bluuebunny/crossref_metadata_2025 huggingface dataset:
CTIM-39. A PHASE 1B STUDY OF PEMBROLIZUMAB, IBRUTINIB AND RITUXIMAB IN RECURRENT/REFRACTORY (RR) PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL)
Authors: Chukwueke Ugonma , Wright Isobel , Muzikansky Alona , Russ Alyssa , Fontana Brittney , Kats Vanessa , O'Donnell Colin , Scalfani Renee , Acevedo-Naranjo Brenda , Lee Eudocia , Castro Luis Nicolas Gonzalez , McFaline-Figueroa Jose Ricardo , Aquilanti Elisa , Youssef Gilbert , Beroukhim Rameen , Forst Deborah , Reardon David , Wen Patrick , Batchelor Tracy , Torres Alexandra , Stefanik Jennifer , Fisher Jennifer , Meredith David , Murakami Mark , Garcia Yuri , Shipp Margaret , Nayak Lakshmi
Published: November 2023

BACKGROUND

PCNSL exhibit B-cell receptor (BCR) pathway activation due to CD79B and MYD88 mutations, concurrently with 9p24.1/PD-L1/PD-L2 copy number alterations. These genetic features suggest complementary approaches of targeting PD1, BCR/BTK (Bruton’s tyrosine kinase) and CD20. Pembrolizumab, ibrutinib and rituximab have each been used as monotherapy in RR PCNSL. We investigate these agents in combination to determine tolerability and synergistic efficacy.

METHODS

This is a phase 1b/2 study of pembrolizumab, ibrutinib and rituximab in RR PCNSL patients. In phase 1b, patients were accrued using a 3 + 3 design to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D). Patients were treated with pembrolizumab 200mg IV every 3 weeks, ibrutinib oral daily and rituximab 375mg/m2 IV weekly (for 4 doses). Two dose levels (DL) of ibrutinib (DL1: 560 mg, DL2: 840 mg) were evaluated. Primary endpoint is progression-free survival at six months (PFS6); secondary endpoints include safety, tolerability, objective response rate (ORR), duration of response (DOR), progression-free and overall survival.

RESULTS

We completed accrual on the phase 1b part and report results of 10 evaluable patients (50% women). The median age was 74 years (38-82) and median ECOG 1 (0-1). There was 1 DLT at DL1 (grade 4 transaminases) and 2 DLTs at DL2 (hypertension, flu-like symptoms); the MTD/R2PD of ibrutinib with pembrolizumab and rituximab is 560mg. The most common grade 3/4 adverse events were elevated transaminases and decrease in lymphocyte counts. There were 13 dermatologic events, all < grade 3. Reasons for discontinuing treatment include progression (6), consent withdrawal (1), toxicity (2). The ORR is 80% (6 complete responses, 2 partial responses). As of June 2023, the median DOR is 177 days (49-619); PFS6 is 50%.

CONCLUSIONS

The combination of pembrolizumab, ibrutinib and rituximab is well-tolerated with manageable side effects and encouraging efficacy. The phase 2 portion of the study is open.
CTIM-40. EARLY RADIOGRAPHIC RESPONSE AND ENGRAFTMENT OF PHASE I FIRST-IN-HUMAN BICISTRONIC CAR T CELLS CORRELATE WITH REAL-TIME AUTOLOGOUS GBM ORGANOID CYTOLYSIS
Authors: Logun Meghan , Bagley Stephen J , Wang Xin , Zhang Daniel , Sun Yusha , Ming Guo-li , Nabavizadeh Ali , Marshall Amy , Maloney Eileen , Hwang Wei-Ting , Fraietta Joseph , Gonzalez Vanessa , Desai Arati , Bagley Linda , Hexner Elizabeth , Nasrallah MacLean P , Song Hongjun , Binder Zev , O'Rourke Donald M
Published: November 2023

Glioblastoma (GBM) is a highly treatment-resistant cancer, in part due to prominent inter- and intratumoral heterogeneity. To date, monovalent CAR T-cell therapies have failed to overcome this heterogeneity. Bivalent CAR-T cells may overcome this challenge by expanding the population of target-positive tumor cells. NCT05168423 is first-in-human, phase 1 dose escalation study to assess safety and feasibility of intrathecal delivery of autologous bicistronic CAR-T cells, targeting both EGFR and IL13Rα2, in patients with EGFR-amplified recurrent GBM. For each patient enrolled in this study, high-fidelity glioblastoma organoids (GBOs) are derived from tumor tissue and utilized to test the autologous CAR-T product in real-time. GBOs are co-cultured with autologous CAR-T cells and individually monitored using modified impedance spectroscopy assays over six days for quantification of real-time tumor cytolysis. CAR-T efficacy in GBOs was correlated to matched clinical trial patient outcomes, including CAR-T engraftment. To date, three patients have been treated at the initial dose level (10,000,000 CART-EGFR-IL13Rα2 cells). All three patients demonstrated tumor shrinkage on MRI obtained within 24-48hrs post-infusion. MRI changes were accompanied by significant tumor-inflammation associated neurotoxicity that resolved with steroids and IL1R blockade. Serial CSF collection for qPCR following CAR-T infusion revealed average peaks of >100,000 copies of CAR-T cells/μg of gDNA, comparable to CART19-treated patients. Cytotoxicity values in GBOs strongly correlated with peak CSF engraftment levels of CAR-T cells in all three patients (r = 0.998, p = 0.037). In summary, we present striking radiographic and biological responses from the first cohort of recurrent GBM patients treated with a bivalent, intrathecally delivered CAR T cell product simultaneously targeting EGFR and IL13Rα2. Potent anti-tumor activity of CART-EGFR-IL13Rα2 cells was also observed by treating patient-derived GBOs with the patients’ corresponding autologous CAR T-cell products, providing a parallel, ex vivo system for real-time prediction of CAR T-cell engraftment.
CTNI-05. INTRATHECAL PEMETREXED FOR LEPTOMENINGEAL METASTASES FROM SOLID TUMOR: A MULTICENTER, PHASE I/II, OPEN-LABEL STUDY (PMLM, NCT 05289908)
Authors: Pan Zhenyu , Yang Guozi , Wang Zhuo , Shen Longhai , Yuan Tingting , Pang Xiaochuan , Li Sijia , Dong Lihua
Published: November 2023

OBJECTIVES

This phase I/II study was to evaluate maximum tolerated dose (MTD) of intrathecal pemetrexed (IP) with vitamin supplementation and antitumor activity for leptomeningeal metastases (LM) from solid tumors.

