Background

Grade 2 gliomas are slowly progressive brain tumours with poor long-term prognosis. Current treatments are not curative and can be associated with toxicities. Mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in nearly all grade 2 gliomas and are a disease-defining characteristic in the World Health Organization 2021 definition. Vorasidenib (VOR) is an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes.

Methods

In this double-blind phase 3 study, patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles, stratified by 1p19q status and baseline tumour size. Key eligibility criteria: age ≥12 y; Karnofsky performance scale (KPS) >80; residual or recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1–5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent review committee (BIRC). Key secondary endpoint: time to next intervention (TTNI).

Results

As of 6 Sep 2022 (2nd planned interim analysis data cut-off date), 168 pts were randomized to VOR and 163 to PBO (median age, 40.4 y; KPS=100, 53.5%; oligodendroglioma, 172; astrocytoma, 159; median time from last surgery to randomization, 2.4 y). Median follow-up was 14.2 mo. PFS by BIRC was significantly improved with VOR vs PBO (hazard ratio [HR] 0.39, 95% CI 0.27–0.56; 1-sided P=0.000000067). Median PFS: VOR, 27.7 mo; PBO, 11.1 mo. TTNI was significantly improved with VOR vs PBO (HR 0.26, 95% CI 0.15–0.43; 1-sided P=0.000000019). Median TTNI: VOR, not reached; PBO, 17.8 mo. In pts with IDH1-R132H variant (n=284, 85.8%) the HR for PFS by BIRC was 0.33 (95% CI 0.22–0.50). Adverse event of grade ≥3 elevated alanine aminotransferase was seen in 9.6% of pts with VOR (and 0% with PBO).

Conclusions

In the first randomized phase 3 study of a targeted therapy in grade 2 mIDH1/2 glioma, VOR significantly improved PFS by BIRC compared with PBO, with a manageable safety profile. Findings show the clinical benefit of VOR in pts for whom chemotherapy and radiotherapy are being delayed. (NCT04164901 funded by Servier Pharmaceuticals LLC).

Clinical trial identification

NCT04164901.

Editorial acknowledgement

Medical writing assistance was provided by Debbi Gorman, PhD, at Cogent (an AMICULUM agency), funded by Servier Pharmaceuticals LLC..

Legal entity responsible for the study

Servier Pharmaceuticals LLC.

Funding

Servier Pharmaceuticals LLC.

