Dual Immune Check Point Blockade in MGMT-Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial

Andrew B Lassman; Mei-Yin C Polley; Fabio M Iwamoto; Andrew E Sloan; Tony JC Wang; Kenneth D Aldape; Jeffrey S Wefel; Vinai Gondi; Alonso N Gutierrez; Mohammed H Manasawala; Mark R Gilbert; Erik P Sulman; Jedd D Wolchok; Richard M Green; Elizabeth C Neil; Rimas V Lukas; Samuel A Goldlust; Matija Snuderl; Kristyn Galbraith; James J Dignam; Minhee Won; Minesh P Mehta

doi:10.1200/JCO-25-00618

. 2025 Aug 8;43(27):3032–3040. doi: 10.1200/JCO-25-00618

Dual Immune Check Point Blockade in MGMT-Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial

Andrew B Lassman ^1,^2,^3,^✉, Mei-Yin C Polley ^4,⁵, Fabio M Iwamoto ^1,^2,³, Andrew E Sloan ⁶, Tony JC Wang ^2,^3,⁷, Kenneth D Aldape ⁸, Jeffrey S Wefel ⁹, Vinai Gondi ¹⁰, Alonso N Gutierrez ¹¹, Mohammed H Manasawala ¹², Mark R Gilbert ¹³, Erik P Sulman ^14,¹⁵, Jedd D Wolchok ^3,¹⁶, Richard M Green ^17,¹⁸, Elizabeth C Neil ^19,²⁰, Rimas V Lukas ²¹, Samuel A Goldlust ^22,²³, Matija Snuderl ^15,²⁴, Kristyn Galbraith ^15,²⁵, James J Dignam ^4,⁵, Minhee Won ^4,²⁶, Minesh P Mehta ¹¹

^¹Division of Neuro-Oncology, Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY

^²Herbert Irving Comprehensive Cancer Center, New York, NY

^³NewYork-Presbyterian, New York, NY

^⁴NRG Oncology Statistics and Data Management Center, Philadelphia, PA

^⁵Department of Public Health Sciences, University of Chicago, Chicago, IL

^⁶Department of Neurosurgical Oncology, Piedmont Health, Atlanta, GA

^⁷Deptartment of Radiation Oncology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY

^⁸Laboratory of Pathology, National Cancer Institute, Bethesda, MD

^⁹Department of Neuro-Oncology, Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX

^¹⁰Department of Radiation Oncology, Northwestern Medicine Cancer Center Warrenville and Proton Center, Warrenville, IL

^¹¹Department of Radiation Oncology, Miami Cancer Institute—Baptist Health South Florida, Miami, FL

^¹²Department of Radiology, WellSpan Health, York, PA

^¹³National Institutes of Health Clinical Center, Neuro-Oncology Branch, Bethesda, MD

^¹⁴Department of Radiation Oncology, New York University (NYU) Grossman School of Medicine, New York, NY

^¹⁵Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY

^¹⁶Department of Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY

^¹⁷Department of Neurology, Kaiser Permanente-Los Angeles Medical Center, Los Angeles, CA

^¹⁸Accrual for Kaiser Permanente NCI Community Oncology Research Program

^¹⁹Department of Neurology, University of Minnesota/M Health Fairview Cancer Center, Minneapolis, MN

^²⁰Accruals for Metro Minnesota Community Oncology Research Consortium

^²¹Department of Neurology, Northwestern University, Chicago, IL

^²²Department of Neuro-Oncology, Saint Luke's Hospital, Saint Luke's Cancer Institute, Kansas City, MO

^²³Accruals for Hackensack University Medical Center

^²⁴Department of Pathology, New York University (NYU) Grossman School of Medicine, New York, NY

^²⁵Department of Pathology, University of Washington, Seattle, WA

^²⁶Statistics Department, American College of Radiology, Philadelphia, PA

^✉

Andrew B. Lassman, MD; e-mail: ABL7@cumc.columbia.edu.

PMCID: PMC12440284 PMID: 40779733

Abstract

PURPOSE

New therapies for glioblastoma are needed, especially MGMT-unmethylated (uMGMT) disease. NRG Oncology BN002 (phase I) demonstrated safety and suggested efficacy of ipilimumab (ipi) with nivolumab (nivo) in newly diagnosed glioblastoma, leading to this phase II/III trial.

METHODS

Adults with newly diagnosed uMGMT glioblastoma and Karnofsky performance status (KPS) ≥70 were randomly assigned to radiotherapy with either immunotherapy (ipi and nivo) or temozolomide (TMZ), stratified by recursive partitioning analysis (RPA) class and intention to use tumor treating fields. With 95% power to detect a hazard ratio (HR) ≤0.58 for progression-free survival (PFS) at a one-sided significance level (P) of .15, superior PFS with immunotherapy in phase II would lead to phase III overall survival (OS) testing. Corticosteroids were disallowed when starting immunotherapy. Diagnosis, biomarkers, and PFS were centrally assessed.

RESULTS

One hundred fifty-nine participants were randomly assigned (79 immunotherapy and 80 TMZ). Arms were well balanced for age (median 60 years, range, 28-79), sex (male n = 105, 66%), KPS (90-100 n = 97, 61%), resection extent (gross total, n = 103, 65%), and RPA class (III, n = 16, 10%; IV, n = 116, 73%; V, n = 27, 17%). A preplanned analysis of phase II data conducted after 100 centrally determined PFS events showed no significant PFS improvement for ipi and nivo versus TMZ (median 7.7 months v 8.5 months, HR, 1.47 [70% CI, 1.19 to 1.83]; one-sided P = .96 [95% CI, 0.98 to 2.2]). OS is immature (>50% alive) but with no observed difference between arms (median approximately 13 months each, HR, 0.95 [95% CI, 0.61 to 1.49]; P = .36).

CONCLUSION

Ipi and nivo did not improve PFS among patients with newly diagnosed uMGMT glioblastoma versus TMZ. Accrual closed permanently; the trial will not proceed to phase III. No new safety signals were identified. Molecular correlative analyses and survival follow-up are ongoing.

INTRODUCTION

The most common primary cancer of the brain in adults is glioblastoma. Prognosis remains poor despite aggressive multimodality first-line therapy,¹ typically cytoreductive surgery followed by radiotherapy and temozolomide (TMZ) chemotherapy, with or without tumor treating fields (TTFields).^2,3 New therapies are needed.

CONTEXT

Key Objective
Does dual immune checkpoint inhibition with the T lymphocyte–associated protein-4 inhibitor ipilimumab and the PD-1 pathway inhibitor nivolumab (without temozolomide [TMZ]) improve survival in newly diagnosed MGMT-unmethylated glioblastoma, when compared with TMZ, each with radiotherapy after maximal safe surgical resection?
Knowledge Generated
Progression-free survival (PFS) was not improved and was numerically shorter with dual immune checkpoint inhibition than with TMZ. Overall survival is immature also but without improvement at the time of analysis.
Relevance (R.G. Maki)
While hope continues that immunotherapy in one its manifestations will be useful for patients with glioblastoma, these data reaffirm the activity of TMZ with radiation for primary resected disease.*
*Relevance section written by JCO Associate Editor Robert G. Maki, MD, PhD, FACP, FASCO.