METHODS

Phase I study followed the classic 3 + 3 design, with dose escalated from 15 mg. Phase II followed Simon 2-stage design with recommended dose determined in phase I. IP was administered twice per week for 2 weeks (induction therapy), followed by once per week for 4 weeks (consolidation therapy). Vitamin B12 (1000 μg) and folic acid (400 μg, q.d.) were given at the beginning of treatment. Primary end points were MTD in phase I and clinical response rate (CRR) in phase I/II.

RESULTS

Between Feb 2022 and Jan 2023, 34 patients were enrolled, including non-small cell lung cancer (20), small-cell lung cancer (3), breast cancer (8), others (3). Ten patients were enrolled in phase I. Three of 4 patients receiving IP at 15 mg completed induction and consolidation treatment without dose limiting toxicity (DLT). Two DLT (1 grade 4 hematologic toxicity and 1 grade 5 arachnoiditis) occurred in 6 patients at 20 mg. MTD was determined to be 15 mg. Then 24 patients were enrolled in phase II and given 15 mg of IP. 82.4% (28/34) and 58.8% (20/34) patients completed induction and consolidation therapy, respectively. Adverse events (AEs) rate was 73.5% (25/34). 50% (17/34) patients showed grade ≥ 3 AEs. Overall CRR was 41.2% (14/34), including 10 (29.4%) with improved neurological dysfunction, 11 (32.4%) with CSF cytological response and 4 (11.8%) with neuroimaging improvement. Median survival was 7.6 (range 0.3–13.7) months in phase I, while has not yet been achieved in phase II.

CONCLUSION

MTD of IP was 15 mg with folic acid and vitamin B12 supplementation. IP is an optimal therapeutic option for LM from solid tumors.
CTNI-13. CONCURRENT INTRATHECAL CHEMOTHERAPY AND INVOLVED-FIELD RADIOTHERAPY FOR LEPTOMENINGEAL METASTASIS FROM SOLID TUMORS: A PHASE II STUDY (NCT03082144)
Authors: Yang Guozi , Pan Zhenyu , Chen Kunzhi , Jiang Tongchao , Song Yuanyuan , Dong Lihua , He Hua , Ye Xiaojun , Wang Min , Zhou Tao
Published: November 2023

BACKGROUND

The role of involved-field radiation therapy (IFRT) and intrathecal chemotherapy (IC) in leptomeningeal metastasis (LM) from solid tumors was gradually underestimated in the era of targeted therapy. This study was aimed to investigate the safety and effectiveness of concurrent IFRT and intrathecal methotrexate (MTX)/cytarabine (Ara-C) for LM, particularly for those who developed LM while receiving targeted therapy.

METHODS

Enrolled patients were randomly assigned to two subgroups (IFRT&IC-MTX and IFRT&IC-Ara-C), and first treated with induction IC (MTX or Ara-C) twice per week, up to 4 times. Then patients were given concurrent treatment, which consisted of IFRT (40 Gy total; 2 Gy/f) and IC (MTX 15 mg or Ara-C 50 mg, once per week). The involved field consisted of symptomatic or painful sites and disease observed on magnetic resonance imaging (MRI), including the whole brain and basis crania and/or segment of spinal canal. Primary endpoint was clinical response rate (RR). Secondary endpoints were safety and overall survival (OS).

RESULTS

Fifty-three patients received induction intrathecal MTX (n = 27) or Ara-C (n = 26). Forty-two patients completed concurrent therapy. Total RR was 34% (18/53). The improvement rate of neurological symptoms and KPS scores were 72% (38/53) and 66% (35/53) respectively. Adverse events (AEs) rate was 28% (15/53). Eight patients (15%, 8/53) showed grade 3-4 AEs, including myelosuppression (n = 4) and radiculitis (n = 5). Median OS was 6.5 months (95% CI, 5.3-7.7 months). Median survival for 18 patients who had clinical response was 7.9 months (95% CI, 4.4-11.4 months), and 0.8 months (95% CI, 0.08-1.5 months) for 6 patients who had LM progression. The median survival in 22 patients who received prior targeted therapy was 6.3 months (95% CI, 4.5-8.1 months).

CONCLUSION

Concurrent IFRT and intrathecal MTX or Ara-C was proved to be a feasible treatment option with an acceptable safety profile for LM from a common tumor entity.
CTNI-14. NEOADJUVANT STEREOTACTIC RADIOSURGERY (NASRS) FOR LARGE BRAIN METASTASES (BRM): RESULTS OF AN INTERNATIONAL MULTICENTER PHASE II TRIAL
Authors: Shultz David , Li Dianna , Rodriguez Ruth Lau , Higazy Randa , Laperriere Normand , Millar Barbara-Ann , Conrad Tatiana , Zadeh Gelareh , Kalyvas Aristotelis , Senger Carolin , Acker Gueliz , Spears Julian , Kongkham Paul
Published: November 2023

BACKGROUND

We conducted an international multi-center phase II trial evaluating NASRS for BrM. We hypothesized that radiation necrosis (RN) would be lower than post-operative cavity radiotherapy since the tissues receiving the highest radiation dose are resected in NASRS.

METHODS

BrM patients with 1 index lesion ( >2 and <5 cm in greatest diameter) suitable for resection, and 9 or less additional BrM (< 3 cm in greatest diameter, not requiring resection) were recruited across 3 centres. SRS was administered a median 3 (range: 2-21) days prior to surgical resection. A single fraction of 15-21 Gy was delivered, targeting the index tumor with a 2mm margin. From a sample of 30 patients, the primary endpoint was the 1-year rate of grade 2+ (G2+) RN from the index lesion. Secondary endpoints included local failure (LF), leptomeningeal disease (LMD) and overall survival (OS).

