Phase 2 clinical trial of VAL-083 as  first-line treatment in newly-diagnosed MGMT-unmethylated glioblastoma multiforme (GBM): Halfway report

Guo, Chengcheng; Yang, Qiulan; Li, Jiawei; Wu, Shaoxiong; Deng, Meiling; Du, Xiaojing; Sai, Ke; Jiang, Xiaobing; Chen, Zhenghe; Zhang, Ji; Lin, Fei; Wang, Jian; Chen, Yinsheng; Ke, Chao; Zhang, Xiangheng; Ju, Xue; Mou, Yonggao; Bacha, Jeffrey; Steinø, Anne; Kanekal, Sarath; Kwan, Claire; Johnson, Gregory R.; Schwartz, Richard; Langlands, John; Brown, Dennis; Chen, Zhongping

doi:10.4103/glioma.glioma_25_19

Cited by 5 publications

(1 citation statement)

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“…[2][3][4][5][6] Despite aggressive treatment, the long-term survival of patients with HGG is still not promising, with 5-year overall survival (OS) of 30.9% for grade 3 gliomas and 6.6% for grade 4 gliomas. Moreover, patients with an unmethylated promoter for the gene encoding O6-methylguanine-DNA methyltransferase (MGMT) had a more aggressive prognosis and resistance to temozolomide, 7 with a median progression-free survival (PFS) of 5.3 to 6.9 months in patients with GBM. Methylation of MGMT not only changes the biology of a tumor but also affects its vulnerability to temozolomide.…”

Section: Introductionmentioning

confidence: 99%

Adjuvant Temozolomide Chemotherapy With or Without Interferon Alfa Among Patients With Newly Diagnosed High-grade Gliomas

Guo

Yang

et al. 2023

JAMA Netw Open

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ImportanceHigh-grade gliomas (HGGs) constitute the most common and aggressive primary brain tumor, with 5-year survival rates of 30.9% for grade 3 gliomas and 6.6% for grade 4 gliomas. The add-on efficacy of interferon alfa is unclear for the treatment of HGG.ObjectivesTo compare the therapeutic efficacy and toxic effects of the combination of temozolomide and interferon alfa and temozolomide alone in patients with newly diagnosed HGG.Design, Setting, and ParticipantsThis multicenter, randomized, phase 3 clinical trial enrolled 199 patients with newly diagnosed HGG from May 1, 2012, to March 30, 2016, at 15 Chinese medical centers. Follow-up was completed July 31, 2021, and data were analyzed from September 13 to November 24, 2021. Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed HGG and had received no prior chemotherapy, radiotherapy, or immunotherapy for their HGG.InterventionsAll patients received standard radiotherapy concurrent with temozolomide. After a 4-week break, patients in the temozolomide with interferon alfa group received standard temozolomide combined with interferon alfa every 28 days. Patients in the temozolomide group received standard temozolomide.Main Outcomes and MeasuresThe primary end point was 2-year overall survival (OS). Secondary end points were 2-year progression-free survival (PFS) and treatment tolerability.ResultsA total of 199 patients with HGG were enrolled, with a median follow-up time of 66.0 (95% CI, 59.1-72.9) months. Seventy-nine patients (39.7%) were women and 120 (60.3%) were men, with ages ranging from 18 to 75 years and a median age of 46.9 (95% CI, 45.3-48.7) years. The median OS of patients in the temozolomide plus interferon alfa group (26.7 [95% CI, 21.6-31.7] months) was significantly longer than that in the standard group (18.8 [95% CI, 16.9-20.7] months; hazard ratio [HR], 0.64 [95% CI, 0.47-0.88]; P = .005). Temozolomide plus interferon alfa also significantly improved median OS in patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylation (24.7 [95% CI, 20.5-28.8] months) compared with temozolomide (17.4 [95% CI, 14.1-20.7] months; HR, 0.57 [95% CI, 0.37-0.87]; P = .008). Seizure and influenzalike symptoms were more common in the temozolomide plus interferon alfa group, with 2 of 100 (2.0%) and 5 of 100 (5.0%) patients with grades 1 and 2 toxic effects, respectively (P = .02). Finally, results suggested that methylation level at the IFNAR1/2 promoter was a marker of sensitivity to temozolomide plus interferon alfa.Conclusions and RelevanceCompared with the standard regimen, temozolomide plus interferon alfa treatment could prolong the survival time of patients with HGG, especially the MGMT promoter unmethylation variant, and the toxic effects remained tolerable.Trial RegistrationClinicalTrials.gov Identifier: NCT01765088

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