TMZ was demonstrated to prolong survival when added to radiotherapy 20 years ago.¹ Since then, most clinical trials incorporated TMZ as the standard of care, and experimental agents have been added on to, rather than in lieu of, the radiochemotherapy backbone, including trials from National Cancer Institute (NCI) networks, such as Radiation Therapy Oncology Group (RTOG) 0525 (dose-dense TMZ),⁴ RTOG 0825 (bevacizumab),⁵ RTOG 3508 (EGFR-directed antibody drug conjugate),⁶ and most recently Alliance A071102 (veliparib).⁷ However, none of these approaches improved survival.

Immune checkpoint inhibitors (ICIs), first the T lymphocyte–associated protein-4 inhibitor ipilimumab (ipi) and later the PD-1 pathway inhibitors such as nivolumab (nivo), revolutionized treatment of other cancers.^8,9 Dual ICI therapy has superior efficacy, with reasonable safety, over single agents in other solid tumors such as malignant skin (melanoma),¹⁰ urothelial,¹¹ colorectal,¹² and ovarian cancers,¹³ including those with brain metastases¹⁴ and low PD-L1 expression¹⁵ that typifies most glioblastomas.

Therefore, NRG Oncology first conducted a phase I clinical trial (BN002) in newly diagnosed glioblastoma, demonstrating both safety and a possible early efficacy signal (median survival 21 months, n = 19) with combined ipi and nivo, despite limited potential brain penetration of checkpoint inhibitors.¹⁶ As a randomized trial was a logical next step, NRG Oncology designed the phase II/III BN007, especially as there were no other NCI- or industry-sponsored dual ICI trials for newly diagnosed glioblastoma ongoing or planned. To ensure appropriate resource utilization, the trial was designed with a go–no go strategy to proceed to the full randomized phase III effort after 100 initial progression of disease (PD) events in the randomized phase II.

Finally, TMZ is most effective in tumors demonstrating silencing of the alkylator resistance gene O⁶-methylguanine-DNA-methyltransferase (MGMT) through promoter methylation; conversely, tumors with an unmethylated MGMT promoter (uMGMT), representing >60% of all cases, are generally considered TMZ-insensitive.¹⁷ As TMZ is neither curative nor innocuous, replacing TMZ with a potentially superior alternative is an attractive therapeutic strategy.¹⁸ Therefore, we focused on the patients with uMGMT glioblastomas, omitting TMZ in an experimental immunotherapy (ipi plus nivo) arm, both to simplify the study design and to avoid potential toxicities of TMZ, including lymphopenia that could reduce ICI efficacy. In addition, uMGMT glioblastoma is more aggressive than methylated disease; therefore, restricting eligibility to patients with uMGMT tumors would also abbreviate the trial.

METHODS

Eligibility

Adults with a Karnofsky performance status (KPS) ≥70¹⁹ and newly diagnosed uMGMT glioblastoma were the patient population. Active autoimmune disease and immunosuppressive therapy were exclusionary. Systemic corticosteroids were disallowed within 3 days of random assignment (below).

All patients or their legally authorized representatives provided written informed consent before any study-specific procedures. The study was approved and overseen by the NCI-Central Institutional Review Board.

Biomarkers

Diagnosis (glioblastoma by K.D.A., M.S., and K.G.) and MGMT promoter methylation (E.P.S.) by MGMT-STP27²⁰ were confirmed centrally before random assignment using the Illumina EPIC v1 Array with previously reported protocols.²¹ The WHO 2016 criteria²² for the definition of glioblastoma were used as they were active during trial design. However, we (K.D.A.) were aware of and contributed to an emerging consensus²³ that isocitrate dehydrogenase (IDH) mutation would become mutually exclusive with a diagnosis of glioblastoma in the 2021 criteria, which were published after the trial launched.²⁴ Therefore, anticipating the evolving definition of glioblastoma, we required IDH testing (locally) by at least one standard method during screening, and IDH mutation was exclusionary. Although confirmatory IDH-specific gene sequencing was not conducted in all cases when IDH1 (R132H) immunohistochemistry did not detect an IDH1 R132H mutant protein (which could fail to identify approximately 10% of all IDH mutations²⁵), high-grade IDH-mutated gliomas and other glioblastoma histopathologic mimickers were excluded using the central nervous system tumor classifier as described previously.²⁶ Tissue and serum were also collected for molecular correlative analyses, such as PD-L1 expression and mutational burden, to be performed post hoc and reported separately.

Treatment

Radiotherapy

In all patients, radiotherapy was planned using a contrast-enhanced brain magnetic resonance imaging (MRI) performed within 3 days postoperatively to a total dose of 60 Gy in 30 fractions of 2 Gy each over approximately 6 weeks, using a shrinking-field approach, typical of all RTOG/NRG glioblastoma trials. In general, treatment was performed using a sequential boost technique based upon the postoperative contrast-enhanced and T2-weighted FLAIR (preferred over conventional T2) MRI—46 Gy in 2 Gy per fraction to the T2-weighted FLAIR abnormality including the surgical cavity (GTV_4600) followed by a boost of 14 Gy in 2 Gy per fraction to the contrast-enhancing T1 abnormality and surgical cavity (GTV_6000) to a total dose of 60 Gy. A 2 cm CTV margin was used, which may be reduced around natural barriers, as well as a 4-5 mm PTV margin. Dose constraints are specified in the protocol. Both intensity-modulated and 3-dimensional conformal approaches were permitted. Protons were disallowed.

Chemotherapy and Immunotherapy

Eligible patients were randomly assigned (1:1) to start treatment within 6 weeks after maximal safe surgical resection. Treatment consisted of radiotherapy with and followed by either TMZ (standard arm) or ipi and nivo without TMZ (experimental arm). Neither treating investigators nor patients were blinded to results of random assignment. TMZ was sourced commercially and administered at standard doses during radiotherapy and for six adjuvant 28-day cycles¹ with up to 12 adjuvant cycles allowed. In the experimental arm, no TMZ was given; ipi was dosed at 1 mg/kg once every 4 weeks (4 dose maximum); nivo was dosed at 3 mg/kg once every 2 weeks (or 240 mg flat dose after completion of ipi) and intended to continue until disease progression. Ipi and nivo were supplied by the NCI. Postprogression treatment was at the discretion of the treating investigator and was not collected. Crossover from TMZ to immunotherapy was not offered.

TTFields

As TTFields is an approved therapy in the United States for glioblastoma, we allowed TTFields on the standard arm (after radiotherapy) both to address ethical considerations and reduce dropout. However, TTFields were disallowed on the immunotherapy arm because of concerns about overlapping cutaneous toxicities. To balance these considerations, we followed the design of Alliance A071102, which stratified random assignment by intention to use TTFields.⁷ Intention and actual TTF usage were classified as binary variables (yes or no), and we did not collect other details such as amount of time or duration the device was worn. TTFields was commercially sourced.

Supportive Care

Prophylaxis for Pneumocystis jirovecii (previously carinii) pneumonia during chemoradiotherapy was strongly recommended but not required.¹ Systemic corticosteroids, anticonvulsants, antiemetics, and other general neuro-oncology supportive care measures were unrestricted after treatment initiation on both arms. Immunotherapy-related adverse events were managed with dose delays and reductions and, if needed, corticosteroids according to typical algorithms associated with commercial ipi and nivo usage. Similarly, dose adjustments and delays for TMZ-associated toxicities followed standard-of-care guidance.