RESULTS

We enrolled 35 patients [Mean age (SD): 58.9 (12.9) years, 46% female] between 2018 and 2022. The most common primary histologies were lung (40%), and gastrointestinal (20%) cancers. The median BrM volume prior to surgery was 16.6 cc (range 3.2 -38.0); median index lesion size was 3.2 (range: 1.9-4.5) cm. All participants received planned protocol treatment; n = 30 are currently available for 1 year outcomes. No patients developed G2+ RN; 5 had a LF (1-year rate 38%) at 5-12-months following surgery, all of whom had an en-bloc resection. One patient each developed classic LMD and pachymeningeal failure 3 and 11 months after surgery, respectively. Median OS was 11.5 months.

CONCLUSION

No patients in our study experienced G2+ RN. The 1-year rate of LF was higher than anticipated, indicating the potential benefit of considering a higher radiation dose or larger margins for improved outcomes.
CTNI-15. PILOT STUDY OF HIGH-DOSE PEMETREXED FOR PROGRESSIVE CHORDOMA
Authors: Kesari Santosh , Wagle Naveed , Carrillo Jose , Sharma Akanksha , Nguyen Minhdan , Truong Judy , Gill Jaya , Nersesian Raffi , Nomura Natsuko , Rahbarlayegh Elnaz , Barkhoudarian Garni , Sivakumar Walavan , Kelly Daniel , Krauss Howard , Bustos Matias , Hoon Dave , Anker Lars , Singh Arun , Sankhala Kamalesh , Juarez Tiffany
Published: November 2023

INTRODUCTION

Chordomas are ultra-rare tumors of the spine, and no systemic therapy is approved for refractory disease. Pemetrexed is a multitargeted antifolate that inhibits thymidylate synthase (TS) and other enzymes involved in nucleotide biosynthesis. Considering the majority of chordomas do not express TS, we sought to evaluate the therapeutic activity and safety of high-dose pemetrexed.

METHODS

Adults with previously-treated chordoma were enrolled on an open-label, single-institution, single-arm, pilot clinical trial. Pemetrexed 900 mg/m2 was administered intravenously every 3 weeks, with supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary and exploratory endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in potential tissue and blood-based biomarkers before and after treatment.

RESULTS

Fifteen patients with chordoma received a median of 15 (range 4-31) doses of pemetrexed. Median PFS was 10.5 months (95% CI 9 months-undetermined) and 6-month PFS was 67%. Out of 14 response-evaluable patients, two (14%) achieved a partial response and ten (71%) demonstrated stable disease. Adverse events were generally mild at grades 1-2, the most common being fatigue, rash, nausea, constipation, diarrhea, mucositis, vomiting, alopecia, pruritus, lower extremity edema, and alanine transaminase increased. One Grade 3 creatinine increase, one Grade 3 lymphopenia, and one Grade 4 lymphopenia occurred and there were no Grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities. Clinical improvement in disease-related symptoms occurred in several patients. Tumor molecular profiling revealed low mutational burden and though not statistically significant, positive TS expression trended negatively with disease progression. Cell-free microRNAs (cfmiRs) were concordantly detected in plasma and tissues and a blood cfmiR signature was identified that distinguished chordoma from health donors.

CONCLUSION

High-dose pemetrexed is safe and well-tolerated in chordoma patients. A phase II study is in development. (NCT03955042)
CTNI-18. DESIGNING AND DELIVERING A RANDOMISED CONTROLLED TRIAL OF MEDICINAL CANNABINOIDS IN RECURRENT GLIOBLASTOMA - THE ARISTOCRAT TRIAL
Authors: Short Susan , Savage Joshua , Mant Rhys , Patel Amit , Buckle Peter , Meade Sarah , Boele Florien , Banks Emma , Brazil Lucy , Collinson Fiona , Billingham Lucinda
Published: November 2023

BACKGROUND

ARISTOCRAT is a randomised, double-blind, placebo-controlled phase II trial of temozolomide chemotherapy, with or without cannabinoids (Nabixomols) in patients with MGMT-methylated recurrent GBM and has recently opened to recruitment across the UK.

METHODS

A multi-disciplinary team of co-applicants and trial management group (TMG) members was assembled comprising clinicians, statisticians, trialists, Patient & Public Involvement (PPI), pharmacists and quality of life (QoL) researchers to design a pragmatic phase II randomised study. The protocol randomises on a 2:1 ratio between Nabiximols or matched placebo alongside standard dose temozolomide in patients at first recurrence of IDH wild-type GBM. Patients titrate to an individualised dose based on tolerance to a maximum of 12 oro-mucosal sprays per day. The primary outcome measure is overall survival time with key secondary outcomes including survival at 6, 12 and 24 months, progression-free survival time, health-related QoL and adverse events. Intermediate assessment of feasibility to confirm safety, compliance and achievability of recruitment will be undertaken after 40 patients are randomised. PPI input has been critical in ensuring sensitive and appropriate patient & public messaging and in developing patient information videos.

RESULTS

ARISTOCRAT was rapidly funded via a novel crowdfunding campaign organised by The Brain Tumour Charity during the COVID-19 pandemic. The trial office has since responded to >150 patient enquiries, demonstrating the high level of patient and public enthusiasm for this trial. Coverage in the press also shows a more broad level of interest in the use of cannabis-derived medicines. The study opened to recruitment on 03-Feb-2023 and the first patient was recruited on 08-Mar-2023. The study aims to recruit a total of 234 patients over an 18 month period.

CONCLUSION

ARISTOCRAT will provide robust clinical data on the role of cannabinoids in improving overall survival and the impact on QoL for patients with recurrent GBM.
CTNI-23. SINGLE CELL TRANSCRIPTOMICS, PHARMACOKINETICS, AND PHARMACODYNAMICS OF COMBINED CDK4/6 AND MTOR INHIBITION IN A PHASE 0 TRIAL OF RECURRENT HIGH-GRADE GLIOMA
Authors: Johnson Kevin , Tien An-Chi , Jiang Jun , McNamara James , Chang Yu-Wei , Montgomery Chelsea , DeSantis Anita , Elena Leonel , Fujita Yoko , Kim Seongho , Tovmasyan Artak , Li Jing , Mehta Shwetal , Verhaak Roel , Sanai Nader
Published: November 2023

Adult High-grade gliomas (HGGs) often exhibit deregulation of RB-CDK4/6 and mTOR signaling pathways. This study investigated tumor single cell transcriptomics, pharmacokinetics, and pharmacodynamics immediately following combined CDK4/6 (ribociclib) and mTOR (everolimus) inhibition in recurrent HGG. 24 patients with recurrent gliomas harboring RB+, CDKN2A/B deletion or CDK4/6 amplification, and PTEN loss or PIK3CA mutations were enrolled in a phase 0 trial. Patients received ribociclib treatment for 5 days before surgery, including six who received ribociclib (400mg QD) plus everolimus (2.5mg QD), and six dose-escalation cohorts (n = 3 each) reaching ribociclib 600mg QD plus everolimus 70mg QW. No dose-limiting toxicities were observed. Validated LC-MS/MS methods determined total and unbound drug concentrations. Preoperative MRI revealed a marked decrease in gadolinium-enhancement in all patients. In gadolinium-nonenhancing tumor regions, the median unbound concentration of ribociclib was 561 nM, while no unbound everolimus concentrations were detected. Ribociclib’s pharmacodynamic effects in surgical specimens were compared with matched archival tissue using IHC. Across IDH-wild-type tumors, there was significant decrease in MIB1 levels between the matched archival and surgical specimens (p < 0.05) suggesting drug-associated cell cycle inhibition. Single nuclei RNAseq (snRNA) analyses were performed on 17 IDH-wild-type recurrent samples treated with ribociclib plus everolimus and 29 IDH-wild-type recurrences treated with standard therapies. Cellular state analysis based on snRNAseq data demonstrated a decreased neural progenitor-like (NPC-like) malignant cell state compared with standard therapies (p < 0.01), indicating inhibition of the CDK4-driven neural progenitor-like cell state. This observation was validated using snRNA and patient-derived glioma cell lines exposed to ribociclib, showing a consistent decrease in NPC-like proportions and cycling cells (p < 0.05). This study highlights the value of integrating pharmacokinetics/pharmacodynamics and snRNA data to assess treatment effects in phase 0 surgical tissues. These findings support further development of ribociclib, but not everolimus, for the treatment of glioma patients.
CTNI-24. CLINICAL ACTIVITY AND SAFETY OF THE RAF INHIBITOR TOVORAFENIB IN PATIENTS WITH OPTIC PATHWAY GLIOMAS IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY
Authors: Nysom Karsten , Kilburn Lindsay , Leary Sarah , Landi Daniel , de Vos-Kerkhof E , Perreault Sébastien , Witt Olaf , Ziegler David , Driever Pablo Hernáiz , Franson Andrea , Baxter Patricia , Whipple Nicholas S , Kline Cassie , Segal Devorah , Jabado Nada , Bailey Simon , McCowage Geoffrey , Hansford Jordan , Khuong-Quang Dong-Anh , Gottardo Nicholas , Hassall Timothy , Han Jung Woo , Oren Michal Yalon , Chi Susan , Lee Vai , McLeod Lisa , Qiu Jiaheng , Walter Ashley , Manley Peter , Hargrave Darren
Published: November 2023

BACKGROUND

Optic pathway gliomas (OPG) are low-grade gliomas (LGG) comprising 3-5% of pediatric brain tumors. Morbidity may include visual loss (acuity and visual fields), hypothalamic/pituitary dysfunction, and/or impaired motor function. Genomic alterations of MAPK/BRAF are frequent oncogenic drivers in pediatric LGG. Activity of tovorafenib, an investigational, oral, selective, CNS-penetrant, type II RAF inhibitor in OPGs was analyzed.

METHODS

FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib (420 mg/m2 weekly) in patients 6 months–25 years with BRAF-altered recurrent/progressive LGG or solid tumors. Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints.

RESULTS

Of the 77 patients enrolled in arm 1 (measurable disease per RANO-HGG), 42 (55%) had tumors located in the optic pathway. Median age at enrollment was 8 years (range: 2–16); 37 (88%) harbored a BRAF fusion and 5 (12%) a BRAF V600E mutation. The median prior lines of systemic therapy was 3 (range: 1–9), with 69% having received prior MAPK inhibitors. Of the 39 evaluable patients (RANO-HGG), the ORR was 59% (1 CR, 22 PRs) with a median time to response (TTR) of 2.8 months; 14 (36%) had stable disease (SD). Per RANO-LGG (n = 42), the ORR was 43% (5 PRs; 13 MRs) with a median TTR of 4.1 months; 20 (48%) had SD. Visual acuity remained stable in 79% (23) of patients (Cycle 9, n = 29 assessed). The most common treatment-related adverse events (TRAEs) of any grade in this subgroup were hair color changes (81%), increased creatine phosphokinase (55%), anemia (48%), maculopapular rash (45%), and fatigue (41%). Dose modifications occurred in 14 (33%) and discontinuations in 3 (7%) patients due to TRAEs.

CONCLUSIONS

Tovorafenib demonstrated antitumor activity in recurrent/progressive BRAF-altered OPG and was generally well tolerated. Visual acuity remained stable for the majority with OPGs.
CTNI-25. A PHASE 0/1B STUDY OF AZD1390 PLUS RADIOTHERAPY IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: Sanai Nader , Desai Siddhi , Margaryan Tigran , LoCascio Costanza , Elliott Mackenna , Molloy Jennifer , Harmon Jocelyn , Hong Amy , Melendez Ernesto Luna , Wanebo John , Braun Kelly , Kennedy William , Garcia Michael , Yoo Wonsuk , Tovmasyan Artak , Tien An-Chi , Mehta Shwetal
Published: November 2023

BACKGROUND

ATM inhibition has been hypothesized to potentiate the effects of radiation by preventing acute phase DNA damage repair, and a Phase 1 trial of this combination in patients with GBM is ongoing (NCT03423628). To test this hypothesis, this phase 0/1b study aimed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD1390, an ATM inhibitor with BBB penetration, in combination with ex vivo radiation in patients with GBM (NCT05182905).

