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. 2023 Sep 12;5(1):vdad106.
doi: 10.1093/noajnl/vdad106. eCollection 2023 Jan-Dec.

Phase II trial of concurrent sunitinib, temozolomide, and radiotherapy with adjuvant temozolomide for newly diagnosed MGMT unmethylated glioblastoma

Mame Daro Faye  1 , Jacob Easaw  2 , Paula De Robles  2 , Raman Agnihotram  3 , Alexander Torres-Vasquez  3 , Frederic Lamonde  3 , Kevin Petrecca  4 , Scott Owen  3 , Valerie Panet-Raymond  1 , George Shenouda  1 , Luis Souhami  1 , Maryam Azam  5 , Bushra Hossain  5 , Jad Alkass  5 , Siham Sabri  5 , Bassam Abdulkarim  1   5
Affiliations

Phase II trial of concurrent sunitinib, temozolomide, and radiotherapy with adjuvant temozolomide for newly diagnosed MGMT unmethylated glioblastoma

Mame Daro Faye et al. Neurooncol Adv. .

Abstract

Background: The overall prognosis of glioblastoma (GBM) remains dismal, particularly for patients with unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter. In this phase II trial, we tested the combination of the antiangiogenic agent sunitinib with radiotherapy and temozolomide (TMZ) for newly diagnosed unmethylated MGMT GBM patients.

Methods: We enrolled 37 patients with unmethylated MGMT promoter GBM, age 18-70, and KPS ≥70. Patients received 12.5 mg of daily sunitinib for 7 days, followed by concurrent chemoradiation plus 12.5 mg sunitinib, then adjuvant TMZ. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), safety, and neutrophil-to-lymphocyte ratio (NLR) biomarker.

Results: At a median follow-up time of 15.3 months (range: 3.1-71.3 months), the median PFS was 7.15 months (95% CI: 5.4-10.5) and the 6-month PFS was 54.0%. Median OS was 15.0 months (95% CI: 13.8-19.4) and 2-year OS rate was 17.1%. Patients receiving >3 cycles of adjuvant TMZ, undergoing surgery at progression, and presenting a post-concurrent NLR ≤6 experienced a significant improved OS with hazard ratios of 0.197 (P = .001), 0.46 (P = .049), and 0.38 (P = .021), respectively, on multivariable analysis. Age >65 years predicted for worse OS with hazard ratio of 3.92 (P = .037). Grade ≥3 thrombocytopenia occurred in 22.9%, grade ≥3 neutropenia in 20%, and grade ≥3 thromboembolic events in 14.3% of patients. There were no grade 5 events.

Conclusion: Our findings suggest a potential benefit of combining sunitinib with chemoradiation in newly diagnosed GBM patients with unmethylated MGMT status and provide a strong rationale to test this combination in future studies.

Keywords: glioblastoma; radiation therapy; sunitinib; temozolomide; unmethylated MGMT.

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Conflict of interest statement

None declared. Pfizer provided funding but was not involved in the design, recruitment, and analysis of data in this clinical trial.

Figures

Figure 1.
Figure 1.
Kaplan–Meier estimates of progression-free survival (A) and overall survival (B) in newly diagnosed unmethylated MGMT GBM patients treated with combined Sunitinib, Temozolomide and Radiotherapy. Patients were assessed from time of diagnosis to time of tumor progression clinically or by MR imaging as per RANO criteria.
Figure 2.
Figure 2.
Clinical variables significantly associated with overall survival in newly diagnosed GBM patients with unmethylated MGMT promoter treated with combined sunitinib, Temozolomide, and Radiotherapy. Kaplan–Meier curves for overall survival showing clinical variables that are significantly associated with overall survival on Cox regression and their P values: age (A), number of TMZ cycles (B), surgery at time of progression (C), and post-concurrent neutrophil-to-lymphocyte ratio (D).
See this image and copyright information in PMC

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