Follow-Up

Routine physical, neurologic, and laboratory evaluations were performed at baseline and before every 4-week cycle in all patients. Brain MRI scans were performed 4 weeks after radiotherapy (baseline as detailed below) and before every other cycle thereafter during treatment. Additional evaluations were performed in patients randomly assigned to the experimental arm to enhance the safety and monitoring for immunotherapy toxicities, including thyroid, chemistry, and hepatic function testing before every nivo dose. Patient-reported outcomes were collected and neurocognitive function evaluated at baseline and before every other cycle, intended on the same day as contrast-enhanced brain MRI scans to allow clinical and imaging correlations. No other anticancer therapy other than protocol treatment was permitted. Adverse events were graded according to CTCAE v5.0.

Response Criteria

PD was defined according to the 2010 Response-Assessment in Neuro-Oncology (RANO) criteria²⁷ except that the postradiotherapy MRI, rather than postoperative preradiotherapy MRI, was used as the baseline for patients continuing on protocol therapy,²⁸ the approach which has since become part of the RANO 2.0 criteria.²⁹ PD within 12 weeks after radiotherapy completion was defined as new contrast-enhancing tumor outside the radiation field (beyond the high-dose region or 80% isodose line) or unequivocally viable tumor on histopathologic analysis of a new surgical specimen. After 12 weeks from radiotherapy completion, PD was defined as an increase by ≥25% in cross-sectional area of enhancing disease (relative to the postradiotherapy baseline), or disease-related clinical deterioration. Assessment of PD for purposes of deciding whether to discontinue protocol therapy was made by the treating investigator. Treatment was allowed to continue in ambiguous situations with reassessment for PD (imaging, clinical) after ≤2 additional cycles.

PD for calculating progression-free survival (PFS) was determined centrally by study modality chairs (led by V.G. with contributions from T.J.C.W.). To reduce the potential for real or perceived bias, central reviewers were blinded to treatment allocation, and the overall principal investigator (A.B.L.) was not involved.

Statistical Design

The primary end point for phase II was PFS, defined as the time from random assignment to centrally determined PD or death from any cause. The primary end point for phase III was overall survival (OS), defined as the time from random assignment to death from any cause.

There was a two-step registration process. In step 1, tissue from accrued patients was sent for central MGMT and diagnostic testing. Patients who met diagnostic, MGMT, and other eligibility criteria proceeded to step 2 and were randomly assigned 1:1 using the permuted-block randomization and stratified by intention to use TTFields (yes v no) as above, and by recursive partitioning analysis (RPA) class (III v IV v V), a composite encompassing the known prognostic variables of performance status, extent of resection, neurologic function, and age³⁰.

Phase II planned to randomly assign ≥150 patients; 100 PFS events (from both arms) would provide 95% statistical power to detect an improvement in median PFS from 5.7 months expected in the control arm to 9.7 months in the experimental arm, corresponding to a hazard reduction of 42% (hazard ratio [HR], 0.58) at one-sided significance level of 0.15. The definitive analysis for phase II would be conducted after 100 PFS events were observed and central reviews of progression completed. The analysis was performed on an intention-to-treat basis, including all randomly assigned patients with follow-up information. If the stratified log-rank test had a one-sided P value ≤.15, then continuation of accrual to phase III would occur to evaluate OS; otherwise, accrual would discontinue permanently after phase II. All analyses were performed using SAS version 9.4.

Secondary and exploratory end points to be reported separately included the effect of immunotherapy on patient-reported outcomes and on neurocognitive function, and biomarkers of potential predictive importance for immunotherapy such as PD-L1 expression and tumor mutational burden.

The full protocol contains additional methodological details (Data Supplement, online only).

RESULTS

Enrollment

The trial activated on August 6, 2020, and accrual was suspended on April 27, 2022; 374 patients were screened and 159 randomly assigned (Fig 1, Data Supplement). The most common reason that patients did not proceed to random assignment (n = 215, 57%) was MGMT promoter status (n = 95, 44.2%). Central analyses determined a diagnosis other than glioblastoma in 10 (4.7%) and detected an IDH mutation in two (<1%). Among randomly assigned patients, median age was 60 years (range, 28-79), and 105 (66.0%) were men. The arms were well balanced for age, KPS, extent of resection, RPA class, and TTFields intent (Table 1). Most patients were male, White (n = 140, 88.1%), and not Hispanic or Latino (n = 142, 89.3%). Three patients were randomly assigned despite ineligibility (two TMZ, one ICI), all because corticosteroids were taken within 3 days before step 2 registration; they are included in the intention-to-treat analyses of PFS and OS.

TABLE 1.

Baseline Characteristics Among Randomly Assigned Patients

Baseline Characteristic	RT + TMZ (n = 80)	RT + ipi + nivo (n = 79)	Total (N = 159)
Age, years, median (range)	59.5 (28-77)	61 (35-79)	60 (28-79)
Sex, No. (%)
Male	54 (67.5)	51 (64.6)	105 (66.0)
Female	26 (32.5)	28 (35.4)	54 (34.0)
Race, No. (%)
Asian	3 (3.8)	4 (5.1)	7 (4.4)
Black or African American	1 (1.3)	2 (2.5)	3 (1.9)
White	71 (88.8)	69 (87.3)	140 (88.1)
Unknown/not reported	5 (6.3)	4 (5.1)	9 (5.7)
Ethnicity, No. (%)
Hispanic or Latino	7 (8.8)	9 (11.4)	16 (10.1)
Not Hispanic or Latino	73 (91.3)	69 (87.3)	142 (89.3)
Unknown	0 (0.0)	1 (1.3)	1 (0.6)
KPS, No. (%)
70	10 (12.5)	6 (7.6)	16 (10.1)
80	24 (30.0)	22 (27.8)	46 (28.9)
90	37 (46.3)	36 (45.6)	73 (45.9)
100	9 (11.3)	15 (19.0)	24 (15.1)
Extent of resection, No. (%)
Biopsy	1 (1.3)	0 (0.0)	1 (0.6)
Subtotal	28 (35.0)	27 (34.2)	55 (34.6)
Total (gross)	51 (63.8)	52 (65.8)	103 (64.8)
Neurologic function, No. (%)
No symptoms	22 (27.5)	37 (46.8)	59 (37.1)
Minor symptoms	44 (55.0)	27 (34.2)	71 (44.7)
Moderate symptoms (fully active)	11 (13.8)	10 (12.7)	21 (13.2)
Moderate symptoms (required assistance)	3 (3.8)	5 (6.3)	8 (5.0)
RPA class,^a No. (%)
III	9 (11.3)	7 (8.9)	16 (10.1)
IV	58 (72.5)	58 (73.4)	116 (73.0)
V	13 (16.3)	14 (17.7)	27 (17.0)
Intention to use tumor treating fields,^a No. (%)
No	42 (52.5)	41 (51.9)	83 (52.2)
Yes	38 (47.5)	38 (48.1)	76 (47.8)

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NOTE. RPA Class definitions: III: age <50 years, KPS ≥ 90; IV: age < 50 years, KPS < 90; OR age ≥ 50 years, KPS ≥ 70, EOR > biopsy, INF ≤ minor; V: age ≥ 50 years, KPS ≥ 70, EOR > Bx, INF > minor; OR age ≥ 50 years, KPS ≥ 70, EOR = biopsy.