METHODS

Recurrent GBM patients received 3 days of AZD1390 prior to planned resection at 2-4, 4-6 or 23-25 hours following the final dose. Tumor tissue, cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase. ATM inhibition was assessed via ex vivo radiation and quantification of pRAD50 levels compared to non-radiated control. Patients exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance regimen.

RESULTS

In 17 patients treated to date, AZD1390 was consistently measured in the Gd-non-enhancing tumor region. All patients (n = 17) exceeded the PK threshold to qualify for the expansion phase of the study. With 5Gy ex-vivo radiation of surgical specimen, pRAD50 expression was significantly suppressed in AZD1390 treated patients compared to untreated controls (geomean 1.8% vs 29.1%, average 94% reduction, p < 0.01). Median 6-month progression-free survival has not been reached at a median clinical follow-up of 4.3 months.

CONCLUSION

AZD1390 is well-tolerated in recurrent GBM patients, achieving pharmacologically relevant concentrations in non-enhancing tumor tissue, and substantially suppressing induction of pRAD50 levels ex vivo post-radiation. This is the first pharmacodynamic evidence that AZD1390 may be a potent radio-potentiator in patients with GBM.
CTNI-34. ZOTIRACICLIB (TG02) FOR NEWLY DIAGNOSED GLIOBLASTOMA IN THE ELDERLY OR FOR RECURRENT GLIOBLASTOMA: FINAL RESULTS OF THE EORTC 1608 STEAM TRIAL
Authors: Rhun Emilie Le , Gorlia Thierry , Felsberg Jörg , Furtner Julia , Jongen Joost , Maurage Claude-Alain , Ducray Francois , Roth Patrick , Hau Peter , Chinot Olivier , Preusser Matthias , Cartalat Stephanie , van den Bent Martin , Collienne Maike , Reifenberger Guido , Weller Michael
Published: November 2023

BACKGROUND

Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor that is supposed to suppress tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma.

METHODS

EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients with IDH1R132H-non-mutant newly diagnosed glioblastoma or anaplastic astrocytoma, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), based on O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 in IDH1R132H-non-mutant glioblastoma or anaplastic astrocytoma at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months. Secondary objectives included efficacy, quality of life, and safety. Expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry.

RESULTS

The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B) in elderly patients. Two dose-limiting toxicities were observed at 150 mg, one in group A (grade 3 seizure) and one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders, and hepatotoxicity. Progression-free survival at 6 months in group C was 6.7%. CDK9 and its indirect targets, c-MYC and MCL-1, were confirmed to be expressed and their expression was correlated, supporting a regulatory role for CDK-9. The protein levels of CDK-9 and MCL-1 correlated with overall survival.

CONCLUSION

TG02 exhibits overlapping toxicity with alkylating agents and low clinical activity as a single agent. Larger randomized trials are required to explore activity in combination with RT or TMZ. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.
CTNI-37. CLINICAL ACTIVITY OF RAF INHIBITOR TOVORAFENIB ACCORDING TO PRIOR MAPK INHIBITOR TREATMENT IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY
Authors: Khuong-Quang Dong-Anh , Nysom Karsten , Landi Daniel , Ziegler David , Driever Pablo Hernáiz , Leary Sarah , Bailey Simon , van der Lugt Jasper , Perreault Sébastien , Waanders Angela , Baxter Patricia , Witt Olaf , Hargrave Darren , McCowage Geoffrey , Hansford Jordan , Toledano Helen , Oren Liat , Tan Enrica E K , Gerber Nicolas , Kang Hyoung Jin , Larouche Valérie , Abdelbaki Mohamed S , Cornelio Izzy , Kim Yeonhee , Walter Ashley , Manley Peter , Kilburn Lindsay
Published: November 2023

BACKGROUND

Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor. Genomic alterations of RAF are common oncogenic drivers in pLGG. Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor.

METHODS

FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib monotherapy. Registrational arm 1 enrolled patients aged 6 months–25 years of age with recurrent or progressive LGG harboring an activating BRAF alteration. Tovorafenib 420 mg/m2 (600 mg max) was administered weekly (tablet or liquid suspension). Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints.

RESULTS

As of December 22 2022, 69 (RANO-HGG) and 76 (RANO-LGG) of 77 patients in arm 1 were evaluable at baseline and had ≥9 months of follow-up. Median age at enrollment was 8 years (range 2–21), and 60% (n = 46) patients had received prior MAPK inhibitor (MAPKi) therapy. Among the evaluable patients, the ORR was 62% (RANO-HGG, n = 69) and 45% (RANO-LGG, n = 76), respectively. The ORR in patients previously treated with MAPKis (n = 41 [RANO-HGG]; n = 45 [RANO-LGG]) was 68% (4 CRs; 24 PRs) (RANO-HGG) and 44% (5 PRs; 15 MRs) (RANO-LGG). In MAPKi-naïve patients (28 [RANO-HGG]; 31 [RANO-LGG]), the ORR was 54% (15 PRs) (RANO-HGG) and 45% (7 PRs; 7 MRs) (RANO-LGG). Among 136 patients in arms 1 and 2 of FIREFLY-1, the most common treatment-related adverse events (TRAEs) of any grade were hair color changes (71%), fatigue (40%) and maculopapular rash (38%). Tovorafenib dose modifications occurred in 39 (29%) and discontinuations in 4 (3%) patients due to TRAEs.

