Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA–09): a randomised, open-label, phase 3 trial

doi:10.1016/S0140-6736(18)31791-4

The Lancet

Volume 393, Issue 10172, 16–22 February 2019, Pages 678-688

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Summary

Background

There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial.

Methods

In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18–70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/m² per day concomitant to radiotherapy [59–60 Gy] followed by six courses of temozolomide 150–200 mg/m² per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m² on day 1) plus temozolomide (100–200 mg/m² per day on days 2–6 of the 6-week course) in addition to radiotherapy (59–60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. The primary endpoint was overall survival in the modified intention-to-treat population, comprising all randomly assigned patients who started their allocated chemotherapy. The prespecified test for overall survival differences was a log-rank test stratified for centre and recursive partitioning analysis class. The trial is registered with ClinicalTrials.gov, number NCT01149109.

Findings

Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7–47·1) with temozolomide to 48·1 months (32·6 months–not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35–1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35–1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths.

Interpretation

Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial.

Funding

German Federal Ministry of Education and Research.

Introduction

Chemotherapy for patients with newly diagnosed glioblastoma has not been substantially improved since the registration trial for temozolomide.¹ The addition of tumour-treating fields to temozolomide was associated with moderate improvements in survival.² Randomised trials with dose-intensified temozolomide regimens³ or combinations of temozolomide with other drugs4, 5, 6, 7 did not prolong overall survival. Nevertheless, the low toxicity of temozolomide suggests that a more intense alkylating combination therapy might be feasible and should be further investigated.

Research in context

Evidence before this study

The standard therapy for patients with newly diagnosed glioblastoma is radiotherapy (59–60 Gy) with concomitant daily low-dose (75 mg/m²) temozolomide chemotherapy, followed by six courses of adjuvant temozolomide therapy (150–200 mg/m² per day on days 1–5 of the 4-week course). The MGMT promoter methylation status is a predictor for the benefit of temozolomide therapy: patients with methylated MGMT promoter have a particularly high survival benefit from temozolomide therapy. A single-arm, phase 2 trial (UKT-03) assessing lomustine-temozolomide combination therapy to patients with newly diagnosed glioblastoma found a signal of improvement in overall survival for patients with glioblastoma with methylated MGMT promoter. The CeTeG/NOA–09 trial aimed to further analyse the value of lomustine-temozolomide combination chemotherapy in such patients in a randomised phase 3 setting.

Added value of this study

The predefined final analysis of the primary endpoint showed that combined lomustine-temozolomide chemotherapy plus radiotherapy could improve overall survival compared with standard temozolomide chemotherapy plus radiotherapy.

Implications of all the available evidence

Lomustine-temozolomide combination chemotherapy prolonged overall survival in a selected group of patients with glioblastoma with MGMT promoter methylation in this small randomised trial. These encouraging results require further confirmation and, if confirmed, this regimen has the potential to become a standard-of-care option. Ongoing research aims to further investigate the molecular determinants of response to lomustine-temozolomide and the cellular changes induced by this combination.

Nitrosourea compounds are well established in glioma therapy,8, 9, 10, 11, 12 and they are capable of penetrating the brain through an intact blood–brain barrier. The combination of nitrosoureas with temozolomide would not be simply a dose escalation of alkylating therapy, but might combine different qualities of DNA damage with the potential for additive or even synergistic effects. By contrast with temozolomide, which exerts its therapeutic effect preferably through alkylation of guanine, lomustine has effects beyond DNA alkylation: it acts as an bifunctional agent introducing interstrand crosslinks¹³ and leads to carbamoylation of amino acids, thus interfering with transcriptional, translational, and post-transcriptional processes.¹⁴ By contrast with the alkylating mechanism of action shared by temozolomide and nitrosoureas, the non-alkyating mechanisms of action might not depend on the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter and on the MGMT enzyme activity, which counteracts guanine alkylation. Therefore, it was not surprising that combined nitrosourea and temozolomide therapy showed enhanced activity in high-grade glioma xenograft models.¹⁵ Additionally, a single-arm trial with carmustine (BCNU) and unescalated temozolomide provided promising results in patients with inoperable glioblastoma.¹⁶ These concepts and experimental results provide a clear rationale to assess the efficacy of combined lomustine-temozolomide therapy in glioblastoma patients.

