Dataset Information

ACTR-61. LONG-TERM ANALYSES OF THE NOA-08 RANDOMIZED PHASE III TRIAL

ABSTRACT: Abstract BACKGROUND Optimal treatment and role of O6-methylguanine DNA-methyl transferase (MGMT) status in elderly patients is still not defined. METHODS This is the long-term update (LT) of the NOA-08 trial (NCT01502241) that compared efficacy and safety of RT to TMZ in elderly patients with anaplastic astrocytoma (AA) or glioblastoma (GB) using overall survival (OS) as primary endpoint and event-free survival (EFS) as well as efficacy according to MGMT status as major secondary endpoints. FINDINGS: In the LT with a data cut-off Apr 1 2018 median OS was 8·2 [7·0–10·0] months for TMZ treatment versus 9·4 [8·1–10·4] months for RT; hazard ratio (HR)=0·93 (95% CI: 0·76-1·15)] of TMZ versus RT did not differ between both arms. Also, median EFS [3·4 [3·2–4·1] months versus 4·6 [4·2–5·0] months 3did not differ with a HR=1·02 (0·83-1·25)]. MGMT promoter methylation tested in tumor tissue (82/221 patients, 37·1%) was associated with prolonged OS [13·6 [10·1–16·5] versus 8·0 [6·9-9·9] months; HR=0·53 (0·40-0·70), p<0·0001]. Patients with MGMT promoter methylation had longer OS and EFS when treated with TMZ (18·4 [13·9–24·4] months and 8·5 [6·9–13·3] months) versus RT (9·6 [6·4–13·7] months and 4·8 [4·3–6·2] months, HR 0·44 [0.27–0.70], p<0·001 for OS and 0·46 [0.29–0.73], p=0·001 for EFS). Patients without MGMT promoter methylation had shorter EFS and a shorter OS with the usual testing not significant when treated with TMZ (6·7 [5·6–8·2] months and 3·0 [2·6-3·3] months) versus with RT (10·2 [8·0–12·0] months and 4·6 [3·7-6·4] months), HR 1·33 [0·95-1·87], p=0·099 for OS and 1·86 [1·32-2·62], p<0·001 for EFS). INTERPRETATION: LT of NOA-08 confirms the non-inferiority of TMZ compared with RT in the treatment of elderly patients with AA or GB. To improve OS and EFS, MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ and offers unexpectedly favorable long-term outcome with initial TMZ monotherapy.

SUBMITTER: Kessler T

PROVIDER: S-EPMC6216462 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Abstract Background While the NOA-08 trial and the NORDIC Elderly trial suggested an O6-methylguanine DNA-methyl transferase (MGMT) status-tailored use of radiotherapy (RT) and temozolomide (TMZ), recent data from the NCIC CE.6/EORTC 26062 showed that hypofractionated RT plus TMZ was superior to RT for unselected elderly patients with an impact of MGMT for the effect of TMZ. Material and Methods This is the long-term update of the NOA-08 trial (German Cancer Trials Registry ID 386 and NCT01502241) that compared efficacy and safety of RT alone to TMZ alone in elderly patients with anaplastic astrocytoma (AA) or glioblastoma (GB), both isocitrate dehydrogenase wildtype, using overall survival (OS) as primary endpoint and event-free survival (EFS) as well as efficacy according to MGMT status as major secondary endpoints. NOA-08 had randomized patients (N=412; 39 AA, 373 GB) > 65 years with a Karnofsky performance score ? 60 in electronically generated blocks of variable length without stratification to receive standard RT to 60 Gy in 30 x 2 Gy fractions or TMZ dosed according to tolerance in a one week on/one week off schedule with tolerability dependent dosing. The trial finished enrolment Nov 2 2009 and demonstrated non-inferiority of TMZ compared with RT (p=0·033). Results In the long-term analysis with a data cut-off Apr 1 2018 median OS was 8·2 [7·0–10·0] months for TMZ treatment versus 9·4 [8·1–10·4] months for RT; hazard ratio (HR)=0·93 (95% CI: 0·76-1·15)] of TMZ versus RT did not differ between both arms. Also, median EFS [3·4 [3·2–4·1] months versus 4·6 [4·2–5·0] months did not differ with a HR=1·02 (0·83-1·25)]. MGMT promoter methylation tested in tumor tissue (82/221 patients, 37·1%) was associated with prolonged OS [13·6 [10·1–16·5] versus 8·0 [6·9-9·9] months; HR=0·53 (0·40-0·70), p<0·0001]. Patients with MGMT promoter methylation had longer OS and EFS when treated with TMZ (18·4 [13·9–24·4] months and 8·5 [6·9–13·3] months) versus RT (9·6 [6·4–13·7] months and 4·8 [4·3–6·2] months, HR 0·44 [0.27–0.70], p<0·001 for OS and 0·46 [0.29–0.73], p=0·001 for EFS). Patients without MGMT promoter methylation had shorter EFS and a shorter OS with the usual testing not significant when treated with TMZ (6·7 [5·6–8·2] months and 3·0 [2·6-3·3] months) versus with RT (10·2 [8·0–12·0] months and 4·6 [3·7-6·4] months), HR 1·33 [0·95-1·87], p=0·099 for OS and 1·86 [1·32-2·62], p<0·001 for EFS). Conclusion Also in the long-term analyses, NOA-08 confirms the non-inferiority of TMZ compared with RT in the treatment of elderly patients with WHO grade III or IV astrocytic gliomas. To improve OS and EFS, MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ and offers unexpectedly favorable long-term outcome with initial TMZ monotherapy.

