NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma

Hao-Wen Sim^{1

2

3

4}, Luke Wachsmuth⁵, Elizabeth H Barnes¹, Sonia Yip¹, Eng-Siew Koh^{2

6}, Merryn Hall¹, Ross Jennens^{7

8}, David M Ashley⁹, Roel G Verhaak¹⁰, Amy B Heimberger¹¹, Mark A Rosenthal⁷, Elizabeth J Hovey^{2

12}, Benjamin M Ellingson¹³, Annette Tognela¹⁴, Hui K Gan¹⁵, Helen Wheeler¹⁶, Michael Back¹⁶, Kerrie L McDonald², Anne Long¹⁷, Katharine Cuff¹⁸, Stephen Begbie¹⁹, Craig Gedye²⁰, Anna Mislang^{21

22}, Hien Le²³, Margaret O Johnson⁹, Benjamin Y Kong^{1

2

12}, John R Simes^{1

4}, Zarnie Lwin^{24

25}, Mustafa Khasraw^{1

5

9}

Affiliations

¹ NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
² Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
³ Department of Medical Oncology, The Kinghorn Cancer Centre, Sydney, New South Wales, Australia.
⁴ Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.
⁵ The Brain Tumor Immunotherapy Program, Duke University School of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
⁶ Department of Radiation Oncology, Liverpool Hospital, Sydney, New South Wales, Australia.
⁷ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁸ Epworth HealthCare Richmond, Melbourne, Victoria, Australia.
⁹ The Preston Robert Tisch Brain Tumor Center, Duke University School of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
¹⁰ The Jackson Laboratory for Genomic Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA.
¹¹ Department of Neurological Surgery, Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
¹² Department of Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia.
¹³ UCLA Brain Tumor Imaging Laboratory, University of California Los Angeles, Los Angeles, California, USA.
¹⁴ Department of Medical Oncology, Campbelltown Hospital, Sydney, New South Wales, Australia.
¹⁵ Department of Medical Oncology, Austin Hospital, Melbourne, Victoria, Australia.
¹⁶ Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales, Australia.
¹⁷ Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
¹⁸ Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
¹⁹ Department of Medical Oncology, Port Macquarie Base Hospital, Port Macquarie, New South Wales, Australia.
²⁰ Department of Medical Oncology, Calvary Mater Newcastle, Newcastle, New South Wales, Australia.
²¹ College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
²² Department of Medical Oncology, Flinders Medical Centre, Adelaide, South Australia, Australia.
²³ Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
²⁴ School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
²⁵ Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

PMID: 37841696
PMCID: PMC10576515
DOI: 10.1093/noajnl/vdad124

NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma

Hao-Wen Sim et al. Neurooncol Adv. 2023.

. 2023 Sep 22;5(1):vdad124.

doi: 10.1093/noajnl/vdad124. eCollection 2023 Jan-Dec.

Authors

Affiliations

¹ NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
² Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
³ Department of Medical Oncology, The Kinghorn Cancer Centre, Sydney, New South Wales, Australia.
⁴ Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.
⁵ The Brain Tumor Immunotherapy Program, Duke University School of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
⁶ Department of Radiation Oncology, Liverpool Hospital, Sydney, New South Wales, Australia.
⁷ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁸ Epworth HealthCare Richmond, Melbourne, Victoria, Australia.
⁹ The Preston Robert Tisch Brain Tumor Center, Duke University School of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
¹⁰ The Jackson Laboratory for Genomic Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA.
¹¹ Department of Neurological Surgery, Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
¹² Department of Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia.
¹³ UCLA Brain Tumor Imaging Laboratory, University of California Los Angeles, Los Angeles, California, USA.
¹⁴ Department of Medical Oncology, Campbelltown Hospital, Sydney, New South Wales, Australia.
¹⁵ Department of Medical Oncology, Austin Hospital, Melbourne, Victoria, Australia.
¹⁶ Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales, Australia.
¹⁷ Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
¹⁸ Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
¹⁹ Department of Medical Oncology, Port Macquarie Base Hospital, Port Macquarie, New South Wales, Australia.
²⁰ Department of Medical Oncology, Calvary Mater Newcastle, Newcastle, New South Wales, Australia.
²¹ College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
²² Department of Medical Oncology, Flinders Medical Centre, Adelaide, South Australia, Australia.
²³ Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
²⁴ School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
²⁵ Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

PMID: 37841696
PMCID: PMC10576515
DOI: 10.1093/noajnl/vdad124

Abstract

Background: There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older.

Methods: NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm.

Results: A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events.

Conclusions: Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations.

Keywords: clinical trials; glioblastoma; immunotherapy; older cancer patients; systemic therapy.

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Conflict of interest statement

HWS acknowledges institutional research funding from AbbVie and Bristol-Myers Squibb and has received honoraria from Eli Lilly. ABH serves on the advisory board of Caris Life Sciences and WIRB-Copernicus Group, and is supported by research grants from AbbVie, Alnylam Pharmaceuticals and Cellularity. BME serves on the advisory board and as a consultant for Alpheus Medical, Curtana Pharmaceuticals, Ellipses Pharma, Global Coalition for Adaptive Research, ImmunoGenesis, Medicenna, MedQIA, Monteris, Neosoma, Sagimet Biosciences, Sapience Therapeutics, Servier Pharmaceuticals, Siemens and Sumitomo Pharma Oncology, serves as a consultant for Carthera and Chimerix, and is supported by a research grant from Siemens. HG serves on the advisory board of Merck Serono, and serves as a consultant for Curis and Telix Pharmaceuticals. HL acknowledges institutional research funding from Pfizer, and has received honoraria from AstraZeneca. JRS acknowledges institutional research funding from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Cancer Australia, Cancer Institute NSW, Merck Serono, National Health and Medical Research Council of Australia, Pfizer and Roche. ZL serves on the scientific advisory committee of Merck Sharp Dohme, has received honoraria from AstraZeneca, Bristol-Myers Squibb and Roche, and has received travel funding from Pfizer. MK acknowledges institutional research funding from AbbVie, Bristol-Myers Squibb and Specialized Therapeutics, and has received honoraria from AbbVie, Bristol-Myers Squibb, Eli Lilly, Ipsen, Pfizer and Roche.

Figures

**Figure 1.**
NUTMEG study schema. Abbreviations: irAEs = immune-related adverse events; *MGMT* = O⁶-methylguanine-DNA-methyltransferase promoter methylation status; OD = once daily; RT = radiotherapy; TMZ = temozolomide.

**Figure 2.**
CONSORT diagram. Abbreviations: NIVO = nivolumab; TMZ = temozolomide.

**Figure 3:**
Efficacy Kaplan–Meier curves: (a) overall survival; (b) progression-free survival. Abbreviations: HR (95% CI) = hazard ratio with 95% CI; NIVO = nivolumab; OS = overall survival; PFS = progression-free survival; TMZ = temozolomide.

**Figure 4:**
Mean change in EORTC QLQ-C30 global health status compared to baseline. Abbreviations: ADJ = adjuvant chemotherapy; NIVO = nivolumab; TMZ = temozolomide.

See this image and copyright information in PMC

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NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma

Affiliations

NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

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