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Clinical Trial
. 2021 Jun;22(6):813-823.
doi: 10.1016/S1470-2045(21)00090-5. Epub 2021 May 14.

Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study

Martin J van den Bent  1 , C Mircea S Tesileanu  2 , Wolfgang Wick  3 , Marc Sanson  4 , Alba Ariela Brandes  5 , Paul M Clement  6 , Sarah Erridge  7 , Michael A Vogelbaum  8 , Anna K Nowak  9 , Jean Français Baurain  10 , Warren P Mason  11 , Helen Wheeler  12 , Olivier L Chinot  13 , Sanjeev Gill  14 , Matthew Griffin  15 , Leland Rogers  16 , Walter Taal  2 , Roberta Rudà  17 , Michael Weller  18 , Catherine McBain  19 , Jaap Reijneveld  20 , Roelien H Enting  21 , Francesca Caparrotti  22 , Thierry Lesimple  23 , Susan Clenton  24 , Anja Gijtenbeek  25 , Elizabeth Lim  26 , Ulrich Herrlinger  27 , Peter Hau  28 , Frederic Dhermain  29 , Iris de Heer  2 , Kenneth Aldape  30 , Robert B Jenkins  31 , Hendrikus Jan Dubbink  32 , Johan M Kros  32 , Pieter Wesseling  33 , Sarah Nuyens  34 , Vassilis Golfinopoulos  34 , Thierry Gorlia  34 , Pim French  2 , Brigitta G Baumert  35
Affiliations
Clinical Trial

Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study

Martin J van den Bent et al. Lancet Oncol. 2021 Jun.

Abstract

Background: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear.

Methods: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990.

Findings: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported.

Interpretation: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status.

Funding: Merck Sharpe & Dohme.

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Conflict of interest statement

Declaration of interests MJvdB reports grants from the Dutch Cancer Foundation, Brain Tumor Charity, Strijd van Salland, and Merck Sharp & Dohme (formerly Schering Plough), during the conduct of the study; and personal fees from Carthera, Nerviano, Bayer, Cellgene, Agios, AbbVie, Karyopharm, Boston Pharmaceuticals, and Genenta, outside the submitted work. PMC reports personal fees from Bristol Meyers Squibb, AbbVie, Merck Serono, Merck Sharp & Dohme, Vifor Pharma, DaNchi Sankyo, LEO Pharma, AstraZeneca, and Takeda, outside the submitted work. MAV reports grants from the US National Cancer Institute, during the conduct of the study, and personal fees from Tocagen and Celgene, outside the submitted work. AKN reports grants and personal fees from AstraZeneca, and Douglas Pharmaceuticals, and personal fees from Bayer Pharmaceuticals, Roche Pharmaceuticals, Boehringer Ingelheim, Merck Sharp & Dohme, Pharmabcine, Atara Biotherapeutics, and Trizell, outside the submitted work. MW reports grants and personal fees from AbbVie, Merck Sharp & Dohme, Merck (EMD); grants from Adastra, Novocure; and personal fees from Basilea, Bristol Myer Squibbs, Celgene, Nerviano, Orbus, Roche, and Tocagen, outside the submitted work. UH reports non-financial support from Medac, and personal fees from Novartis, Daiichi-Sankyo, Noxxon, AbbVie, Bayer, Janssen, and Karyopharm, outside the submitted work. HJD reports personal fees from AbbVie, outside the submitted work. BGB reports personal fees and non-financial support from Roche, outside the submitted work. All other authors declare no competing interests.

Figures

Figure 1:
Figure 1:. Trial profile
IDMC=independent data monitoring committee.
Figure 2:
Figure 2:. Univariable analysis of overall survival in all patients regardless of IDH1 and IDH2 mutational status
(A) Patients who received concurrent temozolomide versus those who did not. (B) Patients who received adjuvant temozolomide versus those who did not.
Figure 3:
Figure 3:. Univariable analysis of overall survival in patients with IDH1 and IDH2 wild-type tumours
(A) Patients who received concurrent temozolomide versus those who did not. (B) Patients who received adjuvant temozolomide versus those who did not.
Figure 4:
Figure 4:. Univariable analysis of overall survival in patients with IDH1 or IDH2 mutant tumours
(A) Patients who received concurrent temozolomide versus those who did not. (B) Patients who received adjuvant temozolomide versus those who did not.
See this image and copyright information in PMC

Comment in

References

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