A phase 1 and randomized, placebo‐controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma: Alliance/North Central Cancer Treatment Group N0872

Abstract

BACKGROUND: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM. METHODS: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6). RESULTS: In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%-40.0%] vs 18.4% [95% CI, 7.7%-34.4%]; P = .22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P = .93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P = .52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome. CONCLUSIONS: Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone. Cancer 2019;125:3790-3800.We thank the patients who participated in this clinical trial and their families. We also thank the study investigators for their contributions.

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

“…Dasatinib, an oral ATP-competitive multitarget kinase inhibitor, is able to inhibit all members of the SRC kinase family and has been shown to block growth of bevacizumab-induced glioma invasion in xenograft models [ 134 ]. Galains et al, reported the results of the randomized phase II study analyzing the efficacy of bevacizumab in combination with dasatinib vs. bevacizumab alone in rGBM patients [ 107 ]: the addition of dasatinib did not improve 6m-PFS compared to bevacizumab alone (28.9% [95% CI, 19.5%–40.0%] vs. 18.4% [95% CI, 7.7–34.4%]; p = 0.22) with no significant difference in mOS between the two arms (7.3 m vs. 7.7 m; HR 0.96 [95% CI, 0.64–1.43]; p = 0.83). The epidermal growth factor receptor (EGFR) gene is overexpressed in about 40–60% of GBM and its hyperactivation causes an increase in cell migration, proliferation and invasiveness with a reduction of apoptosis [ 136 , 137 ].…”

Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance

“…Evaluation of clinical samples from completed and ongoing clinical trials [ 47 – 49 ] should be prioritized to determine the contribution of IRS1/2 expression to therapy responsiveness. Additionally, prospective evaluation of the contribution of IRS1/2 overexpression to patient outcomes and tumor aggressiveness in the absence of RTK treatment could further elucidate the mechanistic specificity of these amplifications in patient tumors.…”

SRC Kinase in Glioblastoma: News from an Old Acquaintance

“…Unfortunately, despite these positive preclinical studies, the phase II clinical trial (NCT00892177) recently reported the failure of co-treatment with dasatinib and bevacizumab in patients with recurrent GBM, showing that the combination of these two drugs did not ameliorate the outcomes of GBM patients as compared with the single treatment with bevacizumab [ 105 ]. In addition, the phase II clinical trial (NCT00423735) reported a lack of activity of dasatinib against recurrent GBM [ 106 , 107 ].…”