The single–arm phase 2 UKT-03 trial17, 18 included 31 patients and explored the value of combined lomustine-temozolomide chemotherapy in patients with newly diagnosed glioblastoma. In line with previous trials that used nitrosoureas,8, 9 which defined the standard in 2002, when UKT-03 began, the first course of chemotherapy started during radiotherapy. With lomustine-temozolomide combination therapy, the findings from UKT-03 suggested an improved overall survival with a median of 23 months, as opposed to 15–17 months in contemporary historical controls. However, improved overall survival was exclusively seen in patients with glioblastoma with methylated MGMT promoter. The median overall survival of these patients was 34·5 months, comparing favourably with 23·4 months in the temozolomide registration trial,¹⁹ whereas median overall survival remained at 12·5 months in patients with unmethylated MGMT promoter.¹⁸ Favourable overall survival was also seen in a non–randomised trial in which lomustine-temozolomide combination therapy was received by children with high-grade glioma.²⁰ The encouraging data of the UKT-03 trial led to the CeTeG/NOA-09 trial, which assessed whether lomustine-temozolomide therapy is superior to temozolomide standard therapy in a randomised phase 3 setting. For this, we implemented the same lomustine-temozolomide treatment regimen as the UKT-03 trial (including omission of radiotherapy-concomitant daily chemotherapy) and we restricted enrolment to patients with glioblastoma with methylated MGMT promoter on the basis of the previous UKT-03 trial subgroup analyses.

Section snippets

Study design and participants

CeTeG/NOA–09 was a randomised, open-label, phase 3 trial. Patients were recruited in 17 German university hospitals on the basis of the following inclusion criteria: no previous chemotherapy or radiotherapy, age 18–70 years, newly diagnosed glioblastoma or gliosarcoma (resection or biopsy) centrally confirmed (by TP; appendix), methylated MGMT promoter according to central testing (MDXHealth, Herstal, Belgium), Karnofsky performance score (KPS) of 70% or higher, stable or decreasing

Results

Between May 4, 2011, and April 8, 2014, 657 patients were screened in 17 study centres. We processed submitted tumour tissue from these patients and, in four cases, obligatory central reference neuropathology did not confirm glioblastoma histology (three anaplastic astrocytomas and one pilocytic astrocytoma); these patients were not considered for any further steps in the trial. Therefore, 653 patients with confirmed glioblastoma were assessed for MGMT promoter methylation, and 141 patients

Discussion

The CeTeG/NOA-09 trial results provide evidence that, in patients with newly diagnosed glioblastoma with methylated MGMT promoter, lomustine-temozolomide therapy might be better than standard temozolomide therapy, in the context of well tolerated toxicity. These results could be a first step towards improving drug therapy of glioblastoma beyond temozolomide monotherapy and separating drug therapy for patients with glioblastomas with or without methylated MGMT promoter.

The small size of the

References (34)

R Stupp et al.
Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071–22072 study): a multicentre, randomised, open-label, phase 3 trial
Lancet Oncol
(2014)
M Weller et al.
Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial
Lancet Oncol
(2017)
M Barrié et al.
Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme
Ann Oncol
(2005)
WD Dupont et al.
PS power and sample size program available for free on the Internet
Controlled Clin Trials
(1997)
I Vlassenbroeck et al.
Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma
J Mol Diagn
(2008)
T Mikeska et al.
Optimization of quantitative MGMT promoter methylation analysis using pyrosequencing and combined bisulfite restriction analysis
J Mol Diagn
(2007)
MJ van den Bent et al.
Interim results from the CATNON trial (EORTC study 26053–22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study
Lancet
(2017)
R Stupp et al.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma
N Engl J Med
(2005)
R Stupp et al.
Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial
JAMA
(2017)
MR Gilbert et al.
Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial
J Clin Oncol
(2013)

JA Quinn et al.

Phase II trial of temozolomide (TMZ) plus irinotecan (CPT–11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy

J Neuro–Oncol

(2009)

OL Chinot et al.

Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma

N Engl J Med

(2014)

MD Walker et al.

Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery

N Engl J Med

(1980)

M Weller et al.

Neuro-oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved–field radiotherapy in the first-line treatment of malignant glioma

J Clin Oncol

(2003)

G Cairncross et al.

Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402

J Clin Oncol

(2013)

MJ van den Bent et al.

Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951

J Clin Oncol

(2013)

W Wick et al.

Lomustine and bevacizumab in progressive glioblastoma

N Engl J Med

(2017)

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ArticlesLomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA–09): a randomised, open-label, phase 3 trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Lancet Oncol

Lancet Oncol

Ann Oncol

Controlled Clin Trials

J Mol Diagn

J Mol Diagn

Lancet

Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma

N Engl J Med

Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial

JAMA

Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial

J Clin Oncol

Phase II trial of temozolomide (TMZ) plus irinotecan (CPT–11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy

J Neuro–Oncol

Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma

N Engl J Med

Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery

N Engl J Med

Neuro-oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved–field radiotherapy in the first-line treatment of malignant glioma

J Clin Oncol

Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402

J Clin Oncol

Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951

J Clin Oncol

Lomustine and bevacizumab in progressive glioblastoma

N Engl J Med

Articles
Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA–09): a randomised, open-label, phase 3 trial