Modified RANO, Immunotherapy RANO, and Standard RANO Response to Convection-Enhanced Delivery of IL4R-Targeted Immunotoxin MDNA55 in Recurrent Glioblastoma

Abstract

Purpose: The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM).

Patients and methods: A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied.

Results: A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank, P < 0.0001; HR = 0.3) and mRANO (P < 0.0001; HR = 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local, P = 0.47; central, P = 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements (P = 0.017), but not central measurements (P = 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local (R2 = 0.66, P < 0.0001) and centrally determined reads (R2 = 0.57, P = 0.0007).

Conclusions: No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.

Conflict of interest statement

Conflicts of Interest:

Benjamin Ellingson: Paid advisor for Medicenna, MedQIA, Neosoma, Agios, Siemens, Janssen, Imaging Endpoints, Kazia, VBL, Oncoceutics, Boston Biomedical Inc (BBI), and ImmunoGenesis. Grant funding from Siemens, Agios, and Janssen.

John Sampson: None

Achal Singh Achrol: None

Manish K. Aghi: None

Krystof Bankiewicz: None

Chencai Wang: None

Steven Brem: Advisor for Novocure, Northwest Biotherapeutics, and Tocagen

Andrew Brenner: None

Sajeel Chowdhary: None

John R. Floyd: None

Seunggu Han: None

Santosh Kesari: Advisor and grant funding from Medicenna

Dina Randazzo: None

Michael Vogelbaum: Honoraria from Tocagen and Celgene. Indirect equity and royalty rights from Infuseon Therapeutics.

Frank Vrionis: None

Miroslaw Zabek: None

Nicholas Butowski: Advisor for Hoffman La-Roche; Nativis; Medicenna; Bristol Meyers Squibb; VBL, Pulse Therapeutics, Lynx Group, Boston Bio. Paid Consultant for Nativis; Hoffman La-Roche; Medicenna, DelMar, QED, Karyopharm. Grant funding: Beigene, BMX, Deciphera, DeNovo, Epicentrix, Oncoceutics, Stellar Orbus, Istari, Kiyatec, Amgen, Tocagen.

Martin Bexon: Employed by Medicenna.

Melissa Coello: Employed by Medicenna

Nina Merchant: Employed by Medicenna

Fahar Merchant: Employed by Medicenna

©2021 American Association for Cancer Research.

Figures

Figure 1.. Study schema and representative patients.

(A) Treatment schema for MDNA55-05. Upon tumor recurrence, the MRI scan was submitted centrally for screening end eligibility. After confirmation of eligibility, patients entered the study and received a baseline, planning MRI within 14 days of the screening MRI. This baseline MRI scan was used as the reference for response determination. Following the planning MRI, patients received an additional MRI for catheter placement and started CED infusion of MDNA55 (plus a gadolinium-based contrast agent) including real-time infusion monitoring using MRI. Patients also received an MRI scan at the end of infusion to document the extent of drug distribution throughout the tumor. Following infusion and the post-infusion MRI scan, patients were monitored approximately every 30 days until disease progression or death. (B) A 64 year-old male patient who experienced rapid disease progression on MRI and died 3 months after initiating treatment. Green arrows on the end of infusion MRI scan denote anterior portions of the tumor that appeared to receive adequate coverage of MDNA55 after infusion, which subsequently resulted in disease control. This is contrasted with areas denoted with red arrows that did not receive adequate coverage of MDNA55 after CED, which subsequently showed tumor growth and lack of disease control. (C-D) A 76 year-old male and 68 year-old female who experienced long-term disease control, with OS of 23.4 and 26.7 months, respectively. (E) A 34 year-old male patient who experienced transient, progressive enhancement followed by stabilization, which was determined to meet the threshold of PsP as defined by the mRANO criteria.

Figure 2.

(A) Spider plots showing percentage change in tumor bidirectional product with respect to baseline over time for patients treated with MDNA55. (B) Population-based changes in tumor size estimated using a local polynomial (4th order) regression fitting to the percentage change in bidirectional product. (C) Kaplan-Meier plots showing difference in overall survival (OS) in patients determined to have PsP versus patients who did not experience PsP, as defined by the mRANO critiera. Results suggested patients who exhibited PsP had a small, non-significant survival advantage compared to patients who did not exhibit PsP (Log-rank, P=0.3268, median OS = 450.7 days for PsP vs. 349.2 days for non-PsP).

Figure 3.. Progression-free survival (PFS) and duration of clinical benefit (DOCB) for standard RANO, iRANO, and mRANO evaluated both by local site and independent radiological facility (IRF)-determined measurements.

(A) PFS across different RANO criteria using local measurements. (B) PFS across different RANO criteria using centrally determined IRF measurements. (C) DOCB across different RANO criteria using local measurements. (D) DOCB across different RANO criteria using central IRF measurements. Solid lines = radiographic measurements only. Dashed lines = radiographic plus clinical information.

Figure 4.. Correlation between radiographic PFS and OS for the standard RANO, iRANO, and mRANO criteria.

(A) Correlation between radiographic PFS using the standard RANO criteria applied to local measurements and OS for patients who died. (B) Correlation between radiographic PFS using the iRANO criteria applied to local measurements and OS for patients who died. (C) Correlation between radiographic PFS using the mRANO criteria applied to local measurements and OS for patients who died. (D) Correlation between radiographic PFS using the standard RANO criteria applied to Centrally-determined IRF measurements and OS for patients who died. (E) Correlation between radiographic PFS using the iRANO criteria applied to Centrally-determined measurements and OS for patients who died. (F) Correlation between radiographic PFS using the mRANO criteria applied to Centrally-determined IRF measurements and OS for patients who died. Solid circles = patients who progressed. Open circles = patients who were censored (not used in correlation analysis, only for visualization purposes).

Figure 5.. Correlation between radiographic or clinically-determined PFS and OS for the standard RANO, iRANO, and mRANO criteria.

(A) Correlation between radiographic or clinically-determined PFS using the standard RANO criteria applied to local measurements and OS for patients who died. (B) Correlation between radiographic or clinically-determined PFS using the iRANO criteria applied to local measurements and OS for patients who died. (C) Correlation between radiographic or clinically-determined PFS using the mRANO criteria applied to local measurements and OS for patients who died. (D) Correlation between radiographic or clinically-determined PFS using the standard RANO criteria applied to Centrally-determined measurements and OS for patients who died. (E) Correlation between radiographic or clinically-determined PFS using the iRANO criteria applied to Centrally-determined measurements and OS for patients who died. (F) Correlation between radiographic or clinically-determined PFS using the mRANO criteria applied to Centrally-determined IRF measurements and OS for patients who died. Solid circles = patients who progressed. Open circles = patients who were censored (not used in correlation analysis, only for visualization purposes).