CONCLUSIONS

Tovorafenib provided clinically meaningful tumor responses, including those with a best response reported of SD or PD using another MAPKi, in patients with BRAF-altered pLGG regardless of prior MAPKi therapy, and has a manageable safety profile.
CTNI-39. REGOMA-OS: A LARGE ITALIAN MULTICENTER, PROSPECTIVE, OBSERVATIONAL STUDY ANALYZING REGORAFENIB EFFICACY AND SAFETY IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: Caccese Mario , Desideri Isacco , Villani Veronica , Simonelli Matteo , Buglione Michela , Chiesa Silvia , Franceschi Enrico , Gaviani Paola , Stasi Irene , Caserta Claudia , Brugnara Sonia , Lolli Ivan , Bennicelli Elisa , Bini Paola , Cuccu Angelo Salvatore , Scoccianti Silvia , Magni Giovanna , De Salvo Gian Luca , Zagonel Vittorina , Lombardi Giuseppe
Published: November 2023

BACKGROUND

in the randomized phase 2 REGOMA trial, regorafenib (REG) showed promising activity in recurrent glioblastoma (GBM) patients (PTS); subsequently, in Italy the National Health System has permitted the reimbursement of the REG as second-line therapy. We performed a large multicenter, prospective and observational study to confirm REGOMA data in a real-world setting. Materials and

METHODS

major inclusion criteria were: histologically confirmed diagnosis of GBM according to WHO 2016 and relapse after Stupp treatment, good performance status (ECOG PS 0-1), good liver function. REG was administered at standard dose of 160mg/die for 3 weeks on/1 week off. Brain MRI was performed within 14 days before starting REG and every 8-12 weeks, subsequently. Primary endpoint was overall survival. RANO criteria were used for response evaluation, CTACAE v. 5 for adverse events.

RESULTS

from Sept 2020 to Oct 2022, 192 recurrent GBM PTS were enrolled from 29 Cancer Centres in Italy: median age was 58ys (IQR 52.8-67.0), 68% male, ECOG PS was 0 in 85 (44%), 115 PTS (60%) undertook steroids at baseline. MGMT was methylated in 43%, IDHwt in 92%. Median follow-up was 16.6 months (IQR 12.6-19.6). Median OS was 8.2ms (95% CI 6.5-9.6), 12ms-OS 34.7% (95%CI 27.2-42.4); median PFS was 2.6ms (95%CI 2.3-2.9), 6ms-PFS 14.3%. Radiological response was PR and SD in 12 (8%) and 25 (16%) PTS. 77 (44%) PTS received third-line therapy. The median of REG cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 adverse events (AE) were reported in 53 (28%) PTS; reduction/delay and permanent discontinuation due to AE in 36% and 8% of PTS. No death was considered as treatment-related AE.

CONCLUSIONS

compared to the REGOMA trial, this large Italian multicenter, prospective and observational trial confirmed the results in terms of overall survival with a good toxicity profile of REG in recurrent GBM PTS.
CTNI-44. NEOADJUVANT TREATMENT WITH ST101, C/EBPΒ ANTAGONIST, TRIGGERS NECROSIS AS A PATHOLOGICAL RESPONSE IN NEWLY DIAGNOSED GBM PATIENTS. TISSUE-BASED ANALYSIS FROM A SURGICAL WINDOW OF OPPORTUNITY TRIAL
Authors: Iwamoto Fabio , Vainstein-Haras Abi , Rotolo Jim , Levrero Clara , Michel Robert , Kostelecky Nicolas , Papaioannou Anastasia , Buerki Robin
Published: November 2023

BACKGROUND

CCAAT/enhancer-binding protein β (C/EBPβ) is a master regulator of mesenchymal transformation in GBM (Carro, 2010) and is required for maintenance of immunosuppressive tumor-associated macrophage (TAM) populations. ST101 is a first-in-class C/EBPβ antagonist, that promotes selective tumor cell death without impacting normal cell viability (Darvishi, 2022). In an ongoing phase 1/2 clinical study in rGBM (NCT04478279), ST101 administration resulted in 1 durable PR and 5 SD (range 18 to 53+ weeks). We designed a window of opportunity study to assess the effect of ST101 on clinical outcomes and pharmacodynamic biomarkers in the neoadjuvant setting in newly diagnosed GBM (ndGBM).

METHODS

The study will enroll 12 ndGBM patients to be treated with 2-4 500 mg ST101 IV QW) before surgical resection. After surgery, patients will continue ST101 QW + standard chemoradiation with temozolomide.

RESULTS

As of June 9th, 2023, 6 patients with ndGBM received 2-3 doses of ST101. MRI performed before and after neoadjuvant ST101 indicated stable disease in all patients. At surgery, however, histopathology of tumor samples showed that 4/6 patients had geographic necrosis, indicative of treatment effect after ST101 monotherapy. Evaluation of immunostaining for ST101 and molecular changes in the post-treatment tissue by bulk and single nucleus RNAseq will be conducted.

CONCLUSIONS

ndGBM treated with neoadjuvant ST101 monotherapy shows extensive treatment effects on the tumors that have never been treated with chemoradiation. Stability of enhancing lesions after ST101 monotherapy may not reflect the extent of treatment effect as revealed by treatment-related necrosis in the resected tissue. Analyses of the pharmacodynamics effects of ST101 on GBM cells and tumor microenvironment will be completed and presented. In addition, this study demonstrates the feasibility of a multi-institutional window of opportunity clinical trial in ndGBM patients, a decisive opportunity for determining the penetration and on-target activity of novel agents in neuro-oncology.
CTNI-52. SURVIVAL OUTCOMES IN RECURRENT GLIOBLASTOMA (RGBM) PATIENTS TREATED WITH A SINGLE INTRA-TUMORAL ADMINISTRATION OF BIZAXOFUSP, AN IL-4R-TARGETING TOXIN, IN A PHASE IIB TRIAL
Authors: Sampson John , Achrol Achal Singh , Aghi Manish , Bankiewicz Krystof , Bexon Martin , Brem Steven , Brenner Andrew , Chowdhary Sajeel , Coello Melissa , Desjardins Annick , Ellingson Benjamin , Floyd John , Han Seunggu , Kesari Santosh , Mardor Yael , Merchant Fahar , Merchant Rosemina , Randazzo Dina , Vogelbaum Michael A , Vrionis Frank , Wembacher-Schroeder Eva , To Minh D , Zabek Miroslaw , Butowski Nicholas
Published: November 2023

BACKGROUND

Bizaxofusp (MDNA55) is an IL4R-targeting toxin in development for recurrent (r)GBM, a universally fatal disease with mOS of 6-9 months. IL-4R is overexpressed in GBM and surrounding tumor microenvironment, with high expression associated with poor clinical outcome. Method: Efficacy and safety were evaluated in a single-arm, open-label, multi-center Ph2 study using convection-enhanced delivery of Bizaxofusp. The primary endpoint of mOS was compared to results from a blinded eligibility-matched external control arm (ECA). OS was defined as time from relapse to death/censor. IL-4R expression was determined by immunohistochemistry of available archival tumor tissues from both arms.

