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| Ref Type | Journal Article | ||||||||||||
| PMID | (37722087) | ||||||||||||
| Authors | Rahman R, Trippa L, Lee EQ, Arrillaga-Romany I, Fell G, Touat M, McCluskey C, Wiley J, Gaffey S, Drappatz J, Welch MR, Galanis E, Ahluwalia MS, Colman H, Nabors LB, Hepel J, Elinzano H, Schiff D, Chukwueke UN, Beroukhim R, Nayak L, McFaline-Figueroa JR, Batchelor TT, Rinne ML, Kaley TJ, Lu-Emerson C, Mellinghoff IK, Bi WL, Arnaout O, Peruzzi PP, Haas-Kogan D, Tanguturi S, Cagney D, Aizer A, Doherty L, Lavallee M, Fisher-Longden B, Dowling S, Geduldig J, Watkinson F, Pisano W, Malinowski S, Ramkissoon S, Santagata S, Meredith DM, Chiocca EA, Reardon DA, Alexander BM, Ligon KL, Wen PY | ||||||||||||
| Title | Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization. | ||||||||||||
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| Abstract Text | The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design.Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780).Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05).The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| CDKN2A del | glioblastoma | no benefit | Abemaciclib + Temozolomide | Phase II | Actionable | In a Phase II trial (INSIGhT), concurrent radiation and Temodar (temozolomide) followed by adjuvant Verzenio (abemaciclib) (n=73) improved progression-free survival (PFS; HR 0.72, p=0.046) but not overall survival (OS; HR 0.69, p=0.053) compared to standard chemoradiation (n=51) in newly-diagnosed MGMT-unmethylated glioblastoma patients, PFS (HR 0.69, p=0.053) and OS (HR 0.76, p=0.12) were not improved in the CDK biomarker-positive (CDK4/6 amp or CDKN2A deletion) subgroup (PMID: 37722087; NCT02977780). | 37722087 |