Disclosure

D. Blumenthal: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Novocure, and Takeda; Financial Interests, Personal, Research Grant: Merck Sharp & Dome, Novocure; Financial Interests, Personal, Advisory Role: Servier Pharmaceuticals LLC. I.K. Mellinghoff: Financial Interests, Personal, Speaker, Consultant, Advisor: 501c3 Global Coalition for Adaptive Research; Financial Interests, Personal, Other, Honoraria: Doris Duke Charitable Foundation; Financial Interests, Personal, Advisory Board: Black Diamond Therapeutics, Roche Therapeutics, Prelude Therapeutics Incorporated, Voyager Therapeutics; Financial Interests, Personal, Research Funding: Erasca Therapeutics, Servier Pharmaceuticals LLC, Kazia Therapeutics, Vigeo Therapeutics, and Samus Therapeutics, Inc. M.J. van den Bent: Financial Interests, Personal, Speaker, Consultant, Advisor: Agios, Servier, AstraZeneca, Boehringer Ingelheim, Geneta, Incyte, Nerviano, Chimerix, Roche, Fore Biotherapeutics and Stemline Therapeutics. M. Touat: Financial Interests, Personal, Research Funding: Sanofi; Financial Interests, Personal, Speaker, Consultant, Advisor: Agios Pharmaceuticals, Servier Pharmaceuticals LLC and Novocure. K. Peters: Financial Interests, Personal, Advisory Board: Sapience, Servier Pharmaceuticals LLC, NuVox Therapeutics,Cordance Medical, and Vivicitas Oncology; Financial Interests, Personal, Research Funding: Varian, Biomimetix, Sapience, and Servier Pharmaceuticals LLC. J. Clarke: Financial Interests, Personal, Speaker, Consultant, Advisor: Agios Pharmaceuticals Inc. and Servier Pharmaceuticals LLC; Financial Interests, Personal, Research Funding: Merck, Agios Pharmaceuticals Inc. and Servier Pharmaceuticals LLC. W. Mason: Financial Interests, Personal, Advisory Board: Novocure, Merck; Financial Interests, Personal, Speaker, Consultant, Advisor: Boehringer Ingelheim, Century Therapeutics; Financial Interests, Personal, Research Funding: Hoffman La Roche, Servier Pharmaceuticals LLC, Orbus Therapeutics; Financial Interests, Personal, Other, Data monitoring committee: Ono Therapeutics. A.F. Hottinger: Financial Interests, Personal, Research Funding: Novocure; Financial Interests, Personal, Advisory Board: Novocure and Bayer. J.M. Sepulveda Sanchez: Financial Interests, Personal, Research Grant: Pfizer, IDP Pharma and Cantex; Financial Interests, Personal, Speaker, Consultant, Advisor: Cantex Pharma; Financial Interests, Personal, Advisory Board: MSD, Servier Pharmaceuticals, Novocure and CeCaVa. W. Wick: Financial Interests, Personal, Other, Honoraria: Apogenix, Bayer, Merck Sharp & Dome, AstraZeneca, Merck Serono, Novartis, Roche and Mundipharma; Non-Financial Interests, Personal, Other, Non-financial clinical trial support: Apogenix, Bayer, Merck Sharp & Dome, AstraZeneca, Merck Serono, Novartis, Roche and Mundipharma. R. Soffietti: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck Sharp & Dome, AstraZeneca, Merck Serono, Celldex Therapeutics, Novartis, Puma Technology, AbbVie, and Mundipharma. A. Tron: Financial Interests, Personal, Stocks/Shares: Agios Pharmaceuticals Inc; Financial Interests, Personal, Full or part-time Employment: Agios Pharmaceuticals Inc, Servier Pharmaceuticals LLC. D. Zhao: Financial Interests, Personal, Full or part-time Employment: Agios Pharmaceuticals Inc, Servier Pharmaceuticals LLC; Financial Interests, Personal, Stocks/Shares: Agios Pharmaceuticals Inc. S. Pandya: Financial Interests, Personal, Full or part-time Employment: Agios Pharmaceuticals Inc, Servier Pharmaceuticals LLC; Financial Interests, Personal, Stocks/Shares: Agios Pharmaceuticals Inc. L. Steelman: Financial Interests, Personal, Full or part-time Employment: Servier Pharmaceuticals LLC, Agios Pharmaceuticals Inc; Financial Interests, Personal, Stocks/Shares: Agios Pharmaceuticals Inc. I. Hassan: Financial Interests, Personal, Stocks/Shares: Agios Pharmaceuticals Inc; Financial Interests, Personal, Full or part-time Employment: Agios Pharmaceuticals Inc, Servier Pharmaceuticals LLC.. P. Wen: Financial Interests, Personal, Research Funding: AstraZeneca/MedImmune, BeiGene, Celgene, Chimerix, Eli Lily, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier Pharmaceuticals LLC, Vascular Biogenics, and VBI Vaccines; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Black Diamond, Boehringer Ingelheim, Boston Pharmaceuticals, Celularity, Chimerix, Day One Bio, Genenta, GSK, Karyopharm, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier Pharmac. T. Cloughesy: Financial Interests, Personal, Member of Board of Directors, Cofounder, major stock holder, consultant and board member: Katmai Pharmaceuticals; Financial Interests, Personal, Speaker, Consultant, Advisor: 501c3 Global Coalition for Adaptive Research, Sagimet, Clinical Care Options, Ideology Health, Servier Pharmaceuticals LLC, Jubilant, Immvira, Gan & Lee, BrainStorm, Katmai, Sapience, Inovio, Vigeo Therapeutics, DNATrix, Tyme, SDP, Novartis, Roche, Kintara, Bayer, Merck, Boehringer Ingelheim, VBL, Am; Financial Interests, Personal, Stocks or ownership, And receiving milestone payments and possible future royalties: Chimerix; Financial Interests, Personal, Stocks or ownership: Erasca; Non-Financial Interests, Personal, Membership or affiliation, Membership of the scientific advisory boards: Break Through Cancer and Cure Brain Cancer Foundation; Financial Interests, Personal, Other, Contracts with UCLA for the Brain Tumor Program: Oncovir, Merck, Oncoceutics, Novartis, Amgen, AbbVie, DNAtrix, BeiGene, Bristol Myers Squibb, AstraZeneca, Kazia, Agios, Boston Biomedical, Deciphera, Tocagen, Orbus, AstraZeneca, and Karyopharm; Financial Interests, Institutional, Licencing Fees, Regents of the University of California (T.F.C.’s employer) have licensed intellectual property co-invented by T.F.C. to Katmai Pharmaceuticals: Regents of the University of California. All other authors have declared no conflicts of interest.

Background

The MAPK pathway over-activation is the primary driver in most of pLGG, mainly including BRAF^V600E, KIAA1549-BRAF fusion and NF1^mut with limited therapeutic options available. FCN-159 is an oral inhibitor of MEK1/2 with highly potent selectivity, and is expected to be an efficacious targeted therapy of pLGG. A multi-center, single-arm phase II study was designed to evaluate safety and efficacy of FCN-159 in pediatric patients (pts) with recurrent or progressive LGG.

Methods

Pediatric pts with recurrent or progressive LGG were enrolled and received FCN-159 monotherapy continuously 5mg/m² once daily based on body surface area (BSA). The primary endpoint was to assess preliminary efficacy of FCN-159 by RANO criteria.

Results

As the cut-off date of July 31^th, 2023, 23 subjects have been enrolled. Median age is 8 years (range: 3-17) at study entry, 56.5% were female. All pts were identified as BRAF or NF1 alterations (BRAF ^V600E 12/23, 52.2%, KIAA1549-BRAF fusion 8/23, 34.8% and NF1 ^mut 3/23, 13.0%). At a median follow-up of 7.79 months, 22 pts were evaluated for efficacy: 6 partial response (PR, 27.3%, unconfirmed PR 3), 9 minor response (MR, 40.9%, unconfirmed MR 2), and 7 stable disease (SD, 31.8%). Among 23 pts, 22 pts (95.7%) experienced treatment-emergent adverse events (TEAEs), which were reported to be drug-related. Most common TEAEs (incidence ≥ 20%) included blood lactate dehydrogenase increased, α-hydroxybutyrate dehydrogenase increased, blood creatine phosphokinase increased, upper respiratory tract infection, paronychia and rash. Majority were grade 1 or 2, and 2 pts reported grade 3, no grade 4 or above reported. One pt experienced serious adverse event as liver function test abnormal. TEAEs leading to drug interruption were reported in 16 pts, and 10 pts were related to study drug. No TEAEs leading to drug dose reduction, discontinuation or death were reported.

Conclusions

The preliminary study results showed that treatment of FCN-159 was remarkably efficacious for pLGG pts. FCN-159 is well tolerated and easily manageable, without new safety signal observed. Long-term efficacy and safety follow-up are ongoing.

Clinical trial identification

ChiCTR2300069156.

Legal entity responsible for the study

The authors.

Funding

Shanghai Fosun Pharmaceutical Development Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

Trotabresib (TROTA) is a novel bromodomain and extraterminal protein inhibitor that has shown brain tumor tissue penetration, encouraging tolerability and preliminary efficacy in combination with standard of care (SOC) concomitant TMZ + RT and adjuvant TMZ in pts with ndGBM. We present long-term follow-up for part A (dose escalation) and an update on part B (expansion) of the ph 1b/2 CC-90010-GBM-002 study (NCT04324840).

Methods

Study design has been previously described (Vieito et al. SNO 2022 . Abstr CTNI-21). Part B enrolled pts with IDH wild-type ndGBM; pts were randomized 2:1 to TROTA + SOC then maintenance TROTA (arm A) vs SOC alone (arm B).

Results

As of 20 Jan 2023, part A has closed with 32 pts enrolled (concomitant, n = 14; adjuvant, n = 18); part B has enrolled 136 pts (arm A, n = 91; arm B, n = 45). In part A, no new safety events were observed with longer follow-up; median follow-up was 21.6 mo (range 3.4–27.6). The most frequent grade (G) 3/4 treatment-related adverse event (TRAE) was thrombocytopenia (8/14 pts [57%] in the concomitant group and 9/18 pts [50%] in the adjuvant group). Efficacy in part A is shown in the table. At last follow-up, 8 pts (4 per group) remained on treatment, including 1 pt with ongoing complete response at cycle 24. In part B, the most common all-cause G 3/4 AE was thrombocytopenia occurring in 21/88 (24%) and 5/43 (12%) patients in arms A and B, respectively. TRAEs related to TROTA led to treatment discontinuation in 3 pts (arm A), and TRAEs related to TMZ led to discontinuation in 4 pts (2 in each arm); no treatment-related deaths reported. Enrollment of part B was recently completed; efficacy data are not yet mature.