RESULTS

Bizaxofusp showed an acceptable safety profile at doses of up to 240 μg. Forty-four subjects were treated with Bizaxofusp per protocol; 81 ECA subjects met the eligibility criteria of the study. The Bizaxofusp group had a significantly longer mOS (12.85 months compared to 7.7 months for ECA; HR, 0.62; 95% CI, 0.42-0.89). Amongst the unmethylated MGMT and high IL-4R sub-groups, subjects treated with Bizaxofusp had significantly longer mOS when compared to the ECA. Eleven patients (25%) treated with Bizaxofusp survived >24 months; 3 patients were still alive (29.9, 32.8 and 40.1 months) at last follow-up. High IL-4R expression was associated with improved survival (mOS, 15.8 versus 9.8 months; HR, 0.7; 95% CI, 0.39-1.46) at all doses. However at high doses (180 μg) subjects with low IL-4R expression had significantly longer survival versus low dose Bizaxofusp (mOS, 15.4 versus 9.1 months; HR, 0.28; 95% CI, 0.09-0.91).

CONCLUSION

In patients with rGBM, a single treatment of Bizaxofusp resulted in significantly improved OS compared to eligibility-matched ECA. High-dose Bizaxofusp was equally effective irrespective of IL4R expression. A Phase 3 registration trial will use a novel hybrid design with a propensity-matched ECA comprising two-thirds of the control arm, setting a new precedent for GBM clinical trials.
CTNI-54. A COMBINED ANALYSIS OF TWO RANDOMISED STUDIES EXPLORING THE IMPACT OF EXTENDED POST-RADIATION TEMOZOLOMIDE ON SURVIVAL OUTCOMES IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Gately Lucy , Mesia Carlos , Sepúlveda Juan , del Barco Sonia , Pineda Estela , Gironés Regina , Fuster José , Hong Wei , Gill Sanjeev , Navarro Luis Miguel , Herrero Ana , Dowling Anthony , De La Peñas Ramón , Vaz Maria Angeles , Alonso Miriam , Lwin Zarnie , Harrup Rosemary , Peralta Sergio , Long Anne , Perez-Segura Pedro , Ahern Elizabeth , Garate Clara Olier , Wong Mark , Campbell Robert , Cuff Katharine , Jennens Ross , Gallego Oscar , Underhill Craig , Martinez-García María , Covela Marta , Cooper Adam , Brown Stephen , Rosenthal Mark , Torres Javier , Collins Ian M , Gibbs Peter , Balana Carmen
Published: November 2023

BACKGROUND

The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Stupp protocol uses 6 months, however, in routine care, it is often extended to 12 months, given its tolerability, lack of effective salvage treatments, and extended regimen in lower grade gliomas.

METHODS

GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled patients with newly diagnosed glioblastoma without progression at the end of 6 months post-radiation temozolomide. Participants were randomised in a 1:1 allocation to either six additional months (total 12 months) or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required for 80% power to detect an improvement in 6mPFS from 50% to 60%. Neither study recruited sufficient patients, so we performed a combined analysis of individual patient data.

RESULTS

205 patients were recruited: 169 in GEINO14-01 (2014–2018) and 46 in EX-TEM (2019–2022). Median follow up was 20 and 14.5 months respectively. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR 0.75, p = 0.4), nor across any subgroups including MGMT methylated. There was no significant improvement in PFS (HR 0.92, P = 0.59, median 7.8 vs 9.7 months) or OS (HR 1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required changes to treatment, with 4.5% requiring dose delay, 7.5% dose reduction and 1.5% discontinuation of temozolomide.

CONCLUSION

For patients with newly diagnosed glioblastoma, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any individual patient subset that appeared to benefit from extended treatment. Six months should remain standard of care.
CTNI-55. A MULTICENTER STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND WITH SYSTEMIC MICROBUBBLE OSCILLATORS FOR BLOOD-BRAIN BARRIER DISRUPTION FOR LIQUID BIOPSY IN GLIOBLASTOMA (LIBERATE)
Authors: Ahluwalia Manmeet , McDermott Michael , Burns Terry , de Groot John , Mogilner Alon , Achrol Achal , Shah Bhavya , Bettegowda Chetan , Ozair Ahmad , Khosla Atulya , Schwartz Theodore , Sahgal Arjun , Mishra Mark , Everson Richard , Weinberg Jeffrey , Amankulor Nduka , Sporrer Justin , Cifarelli Christopher , Rezai Ali , Lipsman Nir , Woodworth Graeme F
Published: November 2023

BACKGROUND

Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) blood levels in due to the blood-brain barrier (BBB). Real-time image-guided low-intensity focused ultrasound (LIFU) with intravenously administered microbubble oscillators non-invasively causes BBB disruption (BBBD). This clinical trial aimed to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM.