Abbreviations: EOR, extent of resection; INF, impairment of neurologic function; ipi, ipilimumab; KPS, Karnofsky performance status; nivo, nivolumab; RPA, recursive partitioning analysis; RT, radiotherapy; TMZ, temozolomide.

^{^a}

Stratification factor in random assignment.

Treatment Delivery

On the standard and experimental arms, 93% and 98% of patients, respectively, received radiotherapy per protocol, nearly always (97% and 95%) with IMRT. TMZ was given to 92% of patients on the standard arm (and 0% on the experimental arm) with a median of 4 (range, 1-10) adjuvant postradiotherapy cycles. Ipi and nivo were given to 99% of patients on the experimental arm (and 0% on the standard arm), with a median of 4 (range, 1-4) and 8 (range, 1-25) infusions each (Appendix Tables A1-A3, online only).

Adverse Events

Treatment-related (possibly, probably, or definitely) grade 3 to 4 (highest-grade) adverse events were reported in 22 (29.7%) and six (8.1%) patients on the TMZ arm compared with 26 (33.3%) and four (5.1%) on the immunotherapy arm. There were two treatment-related deaths on the immunotherapy arm: autoimmune disorder reported as probably related, and colitis reported as definitely related, 68 and 84 days after the last ipi/nivo infusion, respectively. There were nine (11.5%) patients with reported grade ≥3 GI disorders on the immunotherapy arm compared with two (2.7%) on the TMZ arm. However, there was no significant difference in the frequency of treatment-related adverse events between arms (n = 28, 37.8%, TMZ arm v n = 32, 41%, immunotherapy arm; P = .69 by chi-square Table 2 and Appendix Table A4).

TABLE 2.

All Reported Treatment-Related (definitely, probably, or possibly) Adverse Events

Treatment-Related AE	RT + TMZ (n = 74), No. (%)	RT + ipi + nivo (n = 78), No. (%)
Grade <3	46 (62.2)	46 (59.0)
Grade 3 to 5	28 (37.8)	32 (41.0)

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NOTE. Seven patients received no study treatment (6 on the standard arm and 1 on the experimental arm) and were excluded from adverse event analyses, which were graded with CTCAE version 5.

Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; ipi, ipilimumab; nivo, nivolumab; RT, radiotherapy; TMZ, temozolomide.

Efficacy

Among 159 randomly assigned patients, PFS was not improved by combined ipi and nivo over TMZ (HR, 1.47 [70% CI, 1.19 to 1.83]; one-sided P = .96 [95% CI, 0.98 to 2.21]; Fig 2). Median PFS among patients randomly assigned to immunotherapy was 7.7 months (95% CI, 6.5 to 8.5) versus 8.5 months (95% CI, 7.1 to 10.4) among patients randomly assigned to TMZ after 12.9 months of median follow-up (95% CI, 8.6 to 14.7). As the threshold for likely superiority of immunotherapy over TMZ did not meet the prespecified goal (one-sided P = .96 > 0.15), accrual was discontinued permanently after phase II and will not reopen for phase III. At the time of the phase II primary analysis, a total of 34 PFS observations were censored within 6 months of random assignment; administrative censoring and consent withdrawal were the primary reasons for these early censored observations. There was also no obvious difference in OS between arms at the time of data analysis (HR, 0.95 [95% CI, 0.61 to 1.49]; P = .36), noting, however, that these data remain immature with 81 (51%) of randomly assigned patients alive (Appendix Fig A1). Among 78 patients who died, PD was the most common reported cause (TMZ: n = 41, 90.2%; ipi + nivo: n = 37, 78.4%).

TTFields

Before random assignment, 72 of 159 patients (45.3%) declared an intention to use TTFields if permitted. Among these, 38 were then randomly assigned to each arm, only four (11%) of whom actually used TTFields on the standard arm (after radiotherapy as permitted). None used TTFields on the experimental arm where it was disallowed per protocol (Appendix Table A5).

DISCUSSION

Ipi and nivo did not improve PFS for patients with newly diagnosed uMGMT glioblastoma in this NCI National Clinical Trials Network (NRG BN007) randomized phase II/III trial. There was no benefit from immunotherapy despite disallowing corticosteroids at the start of immunotherapy, which had emerged as possibly correlated with efficacy from ICIs from subset analyses in other studies.^31,32 In addition, although there was no limit on maximum tumor size for accrual, the requirement for a KPS of at least 70 and a complete tapering of corticosteroids at least 3 days before random assignment indirectly excluded patients with very large tumors with symptomatic surrounding cerebral edema. In this way, we also sought to exclude patients with tumors growing so rapidly that ICI therapy might not take effect before PD. Along these lines, 12 patients with rapidly growing tumors who suffered PD during screening were also excluded (Fig 1). As an additional mechanism to guard against accruing patients with minimally resected tumors, we required sufficient tissue for central MGMT and other biomarker analyses; in fact, all patients randomly assigned to ICIs underwent at least subtotal resection (Table 1).

Only four patients (11%) permitted to use TTFields actually did so, consistent with previous data suggesting limited uptake in the glioblastoma population.^33,34 Therefore, although we cannot exclude an imbalance of benefit from TTFields favoring the standard arm, the minimal use of TTFields suggests that there was no confounding effect on results in this exploratory analysis. Two NCI network trials (this trial and Alliance A071102) have now successfully incorporated intention to use TTFields as a stratification factor during random assignment to balance the ethical concerns with disallowing use of a US Food and Drug Administration–approved therapy against the potential confounding effect of its use on disease control, and future studies for glioblastoma may follow this lead.

Since this trial was designed, several other randomized studies for newly diagnosed^35,36 or recurrent³¹ glioblastoma were completed. Although patients in these other trials were treated with single-agent PD-1 inhibitors rather than dual ICI therapy, none showed superiority of immunotherapy over standard of care. Therefore, NRG BN007 adds to the growing collection of data indicating ICIs are ineffective in glioblastoma, at least without molecular selection or other criteria to enrich accrual for those most likely to benefit.

In addition, an emerging theme surrounding omission of TMZ is concerning. For example, the phase III CheckMate 498 (ClinicalTrials.gov identifier: NCT02617589) randomly assigned 560 patients with newly diagnosed uMGMT glioblastoma to either standard TMZ or nivo.³⁶ There was no benefit from nivo over TMZ overall, or by baseline corticosteroid dose or PD-L1 expression. Moreover, survival was significantly worse among patients randomly assigned to nivo versus TMZ (median 13.4 v 14.9 months; HR, 1.31 [95% CI, 1.09 to 1.58]; P = .0037). Similarly, we found PFS was numerically shorter among patients randomly assigned to ipi and nivo versus TMZ.

