; PD-L1, programmed death-ligand 1; NSCLC, non-small cell lung cancer; RANO, response assessment in neuro-oncology; PD, progressive disease; iRANO, immunotherapy RANO; CR, complete response; PR, partial response; BOR, best overall response; SD, stable disease; PDU, progressive disease unconfirmed; PsP, pseudoprogression; PFS, progression free survival

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