METHODS

LIBERATE is an ongoing, prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating the safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged 18-80 years with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being included. Patients are administered intravenous oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using 220 kHz LIFU device is performed, with real-time acoustic feedback for effective sonication. Pre- and post-procedure, phlebotomies, and MRI brain are performed. The primary study endpoint is defined, per subject, as the ratio between cfDNA levels in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% concordance between biomarker patterns in the cfDNA sample from 1-hour post-LIFU sample and tumor tissue obtained later. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels in samples collected at 30 minutes, 1 hour, 2 hours, and 3 hours post-LIFU to determine the time of greatest yield, (3) correlation of MRI parameters related to BBBD grading and biomarkers in cfDNA from post-LIFU samples. Patient enrollment commenced in 2022, and 13 patients have been recruited by 06/09/2023. Clinical trial information: NCT05383872.
CTNI-58. UPDATED RESULTS AND MOLECULAR SUBGROUP ANALYSES FROM THE RANDOMIZED PHASE 3 MIRAGE TRIAL ON MARIZOMIB IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Roth Patrick , Gorlia Thierry , Reijneveld Jaap , de Vos Filip , Idbaih Ahmed , Frenel Jean-Sébastien , Le Rhun Emilie , Sepúlveda Juan , Perry James , Masucci G Laura , Freres Pierre , Hirte Hal , Seidel Clemens , Walenkamp Annemiek , Lukacova Slavka , Meijnders Paul , Blais Andre , Ducray Francois , Verschaeve Vincent , Nicholas Garth , Balana Carmen , Bota Daniela , Preusser Matthias , Nuyens Sarah , Dhermain Fréderic , van den Bent Martin , O’Callaghan Chris J , Vanlancker Maureen , Mason Warren , Weller Michael
Published: November 2023

BACKGROUND

The standard of care for patients with newly diagnosed glioblastoma includes maximum safe resection followed by radiotherapy (RT) with concomitant and maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Among potential new therapeutic strategies, targeting the proteasome has been considered promising because of its implication in numerous biological processes in tumors cells. Marizomib is a novel small molecule proteasome inhibitor that crosses the blood brain barrier and showed signs of activity in recurrent glioblastoma.

METHODS

EORTC 1709/CCTG CE.8 was a randomized, controlled, multicenter, open label phase 3 superiority trial. Major inclusion criteria were histologically confirmed newly diagnosed glioblastoma, age of 18 years or older and a Karnofsky performance status (KPS) > 70. Patients with tumors known to harbor an isocitrate dehydrogenase mutation were not eligible.

RESULTS

The trial was opened at 82 institutions in Europe, Canada and the US and 749 patients (of 750 planned) were randomized in a 1:1 ratio. Following a pre-planned interim analysis and a recommendation of the independent data monitoring committee, enrolment was discontinued. No significant difference in the median OS (mOS) was observed (standard arm: 17 months, marizomib arm: 16.5 months; p = 0.64; HR = 1.04). Median PFS was 6.0 vs. 6.3 months (p = 0.67; HR = 0.97). Patients with tumors harboring an unmethylated O6-methylguanine DNA methyltransferase (MGMT) promoter had a mOS of 14.5 months in the standard therapy group and 15.1 months in the marizomib arm (p = 0.27, HR = 1.13). Among patients with an MGMT promoter-methylated tumor, median OS was 29.4 months in the marizomib arm and 25.5 months in the standard arm (p = 0.41, HR = 0.86). More CTCAE grade 3/4 treatment-emergent adverse events were noticed in the marizomib arm than in the standard arm.

CONCLUSIONS

The addition of marizomib to standard temozolomide-based radiochemotherapy was associated with more toxicity but did not confer a survival benefit in glioblastoma patients, independent of the MGMT promoter methylation status.
CTNI-59. RARE AND NOVEL KIAA1549-BRAF FUSION BREAKPOINTS PREDICT POOR CLINICAL OUTCOME FOR PATIENTS WITH RECURRENT OR PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA: PHASE II PNOC001 TRIAL RESULTS
Authors: Waszak Sebastian , Aboian Mariam , Minturn Jane , Leary Sarah , Abdelbaki Mohamed S , Goldman Stewart , Elster Jennifer , Kraya Adam , Lueder Matthew , Ramakrishnan Divya , von Reppert Marc , Liu Kevin , Resnick Adam , Solomon David , Molinaro Annette , Phillips Joanna , Prados Michael , Haas-Kogan Daphne , Mueller Sabine
Published: November 2023

OBJECTIVES

PNOC001 sought to estimate progression-free survival (PFS) associated with everolimus for progressive/recurrent pediatric low-grade glioma (pLGG) and to determine if activated PI3K/AKT/mTOR pathway as measured by positive phosphorylated-ribosomal protein S6 (p-RPS6) was associated with response. A secondary objective was to assess whether somatic drivers influence median PFS.

METHODS

Patients, 3-21 years of age, with recurrent/progressive pLGG received everolimus orally at 5 mg/m2 daily. Somatic drivers, when available, were associated with PFS and compared to four independent molecular pLGG cohorts with newly-diagnosed and progressive/recurrent patients.

RESULTS

From 2012 to 2019, 65 subjects enrolled [median age 9.6 years, 3.0-19.9; 46% female]; Median PFS for all-comers was 11.1 months (95%-CI 7.6-19.8, n = 64). PFS was not modulated by PI3K/AKT/mTOR pathway activation (median PFS 11.2 vs 9.4 months, P = 0.83, n = 62). BRAF alterations were identified in 67.8% (40/59) of patients. Rare/novel KIAA1549-BRAF fusion breakpoints were enriched in PNOC001 compared to newly-diagnosed pLGGs in independent cohorts (28.6% vs 2.6%, P = 1.4e-4, n = 214). In PNOC001, patients with rare/novel KIAA1549-BRAF fusion breakpoints had worse clinical outcomes than patients with common fusion breakpoints (median PFS 6.1 vs 16.7 months, P < 0.05, n = 20). Rare/novel KIAA1549-BRAF fusion breakpoints were also enriched in patients with progressive/recurrent disease in independent pLGG cohorts (17.6% vs 2.6%, P = 2e-3, n = 227). Integration of BRAF alterations and DNA methylation-based tumor subtypes further revealed that rare/novel KIAA1549-BRAF fusion breakpoints are more frequent in supratentorial midline (14.1%) compared to infratentorial (2.0%) pilocytic astrocytomas (P = 1e-4). KIAA1549-BRAF fusion breakpoints remained risk factors for progressive/recurrent disease in PNOC001 (P = 0.05) and independent pLGG cohorts (P < 0.05) after accounting for tumor location and DNA methylation subtypes.

CONCLUSIONS

Rare/novel KIAA1549-BRAF fusion breakpoints are more frequent in supratentorial midline pLGGs and define independent genomic risk factors for disease progression/recurrence. Our results indicate that future clinical trials must interrogate and define KIAA1549-BRAF fusion breakpoints for informative results and conclusions.