Although it is plausible that ipi and nivo shortened survival, we believe that is unlikely, given the lack of a difference in moderate to severe adverse events between arms. Rather, as MGMT promoter status exists on a spectrum from methylated to unmethylated, our results and those from CheckMate 498 reinforce that TMZ accordingly has some antitumor activity in glioblastomas classified as uMGMT.³⁷ By extension, this means that, in designing future studies, replacing TMZ with the special sauce du jour may be reasonable, but the said sauce must demonstrate superiority not only to nothing, but also to the limited but nonzero benefit provided by TMZ in uMGMT cases. We relied on central MGMT analysis, rather than local results, to avoid enrolling patients with MGMT-promoter methylated disease because concordance between laboratories is poor.³⁸ However, it may have been prudent to require dual testing (with uMGMT results on both), an approach used by others.³⁹

Finally, although we observed no difference in OS between arms at the time of the interim analysis, the data are immature (Appendix Fig A1). Follow-up continues and biomarker analyses are ongoing seeking a subset that may have benefited from dual ICI therapy.

ACKNOWLEDGMENT

The authors thank NRG Oncology headquarters and the Brain Committee, site investigators and teams from accruing institutions (Data Supplement), patients, and caregivers, all of whom were essential to making this trial possible as contributors to the ongoing mission to lengthen and improve the lives of patients with cancer by conducting practice-changing multi-institutional clinical and translational research. A.B.L., F.M.I., and T.C.J.W. thank the Herbet Irving Comprehensive Cancer Center and the clinicians, coordinators, and other staff from its Clinical Protocol & Data Management Office for supporting trial conduct at Columbia University Irving Medical Center/NewYork-Presbyterian. The authors also appreciate publication support from Suzanne Baldwin of NRG Oncology.

APPENDIX

FIG A1. — OS by treatment arm. Median follow-up for survival was 13.7 months (95% CI, 11.9 to 14.9). HR, hazard ratio; ipi, ipilimumab; nivo, nivolumab; OS, overall survival; RT, radiotherapy; TMZ, temozolomide.

TABLE A1.

Radiotherapy Delivery

Radiotherapy	Radiotherapy + Temozolomide (n = 80)	Radiotherapy + Ipilimumab+ Nivolumab (n = 79)
Radiotherapy given, No. (%)
No	6 (7.5)	1 (1.3)
Yes	74 (92.5)	77 (97.5)
Not reported	0 (0.0)	1 (1.3)
Reasons radiotherapy not started or discontinued, No. (%)
Completed	72 (90.0)	71 (89.9)
Adverse event	0 (0.0)	1 (1.3)
Physician decision	0 (0.0)	1 (1.3)
Progressive disease	1 (1.3)	1 (1.3)
Withdrawal by patient	5 (6.3)	2 (2.5)
Other	1 (1.3)	2 (2.5)
Unknown	1 (1.3)	0 (0.0)
Not reported	0 (0.0)	1 (1.3)
Radiotherapy technique, No. (%)	(n = 74)	(n = 77)
3-dimensional conformal radiotherapy	1 (1.4)	2 (2.6)
Intensity-modulated radiotherapy	72 (97.3)	73 (94.8)
Not reported	1 (1.4)	2 (2.6)

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TABLE A2.

Temozolomide Delivery

Chemotherapy	Control Arm (n = 80)
Temozolomide given, No. (%)
Yes	74 (92.5)
No	6 (7.5)
Adjuvant cycles, No.
Median (range)	4 (1-10)

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TABLE A3.

Immunotherapy (experimental arm only, n = 79)

Immunotherapy	Ipilimumab	Nivolumab
Immunotherapy given, No. (%)
Yes	78 (98.7)	78 (98.7)
No	1 (1.3)	1 (1.3)
Infusions given, No.
Median (range)	4 (1-4)	8 (1-25)

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NOTE. Ipilimumab given once every 4 weeks for up to four doses, and nivolumab given once every 2 weeks.

TABLE A4.

Highest-Grade Adverse Events Reported as Possibly, Probably, or Definitely Related to Protocol Treatment

System Organ Class	Radiotherapy + Temozolomide (n = 74)					Radiotherapy + Ipilimumab + Nivolumab (n = 78)
	Patients by Grade, No. (%)					Patients by Grade, No. (%)
	1	2	3	4	5	1	2	3	4	5
Overall highest grade	16 (21.6)	23 (31.1)	22 (29.7)	6 (8.1)	0 (0.0)	9 (11.5)	32 (41.0)	26 (33.3)	4 (5.1)	2 (2.6)
Blood and lymphatic system disorders	13 (17.6)	1 (1.4)	0 (0.0)	0 (0.0)	0 (0.0)	11 (14.1)	1 (1.3)	1 (1.3)	0 (0.0)	0 (0.0)
Cardiac disorders	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	3 (3.8)	1 (1.3)	0 (0.0)	0 (0.0)	0 (0.0)
Endocrine disorders	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	6 (7.7)	7 (9.0)	2 (2.6)	0 (0.0)	0 (0.0)
Eye disorders	1 (1.4)	1 (1.4)	0 (0.0)	0 (0.0)	0 (0.0)	8 (10.3)	1 (1.3)	0 (0.0)	0 (0.0)	0 (0.0)
GI disorders	25 (33.8)	17 (23.0)	2 (2.7)	0 (0.0)	0 (0.0)	13 (16.7)	16 (20.5)	6 (7.7)	2 (2.6)	1 (1.3)
General disorders and administration site conditions	27 (36.5)	16 (21.6)	3 (4.1)	0 (0.0)	0 (0.0)	21 (26.9)	23 (29.5)	1 (1.3)	1 (1.3)	0 (0.0)
Immune system disorders	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.3)	1 (1.3)
Infections and infestations	2 (2.7)	2 (2.7)	1 (1.4)	0 (0.0)	0 (0.0)	0 (0.0)	5 (6.4)	2 (2.6)	1 (1.3)	0 (0.0)
Injury, poisoning, and procedural complications	5 (6.8)	1 (1.4)	0 (0.0)	0 (0.0)	0 (0.0)	5 (6.4)	5 (6.4)	1 (1.3)	0 (0.0)	0 (0.0)
Investigations	9 (12.2)	16 (21.6)	15 (20.3)	5 (6.8)	0 (0.0)	18 (23.1)	12 (15.4)	8 (10.3)	2 (2.6)	0 (0.0)
Metabolism and nutrition disorders	15 (20.3)	9 (12.2)	0 (0.0)	0 (0.0)	0 (0.0)	17 (21.8)	6 (7.7)	4 (5.1)	1 (1.3)	0 (0.0)
Musculoskeletal and connective tissue disorders	6 (8.1)	0 (0.0)	2 (2.7)	0 (0.0)	0 (0.0)	8 (10.3)	8 (10.3)	5 (6.4)	0 (0.0)	0 (0.0)
Nervous system disorders	17 (23.0)	9 (12.2)	6 (8.1)	0 (0.0)	0 (0.0)	12 (15.4)	13 (16.7)	8 (10.3)	1 (1.3)	0 (0.0)
Psychiatric disorders	6 (8.1)	1 (1.4)	0 (0.0)	0 (0.0)	0 (0.0)	4 (5.1)	5 (6.4)	1 (1.3)	0 (0.0)	0 (0.0)
Renal and urinary disorders	1 (1.4)	2 (2.7)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Respiratory, thoracic, and mediastinal disorders	2 (2.7)	0 (0.0)	0 (0.0)	1 (1.4)	0 (0.0)	8 (10.3)	3 (3.8)	2 (2.6)	0 (0.0)	0 (0.0)
Skin and subcutaneous tissue disorders	17 (23.0)	7 (9.5)	0 (0.0)	0 (0.0)	0 (0.0)	23 (29.5)	7 (9.0)	3 (3.8)	0 (0.0)	0 (0.0)
Vascular disorders	2 (2.7)	1 (1.4)	2 (2.7)	0 (0.0)	0 (0.0)	3 (3.8)	5 (6.4)	4 (5.1)	1 (1.3)	0 (0.0)

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NOTE. Seven patients received no study treatment and are not included. Adverse events were graded with CTCAE, version 5.0.

Abbreviation: CTCAE, Common Terminology Criteria for Adverse Events.

TABLE A5.

Tumor Treating Fields, Intention to Use Versus Actually Used

Intent to Use Tumor Treating Fields	Tumor Treating Fields Not Used, No. (%)	Tumor Treating Fields Used, No. (%)	Total, No. (%)
Radiotherapy + temozolomide arm	(n = 76)	(n = 4)	(n = 80)
No	42 (55.3)	0 (0.0)	42 (52.5)
Yes	34 (44.7)	4 (100.0)	38 (47.5)
Radiotherapy + ipilimumab + nivolumab arm	(n = 79)	(n = 0)	(n = 79)
No	41 (51.9)	0 (0.0)	41 (51.9)
Yes	38 (48.1)	0 (0.0)	38 (48.1)

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Andrew B. Lassman

Stock and Other Ownership Interests: Moderna (ended)

Consulting or Advisory Role: Sapience Therapeutics, Global Coalition for Adaptive Research, Orbus, Servier, Fore, Curio Science, Alpha Detail, Bluestar Bioadvisors, Gerson Lehrman Group, Reach Market Research, Guidepoint Global, Modifibio, Nerviano Medical Sciences, Rigel, BioClinica as an expert blinded independent reviewer of clinical and imaging data for a BMS-sponsored trial

Research Funding: AbbVie (Inst), Genentech/Roche (Inst), Aeterna Zentaris (Inst), VBI Vaccines (Inst), Pfizer (Inst), Karyopharm Therapeutics (Inst), Bayer (Inst), QED Therapeutics (Inst), Orbus Therapeutics (Inst), BMS (Inst), Chimerix (Inst), NextSource (Inst), DelMar Pharmaceuticals (Inst), Corden (Inst), Kazia Therapeutics (Inst), Servier (Inst), Biohaven Pharmaceuticals (Inst), Vigeo Therapeutics (Inst), Incyte (Inst), Abbott Laboratories (Inst), Polaris (Inst), Kintara Therapeutics (Inst), Novartis (Inst), Global Coalition for Adaptive Research (Inst), AstraZeneca (Inst)

Travel, Accommodations, Expenses: AbbVie, Foundation Medicine, Servier, Anheart/Nuvation, Global Coalition for Adaptive Research, Gilead, Sapience, Orbus, Incyte, Moving Innovation and Technology, Modifibio, VBI Vaccines, Curio Science, Fortrea

Mei-Yin Polley

Consulting or Advisory Role: NeuroTrials, LLC

Fabio M. Iwamoto

Stock and Other Ownership Interests: Praesidia Biotherapeutics

Consulting or Advisory Role: Novocure, Regeneron, AbbVie, Merck, Tocagen, Alexion Pharmaceuticals, Guidepoint Global, Gennao Bio, xCures, PPD, Medtronic, Massive Bio, Kiyatec, MimiVax, Praesidia Biotherapeutics, ClearView Healthcare Partners, Ono Pharmaceutical, Anheart Therapeutics

Speakers' Bureau: Prime Oncology

Research Funding: Merck (Inst), Bristol Myers Squibb (Inst), Tocagen (Inst), FORMA Therapeutics (Inst), Celldex (Inst), Northwest Biotherapeutics (Inst), Sapience Therapeutics (Inst), Novocure (Inst), Pfizer (Inst), ABM (Inst), Anheart Therapeutics (Inst), AstraZeneca (Inst)

Travel, Accommodations, Expenses: Oncoceutics

Uncompensated Relationships: Northwest Biotherapeutics

Andrew E. Sloan

Stock and Other Ownership Interests: Surgical Theater

Tony J.C. Wang

Stock and Other Ownership Interests: Doximity

Honoraria: AstraZeneca, Elekta, Novocure, Cancer Panels, University of Iowa, Rutgers

Consulting or Advisory Role: AbbVie, Merck, AstraZeneca, Doximity, Elekta, Novocure, Iylon

Research Funding: AbbVie, RTOG Foundation, Genentech (Inst), Varian Medical Systems (Inst)

Patents, Royalties, Other Intellectual Property: Wolters Kluwer

Travel, Accommodations, Expenses: Novocure, AbbVie, Elekta, Cancer Panels

Kenneth D. Aldape

Patents, Royalties, Other Intellectual Property: Predicting DNA methylation and tumor types from histopathology, DNA methylation-based cancer diagnostics for tumors of the central nervous system, kidney, and hematopoietic system

Jeffrey S. Wefel

Consulting or Advisory Role: Bayer, Juno Therapeutics (Inst), Novocure (Inst), Bayer Schering Pharma (Inst), GT Medical Technologies (Inst), Astellas Pharma, Intra-Cellular Therapies

Vinai Gondi

Honoraria: UpToDate

Consulting or Advisory Role: SERVIER, AstraZeneca

Research Funding: ImmunoChem Therapeutics LLC via NIH STTR grant

Alonso N. Gutierrez

Honoraria: Zap Surgical Systems, RadFormation

Consulting or Advisory Role: IBA

Mohammed H. Manasawala

Stock and Other Ownership Interests: SAfey Medical

Erik P. Sulman

Honoraria: PeerView, BrainLAB, Baptist Health South Florida

Consulting or Advisory Role: Global Coalition for Adaptive Research, Telix Pharmaceuticals, Harvard Medical School

Research Funding: Novocure (Inst)

Patents, Royalties, Other Intellectual Property: CARPOOL pooled cell line drug screening

Travel, Accommodations, Expenses: BrainLAB, PeerView, Baptist Health South Florida

Jedd D. Wolchok

Leadership: Ludwig Institute for Cancer Research

Stock and Other Ownership Interests: Tizona Therapeutics, Inc, Imvaq Therapeutics, Linnaeus Therapeutics, Georgiamune, Apricity Therapeutics, Maverick Therapeutics, Ascentage Pharma, Larkspur, CellCarta, XenImmune Therapeutics

Consulting or Advisory Role: Bristol Myers Squibb, Sellas Life Sciences, Tizona Therapeutics, Inc, Amgen, Ascentage Pharma, PsiOxus Therapeutics, Surface Oncology, Apricity Therapeutics, Recepta Biopharma, AstraZeneca, Daiichi Sankyo,Inc, Dragonfly Therapeutics, Georgiamune, Maverick Therapeutics, Werewolf Therapeutics, Trishula Therapeutics, Idera, Imvaq Therapeutics, Bicara Therapeutics, Truvax, CellCarta, Larkspur, BeiGene, Chugai Pharma, Takeda, XenImmune Therapeutics, Scancell Ltd, Immunocore

Research Funding: Bristol Myers Squibb (Inst), Sephora (Inst)

Patents, Royalties, Other Intellectual Property: I am a coinventor on an issued patent for DNA vaccines for treatment of cancer in companion animals (Inst), I am a coinventor on a patent for use of oncolytic Newcastle Disease virus (Inst), I am a coinventor and receive royalties for a blood test for monitoring myeloid derived suppressor cells (Inst), I am coinventor and receive royalties for a patent for immune modulating antibodies (Inst), I am a coinventor on a patent for CAR+ T cells targeting differentiation antigens as means to treat cancer (Inst), I am a co-inventor on a patent for Anti-CD40 agonist mAb fused to Monophosphoryl Lipid A (MPL) for cancer therapy (Inst), ALPHAVIRUS REPLICON PARTICLES EXPRESSING TRP2 (Inst), Engineered Vaccinia Viruses for Cancer Immunotherapy (Inst), RECOMBINANT POXVIRUSES FOR CANCER IMMUNOTHERAPY (Inst), WITH IMMUNOMODULATORY THERAPEUTICS AND METHOD OF MONITORING ABSCOPAL EFFECTS DURING SUCH TREATMENT (Inst), Antigen-binding proteins targeting melanoma differentiation antigens and uses thereof CTLA 4 (Inst), Peripheral Blood Phenotype Linked to Outcomes After Immunotherapy Treatment (Inst), CD40 BINDING MOLECULES AND USES THEREOF (Inst), CD40 binding Molecules and uses thereof (Inst), Anti-GITR antibodies and methods of use thereof (Inst), Antigen-binding proteins targeting melanoma differentiation antigens and uses thereof (Inst), Immunosuppressive follicular helper-like T cells modulated by immune checkpoint blockade (Inst), Phosphatidylserine Targeting Agents and uses thereof for adoptive T-cell therapies (Inst), ANTIGEN-RECOGNIZING RECEPTORS TARGETING B7-H3 AND USES THEREOF (Inst)

Other Relationship: Immunocore

Elizabeth C. Neil

Speakers' Bureau: SERVIER

Rimas V. Lukas

Consulting or Advisory Role: Merck, Novocure, Cardinal Health, SERVIER, Telix Pharmaceuticals, Novartis

Speakers' Bureau: Novocure, Merck, SERVIER

Research Funding: BMS

Travel, Accommodations, Expenses: Novocure, Gamma Tile

Other Relationship: EBSCO, MedLink Neurology, American Physician Institute, Clinical Care Options, Elsevier, Oxford University Press

Samuel A. Goldlust

Leadership: Cellevolve

Stock and Other Ownership Interests: COTA

Honoraria: Cornerstone Specialty Network

Consulting or Advisory Role: Novocure, Cellevolve, Cornerstone Specialty Network

Speakers' Bureau: Novocure

Research Funding: Wex Pharmaceuticals (Inst), Sumitomo Dainippon Pharma Oncology (Inst), Dogwood Therapeutics (Inst), NuvOx Pharma (Inst), Genentech (Inst), Orbus Therapeutics (Inst), GlaxoSmithKline (Inst)

Travel, Accommodations, Expenses: Novocure, Caris Life Sciences, Cornerstone Specialty Network

Matija Snuderl

Leadership: Imagenomix

Stock and Other Ownership Interests: HALO Diagnostics, Heidelberg Epignostix

Honoraria: SERVIER

Consulting or Advisory Role: Arima Genomics, InnoSIGN

Travel, Accommodations, Expenses: SERVIER

James J. Dignam

This author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.

Consulting or Advisory Role: Merck, Celgene, Duality Biologics

Minesh P. Mehta

Employment: Miami Cancer Institute

Consulting or Advisory Role: Mevion Medical Systems, Novocure, Telix Pharmaceuticals, AIQ Solutions, Chimeric

Patents, Royalties, Other Intellectual Property: WARF patent 14/934,27, Topical Vasoconstritor Preparations and Methods for Protecting Cells During Cancer Chemotherapy and Radiotherapy

No other potential conflicts of interest were reported.

PRIOR PRESENTATION

The study was presented as an abstract at the European Association of Neuro-Oncology 2023 annual meeting (award-winning) in Rotterdam, the Netherlands, and as an encore at the Society for Neuro Oncology 2023 annual meeting in Vancouver, Canada.

SUPPORT

This project was directly supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), and U24CA196067 (NRG Specimen Bank) from the National Cancer Institute (NCI). A.B.L. was supported in part by The William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at NewYork-Presbyterian, The Michael Weiner Glioblastoma Research Into Treatment Fund, the Hearst Foundations, and NIH/NCI/NCATS P30CA013696, UG1CA189960, and 5UL1TR001873.

CLINICAL TRIAL INFORMATION

NCT04396860 (NRG-BN007)

DATA SHARING STATEMENT

A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-25-00618.

AUTHOR CONTRIBUTIONS

Conception and design: Andrew B. Lassman, Mei-Yin C. Polley, Andrew E. Sloan, Tony J.C. Wang, Jeffrey S. Wefel, Vinai Gondi, Mark R. Gilbert, Erik P. Sulman, Jedd D. Wolchok, James J. Dignam, Minesh P. Mehta

Financial support: Richard M. Green, James J. Dignam

Administrative support: Andrew B. Lassman, Andrew E. Sloan, Richard M. Green, James J. Dignam, Minesh P. Mehta

Provision of study materials or patients: Andrew B. Lassman, Fabio M Iwamoto, Andrew E. Sloan, Kenneth D. Aldape, Richard M. Green, Elizabeth C. Neil, Minesh P. Mehta

Collection and assembly of data: Andrew B. Lassman, Mei-Yin C. Polley, Fabio M Iwamoto, Andrew E. Sloan, Kenneth D. Aldape, Jeffrey S. Wefel, Erik P. Sulman, Richard M. Green, Elizabeth C. Neil, Samuel A. Goldlust, Matija Snuderl, Kristyn Galbraith, James J. Dignam, Minhee Won

Data analysis and interpretation: Andrew B. Lassman, Mei-Yin C. Polley, Fabio M. Iwamoto, Andrew E. Sloan, Jeffrey S. Wefel, Vinai Gondi, Alonso N. Gutierrez, Mohammed H. Manasawala, Erik P. Sulman, Jedd D. Wolchok, Rimas V. Lukas, James J. Dignam, Minhee Won, Minesh P. Mehta

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Dual Immune Check Point Blockade in MGMT-Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Andrew B. Lassman

Stock and Other Ownership Interests: Moderna (ended)

Mei-Yin Polley

Consulting or Advisory Role: NeuroTrials, LLC

Fabio M. Iwamoto

Stock and Other Ownership Interests: Praesidia Biotherapeutics

Speakers' Bureau: Prime Oncology

Travel, Accommodations, Expenses: Oncoceutics

Uncompensated Relationships: Northwest Biotherapeutics

Andrew E. Sloan

Stock and Other Ownership Interests: Surgical Theater

Tony J.C. Wang

Stock and Other Ownership Interests: Doximity

Honoraria: AstraZeneca, Elekta, Novocure, Cancer Panels, University of Iowa, Rutgers

Consulting or Advisory Role: AbbVie, Merck, AstraZeneca, Doximity, Elekta, Novocure, Iylon

Research Funding: AbbVie, RTOG Foundation, Genentech (Inst), Varian Medical Systems (Inst)

Patents, Royalties, Other Intellectual Property: Wolters Kluwer

Travel, Accommodations, Expenses: Novocure, AbbVie, Elekta, Cancer Panels

Kenneth D. Aldape

Jeffrey S. Wefel

Consulting or Advisory Role: Bayer, Juno Therapeutics (Inst), Novocure (Inst), Bayer Schering Pharma (Inst), GT Medical Technologies (Inst), Astellas Pharma, Intra-Cellular Therapies

Vinai Gondi

Honoraria: UpToDate

Consulting or Advisory Role: SERVIER, AstraZeneca

Research Funding: ImmunoChem Therapeutics LLC via NIH STTR grant

Alonso N. Gutierrez

Honoraria: Zap Surgical Systems, RadFormation

Consulting or Advisory Role: IBA

Mohammed H. Manasawala

Stock and Other Ownership Interests: SAfey Medical

Erik P. Sulman

Honoraria: PeerView, BrainLAB, Baptist Health South Florida

Consulting or Advisory Role: Global Coalition for Adaptive Research, Telix Pharmaceuticals, Harvard Medical School

Research Funding: Novocure (Inst)

Patents, Royalties, Other Intellectual Property: CARPOOL pooled cell line drug screening

Travel, Accommodations, Expenses: BrainLAB, PeerView, Baptist Health South Florida

Jedd D. Wolchok

Leadership: Ludwig Institute for Cancer Research

Research Funding: Bristol Myers Squibb (Inst), Sephora (Inst)

Other Relationship: Immunocore

Elizabeth C. Neil

Speakers' Bureau: SERVIER

Rimas V. Lukas

Consulting or Advisory Role: Merck, Novocure, Cardinal Health, SERVIER, Telix Pharmaceuticals, Novartis

Speakers' Bureau: Novocure, Merck, SERVIER

Research Funding: BMS

Travel, Accommodations, Expenses: Novocure, Gamma Tile

Other Relationship: EBSCO, MedLink Neurology, American Physician Institute, Clinical Care Options, Elsevier, Oxford University Press

Samuel A. Goldlust

Leadership: Cellevolve

Stock and Other Ownership Interests: COTA

Honoraria: Cornerstone Specialty Network

Consulting or Advisory Role: Novocure, Cellevolve, Cornerstone Specialty Network

Speakers' Bureau: Novocure

Travel, Accommodations, Expenses: Novocure, Caris Life Sciences, Cornerstone Specialty Network

Matija Snuderl

Leadership: Imagenomix

Stock and Other Ownership Interests: HALO Diagnostics, Heidelberg Epignostix

Honoraria: SERVIER

Consulting or Advisory Role: Arima Genomics, InnoSIGN

Travel, Accommodations, Expenses: SERVIER

James J. Dignam

This author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.

Consulting or Advisory Role: Merck, Celgene, Duality Biologics

Minesh P. Mehta

Employment: Miami Cancer Institute

Consulting or Advisory Role: Mevion Medical Systems, Novocure, Telix Pharmaceuticals, AIQ Solutions, Chimeric

Patents, Royalties, Other Intellectual Property: WARF patent 14/934,27, Topical Vasoconstritor Preparations and Methods for Protecting Cells During Cancer Chemotherapy and Radiotherapy

No other potential conflicts of interest were reported.

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20. Bady P, Delorenzi M, Hegi ME. Sensitivity analysis of the MGMT-STP27 model and impact of genetic and epigenetic context to predict the MGMT methylation status in gliomas and other tumors. J Mol Diagn. 2016;18:350–361. doi: 10.1016/j.jmoldx.2015.11.009. [DOI] [PubMed] [Google Scholar]
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36. Omuro A, Brandes AA, Carpentier AF, et al. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial. Neuro Oncol. 2023;25:123–134. doi: 10.1093/neuonc/noac099. [DOI] [PMC free article] [PubMed] [Google Scholar]
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39. Wick W, Dettmer S, Berberich A, et al. N2M2 (NOA-20) phase I/II trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed non-MGMT hypermethylated glioblastoma. Neuro Oncol. 2019;21:95–105. doi: 10.1093/neuonc/noy161. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-25-00618.

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[b35] 35. Lim M, Weller M, Idbaih A, et al. Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Neuro Oncol. 2022;24:1935–1949. doi: 10.1093/neuonc/noac116. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[b37] 37. Hegi ME, Genbrugge E, Gorlia T, et al. MGMT promoter methylation cutoff with safety margin for selecting glioblastoma patients into trials omitting temozolomide: A pooled analysis of four clinical trials. Clin Cancer Res. 2019;25:1809–1816. doi: 10.1158/1078-0432.CCR-18-3181. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b38] 38. Lassman AB, Dimino C, Mansukhani M, et al. Concordance of EGFR and MGMT analyses between local and central laboratories: Implications for clinical trial design and precision medicine for depatuxizumab-mafodotin (ABT-414) in glioblastoma (GBM) [abstract ACTR-68] Neurooncology. 2017;19:vi15. [Google Scholar]

[b39] 39. Wick W, Dettmer S, Berberich A, et al. N2M2 (NOA-20) phase I/II trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed non-MGMT hypermethylated glioblastoma. Neuro Oncol. 2019;21:95–105. doi: 10.1093/neuonc/noy161. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Dual Immune Check Point Blockade in MGMT-Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial

Andrew B Lassman, MD

Mei-Yin C Polley, PhD

Fabio M Iwamoto, MD

Andrew E Sloan, MD

Tony JC Wang, MD

Kenneth D Aldape, MD

Jeffrey S Wefel, PhD

Vinai Gondi, MD

Alonso N Gutierrez, PhD

Mohammed H Manasawala, MD

Mark R Gilbert, MD

Erik P Sulman, MD, PhD

Jedd D Wolchok, MD, PhD

Richard M Green, MD

Elizabeth C Neil, MD

Rimas V Lukas, MD

Samuel A Goldlust, MD

Matija Snuderl, MD

Kristyn Galbraith, MD

James J Dignam, PhD

Minhee Won, MA

Minesh P Mehta, MD

Abstract

PURPOSE

METHODS

RESULTS

CONCLUSION

INTRODUCTION

CONTEXT

METHODS

Eligibility

Biomarkers

Treatment

Radiotherapy

Chemotherapy and Immunotherapy

TTFields

Supportive Care

Follow-Up

Response Criteria

Statistical Design

RESULTS

Enrollment

FIG 1.

TABLE 1.

Treatment Delivery

Adverse Events

TABLE 2.

Efficacy

FIG 2.

TTFields

DISCUSSION

ACKNOWLEDGMENT

APPENDIX

FIG A1.

TABLE A1.

TABLE A2.

TABLE A3.

TABLE A4.

TABLE A5.

PRIOR PRESENTATION

SUPPORT

CLINICAL TRIAL INFORMATION

DATA SHARING STATEMENT

AUTHOR CONTRIBUTIONS

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Dual Immune Check Point Blockade in MGMT-Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial

REFERENCES

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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