Conclusions

Addition of TROTA to SOC followed by maintenance TROTA in pts with ndGBM was well tolerated with no new safety signals in parts A and B, and promising efficacy in part A. Follow-up is ongoing.

Table: 500O

Clinical trial identification

NCT04324840.

Editorial acknowledgement

Writing and editorial support were provided by Benjamin Levine, PhD, and Agata Shodeke, PhD of Spark Medica Inc, funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

M. Vieito Villar: Non-Financial Interests, Principal Investigator: Roche, Bristol Myers Squibb, Taiho, Hutchinson Pharma, Novartis, Mundipharma, Enterome, Debiopharm. J.M. Sepúlveda Sánchez: Financial Interests, Personal, Advisory Board: Cantex, CeCaVa, MSD, Novocure; Financial Interests, Personal, Invited Speaker: GSK; Non-Financial Interests, Personal and Institutional, Research Grant: Cantex, Pfizer. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, Bristol Myers Squibb, Boehringer, Boheringer, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. G. Lombardi: Financial Interests, Personal, Advisory Board: Janssen, Braun, Helath4U; Financial Interests, Personal, Invited Speaker: Bayer, Orbus, Novartis; Financial Interests, Institutional, Coordinating PI: Bayer SpA. A. Stradella: Financial Interests, Personal, Advisory Board, Advisory about CAPITELLO 291 trial: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory on new activities for residents: Novartis; Financial Interests, Personal, Invited Speaker, Trastu-Deruxtecan clinical case meeting: Daiichi; Financial Interests, Personal, Invited Speaker, meeting on new data on cyclin inhibitors: Novartis. C.A. Haslund: Financial Interests, Personal, Invited Speaker: MSD, GSK, Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Tesaro, MSD, IO Biotech, Chimerix, Incyte; Financial Interests, Institutional, Coordinating PI: GSK, Celgene Aps. E. Pineda: Financial Interests, Personal, Advisory Board: Novocure. F.Y.F.L. De Vos: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Novartis, GSK, Bristol Meyers Squibb; Non-Financial Interests, Member of Board of Directors, Dutch Society of Medical Experts Treating Rare Cancers: Dutch Rare Cancer Platform; Non-Financial Interests, Leadership Role, Chair Quality of Care Committee: Dutch Society of Medical Oncology; Non-Financial Interests, Leadership Role, board member of Quality Assurance in Brain Tumor Group: European Organisation for Research and Treatment of Cancer; Non-Financial Interests, , Member of Board of Directors, national databank on care in brain tumor patients: Dutch Brain Tumor Registry; Non-Financial Interests, Leadership Role, board member of Education Committee: European Association for Neuro-Oncology; Other, grant for research project given bij non-profit patient advocacy group: Foundation STOPBraintumors.org. M.A. Vaz Salgado: Financial Interests, Personal, Advisory Board: Novocure; Financial Interests, Personal and Institutional, Coordinating PI: Pfizer. M. Martinez Garcia: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Takeda, Seagen, Pierre Fabre, Novocure; Financial Interests, Personal, Other, Travel, accommodations, expenses: Pfizer, Daiichi Sankyo, AstraZeneca, Gilead; Non-Financial Interests, Leadership Role, Member of the board: GEINO, Spanish group of Neuro Oncology; Non-Financial Interests, Principal Investigator, Clinical Trials: Bristol Myers Squibb Celgene, Roche; Non-Financial Interests, Principal Investigator, Clinical trial: Cantargia; Non-Financial Interests, Principal Investigator, Clinical Trial: Laminar Pharma; Non-Financial Interests, , Principal Investigator, clinical trial: Incyte. T. Sanchez: Financial Interests, Personal, Full or part-time Employment, I work as Clinical Scientist for Bristol Myers Squibb: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares, I own some shares in Bristol Myers Squibb: Bristol Myers Squibb. B. Hanna: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. X. Li: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. Z. Nikolova: Financial Interests, Institutional, Full or part-time Employment, I am full time employee of Bristol Myers Squibb and possess shares: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb; Non-Financial Interests, Project Lead, Clinical Leader for MoCR TRC: Bristol Myers Squibb. M. Simonelli: Financial Interests, Personal, Advisory Board: Incyte, Cytovia; Financial Interests, Personal, Invited Speaker: GSK, Bristol Myers Squibb; Financial Interests, Personal, Other, Data Monitoring Committee: Sanofi. All other authors have declared no conflicts of interest.

Background

Glioblastoma (GB) resistance against anticancer therapies is enhanced by Smoothened (SMO) signaling. Glasdegib (GLG), a SMO inhibitor, may lead to improved efficacy of the Stupp scheme.

Methods

Newly diagnosed GB patients (pts) received GLG with standard radiotherapy (RT)/ temozolomide (TMZ) followed by maintenance with GLG monotherapy. The study was carried out in two phases. In phase Ib the primary objective was the recommended phase 2 dose (RP2D) in a 3+3 dose escalation strategy. The dose of 75 mg/QD of GLG was declared the RP2D. The primary objective in phase II was 15-m overall survival (OS) rate. The study established a futility threshold of 60% for 15-m OS to consider the trial positive; accrual required: 70 evaluable pts in phase II. Secondary objectives included progression-free survival (PFS) according to RANO criteria, safety, changes in performance status, pharmacokinetic and exploratory biomarker analysis.

Results

Between 2018 and 2020, 79 GB pts were enrolled, and 74 (98.7%) pts received GLG at 75mg/QD. The median age was 55 years (range: 28-78), 54% were male, 58.1% were ECOG 1, 39.2% were MGMT methylated, and 1 pts had an IDH1/2 mutation. Complete surgical resection was achieved in 35 (47.3%) pts. GLG treatment lasted a median of 6.9 m (range 0.7-24). 68 (91.9%) finalized concomitant period with RT/TMZ, 64 (86.5%) started adjuvant therapy with TMZ, 33 (51.6%) finalized adjuvant period, and 28 (37.8%) continued GLG monotherapy. 53 pts (71.6%) presented stable disease. After a median follow up of 14.8 m (range 0.7-36.4), mPFS was 7 m (95% CI: 6.1-8.6), and the 12-m PFS rate was 22.2% (95% CI: 14.4-34.2). The mPFS based on MGMT status was 8.4 m (95% CI: 6.5-16.9) and 7.3 m (95% CI: 4.9-9.1) for MGMT methylated and unmethylated respectively (p= 0.044). The mOS was 15.3 m (95% CI: 14-21.2). At data cut-off, 22 (29.7%) pts alive. The mOS was 25.6 m (95% CI: 16-NR) and 14.3 m (95% CI: 11.7-19) for MGMT methylated and unmethylated respectively (p= 0.005).

Conclusions

The addition of GLG to standard RT and TMZ showed preliminary efficacy for newly diagnosed GBM, with almost 30% pts still alive at data cutoff. Long-term survival will be updated. No new safety alerts were reported.

Clinical trial identification

NCT03466450, EudraCT 2017-002410-31.

Editorial acknowledgement

We acknowledge MFAR Clinical Research staff for their assistance in the development of this abstract.

Legal entity responsible for the study

Grupo Español de Investigación en NeuroOncología (GEINO).

Funding

Grupo Español de Investigación en NeuroOncología (GEINO) as Sponsor, Pfizer as industry partner. Grupo Español de Investigación en NeuroOncología (GEINO) as Sponsor, Pfizer as industry partner. Grupo Español de Investigación en NeuroOncología (GEINO) as Sponsor, Pfizer as industry partner.

Disclosure

J.M. Sepúlveda: Financial Interests, Personal, Advisory Board: Cantex, CeCaVa, MSD, Novocure; Financial Interests, Personal, Invited Speaker: GSK; Non-Financial Interests, Personal and Institutional, Research Grant: Cantex, Pfizer. M. Martínez-García: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Novocure, Pierre Fabre, Seagen, Takeda; Financial Interests, Personal, Other, Travel, Accomodation, Expenses: Daiichi Sankyo, AstraZeneca, Gilead, Pfizer; Non-Financial Interests, Personal, Principal Investigator, Clinical Trials: Bristol Myers Squibb, Gelgene, Cantargia; Non-Financial Interests, Personal, Leadership Role, Member of the board: Geino; Non-Financial Interests, Personal, Principal Investigator, Clinical trial: Incyte, Laminar Pharma, Roche. R. Gironés: Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, Astellas, Janssen, Pfizer, Merck; Financial Interests, Personal, Advisory Board: Ipsen, Novocure; Financial Interests, Personal, Other, Travel: MSD. All other authors have declared no conflicts of interest.