Project description:BackgroundTildrakizumab is a specific anti-interleukin-23p19 monoclonal antibody approved for the treatment of plaque psoriasis.ObjectivesTo evaluate the long-term efficacy and safety of tildrakizumab treatment for patients with moderate-to-severe psoriasis for up to 148 weeks.MethodsPooled analysis from two double-blind, randomized controlled trials: reSURFACE 1 and reSURFACE 2. Efficacy was assessed for responders (≥ 75% improvement in Psoriasis Area and Severity Index; PASI 75) and partial responders (PASI 50-75) to tildrakizumab 100 mg and 200 mg at week 28 who were maintained on the same dose (administered every 12 weeks), and for partial responders or nonresponders (PASI < 50) to etanercept 50 mg at week 28 who, after a 4-week washout, were switched to tildrakizumab 200 mg (administered at weeks 32 and 36, and every 12 weeks thereafter). Safety was assessed in the all-patients-as-treated population. Three different methods of imputing missing data were used: nonresponder imputation (NRI), multiple imputation and observed cases. The Clinicaltrials.gov numbers are NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2).ResultsAt week 148 (NRI), 72·6%, 53·8% and 28·9% of tildrakizumab 100-mg responders and 80·2%, 59·9% and 32·6% of tildrakizumab 200-mg responders had PASI 75, 90 and 100 responses, respectively. For partial responders to tildrakizumab 100 mg and 200 mg, the proportions of patients achieving PASI 75, 90 and 100 responses were 32·5%, 25·0% and 10·0%; and 47·1%, 27·5% and 12·8%, respectively. For patients who were partial responders or nonresponders to etanercept, the proportions of patients achieving PASI 75, 90 and 100 responses were 66·9%, 43·8% and 14·9% at week 148. Rates of discontinuations due to adverse events [tildrakizumab 100 mg: 1·7 per 100 patient-years (PYs); tildrakizumab 200 mg: 1·2 per 100 PYs] and exposure-adjusted rates of serious adverse events (5·9 per 100 PYs; 5·5 per 100 PYs), severe infections (1·1 per 100 PYs; 1·1 per 100 PYs), malignancies (0·6 per 100 PYs; 0·4 per 100 PYs) and major adverse cardiovascular events (0·4 per 100 PYs; 0·5 per 100 PYs) were low.ConclusionsTildrakizumab was well tolerated and efficacy was well maintained in week 28 responders who continued tildrakizumab treatment through 3 years, or improved among etanercept partial responders or nonresponders who switched to tildrakizumab. What's already known about this topic? Tildrakizumab 100 mg and 200 mg are efficacious and well tolerated with short-term use in the treatment of patients with moderate-to-severe plaque psoriasis. What does this study add? High levels of efficacy are maintained for up to 3 years of psoriasis treatment with tildrakizumab. There is a favourable long-term safety profile with both tildrakizumab 100 mg and 200 mg, with a low incidence of adverse events of special interest through 3 years.

Project description:BackgroundThe number of patients age >65 years with malignant gliomas is increasing. Prognosis of these patients is worse compared with younger patients. To determine biological differences among malignant gliomas of different age groups and help to explain the survival heterogeneity seen in the NOA-08 trial, the prevalence and impact of recently established biomarkers for outcome in younger patients were characterized in elderly patients.MethodsPrevalences of mutations of isocitrate dehydrogenase 1 (IDH1) and histone H3.3 (H3F3A), the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and methylation of alkylpurine DNA N-glycosylase (APNG) and peroxiredoxin 1 (PRDX1) promoters were determined in a representative biomarker subset (n = 126 patients with anaplastic astrocytoma or glioblastoma) from the NOA-08 trial.ResultsIDH1 mutations (R132H) were detected in only 3/126 patients, precluding determination of an association between IDH mutation and outcome. These 3 patients also displayed the G-CIMP phenotype. None of the IDH1 wild-type tumors were G-CIMP positive. Mutations in H3F3A were absent in all 103 patients sequenced for H3F3A. MassARRAY analysis of the APNG promoter revealed generally low methylation levels and failed to confirm any predictive properties for benefit from alkylating chemotherapy. Neither did PRDX1 promoter methylation show differential methylation or association with outcome in this cohort. In a 170-patient cohort from The Cancer Genome Atlas database matched for relevant prognostic factors, age ?65 years was strongly associated with shorter survival.ConclusionsDespite an age-independent stable frequency of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, tumors in this age group largely lack prognostically favorable markers established in younger glioblastoma patients, which likely contributes to the overall worse prognosis of elderly patients. However, the survival differences hint at fundamental further differences among malignant gliomas of different age groups.

Dataset Information

ACTR-61. LONG-TERM ANALYSES OF THE NOA-08 RANDOMIZED PHASE III TRIAL

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure