Fabio M Iwamoto

All Publications

• Evaluation of Regorafenib in Newly Diagnosed and Recurrent Glioblastoma: GBM AGILE Phase II/III Bayesian Randomized Platform Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Wen, P. Y., Berry, D. A., Buxton, M. B., Colman, H., de Groot, J., Lim, M., Mellinghoff, I., Perry, J. R., Weller, M., Blondin, N. A., Butt, O. H., Damek, D. M., de la Fuente, M. I., Drappatz, J., Dunbar, E., Giglio, P., Hyddmark, E. V., Iwamoto, F., Jaeckle, K. A., Kim, L., Kling, H. M., Lee, E. Q., Mantica, M., Mikkelsen, T., Nabors, B., Newton, H. B., Olson, J. J., Schiff, D., Walbert, T., Weathers, S. P., Cloughesy, T., Lassman, A. B. 2026: JCO2501137

  Abstract

  GBM AGILE (ClinicalTrials.gov identifier: NCT03970447) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm.Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped.When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control.GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

  View details for DOI 10.1200/JCO-25-01137

  View details for PubMedID 41980234

• Multicenter Randomized Phase II Study of R-MPV-A Chemoimmunotherapy With or Without Low-Dose Whole-Brain Radiotherapy for Newly-Diagnosed Primary CNS Lymphoma. Neuro-oncology Omuro, A., DeAngelis, L. M., Polley, M. C., Correa, D., Wefel, J. S., Bovi, J. A., Rosenblum, M., Corn, B. W., Aneja, S., Grommes, C., Peereboom, D. M., Lallana, E. C., Werner-Wasik, M., Rogers, C. L., Iwamoto, F. M., Yu, H. M., Donnelly, E. D., Struve, T. D., Won, M., Mehta, M. P. 2025

  Abstract

  Methotrexate-based chemoradiotherapy is effective in primary central nervous system lymphoma (PCNSL) but carries a risk of severe neurotoxicity. In a single-arm study, a regimen with methotrexate, procarbazine, vincristine and cytarabine was combined with rituximab (R-MPV-A) and substantially reduced doses of whole-brain radiotherapy (LD-WBRT), resulting in excellent progression-free survival (PFS) and overall survival (OS). Because R-MPV-A had never been tested without radiation, we sought to evaluate the efficacy of R-MPV-A with and without LD-WBRT, as well as determining if such low radiotherapy doses influenced disease control and/or neurotoxicity.Patients were randomized to receive R-MPV-A alone (Chemo arm) or combined with LD-WBRT (ChemoRT arm), given at 2,340 cGy (180cGy X13). Primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63 (one-sided alpha = 0.15).Ninety-one patients were randomized, with 44 analyzed in the ChemoRT and 46 in the Chemo arm. Median age was 66 and 59.5, respectively. R-MPV-A was well tolerated, achieving complete response rate of 92.3% (ChemoRT) and 76.3% (Chemo). After median follow-up of 4.6 years, median PFS was not reached (ChemoRT) vs 2.1 years (Chemo), HR = 0.47 (p = 0.007; 95% CI: 0.26 to 0.87). The 2-year PFS was 78.7% vs 54%, respectively. Differences in OS did not reach statistical significance (HR 0.71; p = 0.33). Neuropsychological evaluation showed no differences in cognitive outcomes, with several tests favoring ChemoRT.R-MPV-A is a highly efficacious and safe regimen with or without LD-WBRT. LD-WBRT contributes to disease control and increases PFS in PCNSL.

  View details for DOI 10.1093/neuonc/noaf221

  View details for PubMedID 41189315

• TIRABRUTINIB FOR THE TREATMENT OF RELAPSED OR REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: EFFICACY AND SAFETY FROM THE PHASE II PROSPECT STUDY Nayak, L., Grommes, C., Kallam, A., Peereboom, D., Ambady, P., Mendez, J., Aregawi, D., Sumrall, A., Omuro, A., Iwamoto, F., Dietrich, J., Umemura, Y., Munker, R., Chukwueke, U., Schaff, L., Prados, S., Takazawa, A., Aoi, A., Batchelor, T. OXFORD UNIV PRESS INC. 2025: v135

  View details for DOI 10.1093/neuonc/noaf201.0535

  View details for Web of Science ID 001612037600007

• Tirabrutinib for the treatment of relapsed or refractory primary central nervous system lymphoma: Efficacy and safety from the phase II PROSPECT study. Nayak, L., Grommes, C., Kallam, A., Peereboom, D. M., Ambady, P., Mendez, J. S., Aregawi, D., Sumrall, A., Omuro, A., Iwamoto, F., Dietrich, J., Umemura, Y., Munker, R., Chukwueke, U., Schaff, L., Prados, S., Takazawa, A., Aoi, A., Batchelor, T. LIPPINCOTT WILLIAMS & WILKINS. 2025

  View details for DOI 10.1200/JCO.2025.43.16_suppl.2019

  View details for Web of Science ID 001509527500001

• TUMOR RESPONSES IN A RANDOMIZED PHASE IIB TRIAL OF A CMV VACCINE IMMUNOTHERAPEUTIC CANDIDATE (VBI-1901) IN RECURRENT GLIOBLASTOMAS Merrell, R., Wen, P., Forst, D., Schulte, J., Odia, Y., Bota, D., Nagpal, S., Bonm, A., Diaz-Mitoma, F., Anderson, D., Lassman, A., Iwamoto, F. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0362

  View details for Web of Science ID 001362488100044

• Interim analysis of ABM-1310, a blood-brain barrier-penetrant BRAF inhibitor, in patients with <i>BRAF V600</i>-mutated solid tumors Piha-Paul, S. A., De La Fuente, M., Iwamoto, F., Nagpal, S., Weise, A. M., Zhu, J., Chandra, S., Chen, C., Fu, Y., Yang, Z., Tsai, K. K. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400710

• GBM AGILE PLATFORM TRIAL FOR NEWLY DIAGNOSED AND RECURRENT GBM: RESULTS OF FIRST EXPERIMENTAL ARM, REGORAFENIB Wen, P., Alexander, B., Berry, D., Buxton, M., Cavenee, W., Colman, H., de Groot, J., Ellingson, B., Gordon, G., Hyddmark, E., Khasraw, M., Lim, M., Mellinghoff, I., Mikkelsen, T., Perry, J., Powell, A., Sulman, E., Tanner, K., Weller, M., Yung, W., Blondin, N., Brenner, A., Butt, O., de la Fuente, M., Drappatz, J., Iwamoto, F., Kim, L., Lee, E., Mantica, M., Nabors, B., Newton, H., Schiff, D., Walbert, T., Weathers, S., Cloughesy, T., Lassman, A. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245400367

• MGMT promoter methylation predicts overall survival after chemotherapy for 1p/19q-codeleted gliomas. Clinical cancer research : an official journal of the American Association for Cancer Research Kinslow, C. J., Rae, A. I., Taparra, K., Kumar, P., Siegelin, M. D., Grinband, J., Gill, B. J., McKhann, G. M., Sisti, M. B., Bruce, J. N., Canoll, P. D., Iwamoto, F. M., Horowitz, D. P., Kachnic, L. A., Neugut, A. I., Yu, J. B., Cheng, S. K., Wang, T. J. 2023

  Abstract

  PURPOSE: While MGMT promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy and guides treatment decisions in glioblastoma, its role in grade 2 and 3 glioma remains unclear. Recent data suggests that mMGMT is prognostic of progression-free survival in 1p/19q-codeleted oligodendrogliomas, but an effect on overall survival (OS) has not been demonstrated.EXPERIMENTAL DESIGN: We identified patients with newly diagnosed 1p/19q-codeleted gliomas and known MGMT promoter status in the National Cancer Database from 2010-2019. Multivariable Cox proportional hazards regression modeling was used to assess the effect of mMGMT on OS after adjusting for age, sex, race, co-morbidity, grade, extent of resection, chemotherapy, and radiotherapy.RESULTS: We identified 1,297 eligible patients, 938 (72.3%) of whom received chemotherapy in their initial course of treatment. The MGMT promoter was methylated in 1,009 (77.8%) patients. Unmethylated MGMT (uMGMT) was associated with worse survival compared to mMGMT (70% [95%CI 64-77%] vs. 81% [95%CI 78-85%], P<.001, adjusted hazard ratio [aHR] 2.35 [95%CI 1.77-3.14]). uMGMT was associated with worse survival in patients who received chemotherapy (63% [95%CI 55-73%] vs. 80% [95%CI 76-84%], P<.001, aHR 2.61 [95%CI 1.89-3.60]) but not in patients who did not receive chemotherapy (P=.38, HR 1.31 [95%CI 0.71- 2.42]). Similar results were observed regardless of WHO grade and after single- or multiagent chemotherapy.CONCLUSIONS: Our study demonstrates an association between mMGMT and OS in 1p/19qcodeleted gliomas. MGMT promoter status should be considered as a stratification factor in future clinical trials of 1p/19q-codeleted gliomas that use OS as an endpoint.

  View details for DOI 10.1158/1078-0432.CCR-23-1295

  View details for PubMedID 37611077

• Association of MGMT Promotor Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy. JAMA oncology Kinslow, C. J., Mercurio, A., Kumar, P., Rae, A. I., Siegelin, M. D., Grinband, J., Taparra, K., Upadhyayula, P. S., McKhann, G. M., Sisti, M. B., Bruce, J. N., Canoll, P. D., Iwamoto, F. M., Kachnic, L. A., Yu, J. B., Cheng, S. K., Wang, T. J. 2023

  Abstract

  O6-methylguanine-DNA methyltransferase (MGMT [OMIM 156569]) promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy for glioblastomas and is routinely used to guide treatment decisions. However, the utility of MGMT promoter status for low-grade and anaplastic gliomas remains unclear due to molecular heterogeneity and the lack of sufficiently large data sets.To evaluate the association of mMGMT for low-grade and anaplastic gliomas with chemotherapy response.This cohort study aggregated grade II and III primary glioma data from 3 prospective cohort studies with patient data collected from August 13, 1995, to August 3, 2022, comprising 411 patients: MSK-IMPACT, EORTC (European Organization of Research and Treatment of Cancer) 26951, and Columbia University. Statistical analysis was performed from April 2022 to January 2023.MGMT promoter methylation status.Multivariable Cox proportional hazards regression modeling was used to assess the association of mMGMT status with progression-free survival (PFS) and overall survival (OS) after adjusting for age, sex, molecular class, grade, chemotherapy, and radiotherapy. Subgroups were stratified by treatment status and World Health Organization 2016 molecular classification.A total of 411 patients (mean [SD] age, 44.1 [14.5] years; 283 men [58%]) met the inclusion criteria, 288 of whom received alkylating chemotherapy. MGMT promoter methylation was observed in 42% of isocitrate dehydrogenase (IDH)-wild-type gliomas (56 of 135), 53% of IDH-mutant and non-codeleted gliomas (79 of 149), and 74% of IDH-mutant and 1p/19q-codeleted gliomas (94 of 127). Among patients who received chemotherapy, mMGMT was associated with improved PFS (median, 68 months [95% CI, 54-132 months] vs 30 months [95% CI, 15-54 months]; log-rank P < .001; adjusted hazard ratio [aHR] for unmethylated MGMT, 1.95 [95% CI, 1.39-2.75]; P < .001) and OS (median, 137 months [95% CI, 104 months to not reached] vs 61 months [95% CI, 47-97 months]; log-rank P < .001; aHR, 1.65 [95% CI, 1.11-2.46]; P = .01). After adjusting for clinical factors, MGMT promoter status was associated with chemotherapy response in IDH-wild-type gliomas (aHR for PFS, 2.15 [95% CI, 1.26-3.66]; P = .005; aHR for OS, 1.69 [95% CI, 0.98-2.91]; P = .06) and IDH-mutant and codeleted gliomas (aHR for PFS, 2.99 [95% CI, 1.44-6.21]; P = .003; aHR for OS, 4.21 [95% CI, 1.25-14.2]; P = .02), but not IDH-mutant and non-codeleted gliomas (aHR for PFS, 1.19 [95% CI, 0.67-2.12]; P = .56; aHR for OS, 1.07 [95% CI, 0.54-2.12]; P = .85). Among patients who did not receive chemotherapy, mMGMT status was not associated with PFS or OS.This study suggests that mMGMT is associated with response to alkylating chemotherapy for low-grade and anaplastic gliomas and may be considered as a stratification factor in future clinical trials of patients with IDH-wild-type and IDH-mutant and codeleted tumors.

  View details for DOI 10.1001/jamaoncol.2023.0990

  View details for PubMedID 37200021

  View details for PubMedCentralID PMC10196932

• Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors. Journal for immunotherapy of cancer Sanborn, R. E., Pishvaian, M. J., Callahan, M. K., Weise, A., Sikic, B. I., Rahma, O., Cho, D. C., Rizvi, N. A., Sznol, M., Lutzky, J., Bauman, J. E., Bitting, R. L., Starodub, A., Jimeno, A., Reardon, D. A., Kaley, T., Iwamoto, F., Baehring, J. M., Subramaniam, D. S., Aragon-Ching, J. B., Hawthorne, T. R., Rawls, T., Yellin, M., Keler, T. 2022; 10 (8)

  Abstract

  BACKGROUND: Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naive, refractory solid tumors.METHODS: Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures.RESULTS: 175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%).CONCLUSION: Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes.TRIAL REGISTRATION NUMBER: NCT02335918.

  View details for DOI 10.1136/jitc-2022-005147

  View details for PubMedID 35940825

• TOCA 511 & TOCA FC VERSUS STANDARD OF CARE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA Cloughesy, T., Petrecca, K., Walbert, T., Butowski, N., Salacz, M., Perry, J., Damek, D., Bota, D., Bettegowda, C., Zhu, J., Iwamoto, F., Placantonakis, D., Martinez, N., Elder, J., Kaptain, G., Cachia, D., Moshel, Y., Brem, S., Picconi, D., Nam Tran, Nam, D., Park, C., Landolfi, J., Tran, D., Ramakrishna, R., Fink, K., Heros, D., Zadeh, G., Nicholas, G., Mehta, V., Robins, H., Chen, C., Pitz, M., Heth, J., Nagpal, S., Pearlman, M., Ahluwalia, M., Mohile, N., Merrell, R., Schiff, D., Thompson, R., Davis, R., Macdonald, D., Kheoh, T., Kabbinavar, F., Lossos, A., Vogelbaum, M. OXFORD UNIV PRESS INC. 2019: 284

  View details for Web of Science ID 000509478706204

• Go, no-go decision making for phase 3 clinical trials: ACT IV revisited Reply LANCET ONCOLOGY Weller, M., Butowski, N., Tran, D. D., Recht, L. D., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S. A., Iwamoto, F., Drappatz, J., O'Rourke, D. M., Wong, M., Hamilton, M. G., Finocchiaro, G., Perry, J., Wick, W., Green, J., He, Y., Turner, C. D., Yellin, M. J., Keler, T., Davis, T. A., Stupp, R., Sampson, J. H. 2017; 18 (12): E709–E710

  View details for Web of Science ID 000417001900003

• Go, no-go decision making for phase 3 clinical trials: ACT IV revisited - Authors' reply. The Lancet. Oncology Weller, M., Butowski, N., Tran, D. D., Recht, L. D., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S. A., Iwamoto, F., Drappatz, J., O'Rourke, D. M., Wong, M., Hamilton, M. G., Finocchiaro, G., Perry, J., Wick, W., Green, J., He, Y., Turner, C. D., Yellin, M. J., Keler, T., Davis, T. A., Stupp, R., Sampson, J. H. 2017; 18 (12): e709-e710

  View details for DOI 10.1016/S1470-2045(17)30856-2

  View details for PubMedID 29208433

• Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial LANCET ONCOLOGY Weller, M., Butowski, N., Tran, D. D., Recht, L. D., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S. A., Iwamoto, F., Drappatz, J., O'Rourke, D. M., Wong, M., Hamilton, M. G., Finocchiaro, G., Perry, J., Wick, W., Green, J., He, Y., Turner, C. D., Yellin, M. J., Keler, T., Davis, T. A., Stupp, R., Sampson, J. H., ACT IV Trial Investigators 2017; 18 (10): 1373–85

  Abstract

  Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150-200 mg/m2 for 5 of 28 days) for 6-12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour <2 cm2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479.Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5-22·1) in the rindopepimut group versus 20·0 months (18·1-21·9) in the control group (HR 1·01, 95% CI 0·79-1·30; p=0·93). The most common grade 3-4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one-a pulmonary embolism in a 64-year-old male patient after 11 months of treatment-was assessed as potentially related to rindopepimut.Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma.Celldex Therapeutics, Inc.

  View details for PubMedID 28844499

• ACT IV: AN INTERNATIONAL, DOUBLE-BLIND, PHASE 3 TRIAL OF RINDOPEPIMUT IN NEWLY DIAGNOSED, EGFRvIII-EXPRESSING GLIOBLASTOMA Weller, M., Butowski, N., Tran, D., Recht, L., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S., Iwamoto, F., Drappatz, J., O'Rourke, D., Wong, M., Finocchiaro, G., Perry, J., Wick, W., He, Y., Davis, T., Stupp, R., Sampson, J. OXFORD UNIV PRESS INC. 2016: 17

  View details for Web of Science ID 000398604100070