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 Ulrich Herrlinger*, Theophilos Tzaridis*, Frederic Mack, Joachim Peter Steinbach, Uwe Schlegel, Michael Sabel, Peter Hau, Rolf-Dieter Kortmann, Dietmar Krex, Oliver Grauer, Roland Goldbrunner, Oliver Schnell, Oliver Bähr, Martin Uhl, Clemens Seidel, Ghazaleh Tabatabai, Thomas Kowalski, Florian Ringel, Friederike Schmidt-Graf, Bogdana Suchorska, Stefanie Brehmer, Astrid Weyerbrock, Miriam Renovanz, Lars Bullinger, Norbert Galldiks, Peter Vajkoczy, Martin Misch, Hartmut Vatter, Moritz Stuplich, Niklas Schäfer, Sied Kebir, Johannes Weller, Christina Schaub, Walter Stummer, Jörg-Christian Tonn, Matthias Simon, Vera C Keil, Michael Nelles, Horst Urbach, Martin Coenen, Wolfgang Wick, Michael Weller, Rolf Fimmers, Matthias Schmid, Elke Hattingen, Torsten Pietsch, Christoph Coch*, Martin Glas*, for the Neurooncology Working Group of the German Cancer Society 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 intentionto-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. Copyright © 2019 Elsevier Ltd. All rights reserved.

요 약 (Summary)

배 경 (Background)

교모세포종(glioblastoma)의 치료 효과를 개선하기 위한 새로운 치료법이 절실히 필요한 상황이며, 이전의 비무작위 2상 시험에서 lomustine-temozolomide 병용요법과 방사선치료가 표준 temozolomide 화학방사선치료보다 우수할 수 있다는 데이터가 제시된 바 있음. 본 CeTeG/NOA-09 연구는 이 병합요법의 효과를 무작위 3상 임상시험을 통해 보다 명확히 규명하고자 함.

방 법 (Methods)

환자 모집 : 공개, 무작위, 3상 임상시험, 독일 내 17개 대학병원에서 환자를 모집대상자 : 18세~70세의 신규 진단된 교모세포종 환자.         MGMT 프로모터 메틸화 확인되고 Karnofsky 수행능력 점수 70% 이상인 환자.무작위 배정 : 환자들은 SAS를 이용한 사전 정의된 무작위 배정표에 따라 1:1로 무작위 배정

·         표준군: 방사선치료(59–60 Gy)와 병행하여 temozolomide 75 mg/m²/일,        이후 6주기의 temozolomide 150–200 mg/m²/일 (4주 주기 중 처음 5일)

·         실험군: 방사선치료(59–60 Gy)와 병행하여 lomustine 100 mg/m² (1일차)        + temozolomide 100–200 mg/m² (2–6일차, 6주 주기), 최대 6주기

치료 스케줄이 달라 환자 및 연구진은 블라인드 처리 않음.

·         1차 평가 변수(primary endpoint) : 수정된 의도치 분석 집단(modified intention-to-treat)에서의 전체 생존 기간(overall survival)

·         생존 분석 : 센터 및 분할 분석 클래스에 따라 층화된 로그 순위 검정(log-rank test) 으로 수행

결 과 (Findings)

• 연구 기간: 2011년 6월 17일 ~ 2014년 4월 8일

• 등록된 환자 수: 141명

• 수정된 ITT 분석 대상: 129명 (표준군 63명, 병용군 66명)

• 전체 생존 기간 (OS)

  -> 표준 temozolomide군: 31.4개월 (95% CI: 27.7–47.1)

  -> lomustine-temozolomide군: 48.1개월 (95% CI: 32.6–평가 불가)

  -> 위험비(HR): 0.60, 95% CI: 0.35–1.03

  -> p값: 0.0492 (로그 순위 검정)

  -> ITT 전체 집단(n=141)에서도 유사한 유의한 차이(p=0.0432) 확인

• Grade 3 이상의 이상반응 

  -> Temozolomide 단독군: 63명 중 32명 (51%)

  -> Lomustine-temozolomide 병용군: 66명 중 39명 (59%)

  -> 치료 관련 사망은 없었음

해 석 (Interpretation)

lomustine-temozolomide 병합화학요법은 표준 temozolomide 요법에 비해 전체 생존 기간을 향상시킬 수 있음.

다만, 본 시험은 규모가 작고(n=141)단일 국가 내에서 시행된 연구이므로 결과 해석 시 주의가 필요함.