All times are listed in CEST (Central European Summer Time)
- Joan Seoane (Barcelona, Spain)
- Andreas F. Hottinger (Lausanne, Switzerland)
- Emeline Tabouret (Marseille, France)
502MO - Target therapy matched to genomic alterations in patients with recurrent IDH wildtype glioblastoma: A real-life cohort analysis from Veneto Institute of Oncology, Padua (Italy)
- Giulia Cerretti (Padova, Italy)
Abstract
Background
Next-generation sequencing (NGS) allows to identify patients (pts) that may respond to target therapies (TT). Only a few data are available regarding TT for recurrent glioblastoma (rGBM).
Methods
We retrospectively analyzed a cohort of pts with rGBM treated with TT based on NGS profile obtained on formalin-fixed paraffin-embedded tissue samples. We identified 7 druggable alterations, classified according to ESCAT: BRAFV600E (IB), NTRK fusions (IC), FGFR1-3 alterations (IIB), ROS1 fusions, MET amplification/fusions, PIK3CA mutations and PTEN loss/mutations (IIIA).
Results
Between 03/20 and 03/23, 37 pts received TT. All pts received radiotherapy and temozolomide as first-line. Median line of TT was 3 (range 2-7). TT was dabrafenib/trametinib (9 pts), larotrectinib (2 pts), erdafitinib (4 pts), entrectinib (1 pt), vebreltinib (2 pts), capmatinib (1 pt), alpelisib (6 pts), ipatasertib+/-atezolizumab (12 pts). At data cut-off (05/23), 24 patients had died. In the entire cohort, median overall survival and progression-free survival (PFS) after starting TT was 8.19 and 2.11 months (mo), respectively. The dabrafenib/trametinib (D/T) subgroup had the longest median PFS (5.23 mo), a disease control rate (DCR) of 77%, an objective response rate of 22%, and a median duration of response of 22.5 mo. 7/9 pt had died and 2 are continuing D/T. The pt with ROS1-GOCP fusion maintained a complete response for 12 mo with entrectinib. A multifocal rGBM patient with PTPRZ1-MET fusion, identified by Caris MI-Transcriptome, had impressive PR after 8 weeks of vebreltinib in third-line during participation in APL-101-01 study (NCT03175224): duration of response is pending as TT is ongoing. Among the others, no complete/partial responses were detected. DCR was 67% in MET-inhibitors, 50% in larotrectinib and erdafitinib, 8% in ipatasertib+/-atezolizumab subgroups. No toxicities were reported with D/T. Among all pts, no grade 4 adverse events were observed and in any case, TT was interrupted for toxicity.
Conclusions
Our results confirm the activity of D/T in BRAFV600E mutant rGBM. We had a dramatic response to a MET inhibitor. Deeper explorations are needed in targeting FGFR e ROS1.
Legal entity responsible for the study
G. Lombardi.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
503MO - Real-world clinical and genomic characterization of gliomas: Predictive and prognostic insights
- Oriol Mirallas (Barcelona, Spain)
Abstract
Background
Based on our proposal for the first ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) classification for brain tumors [Mirallas et al. ESMO 2022 ] and the descriptive analysis of real-world data in gliomas [Mirallas et al. ASCO 2023 ], we aim to define the clinical actionability of molecular alterations (MA) detected by next-generation sequencing (NGS) in a multicentric glioma cohort.
Methods
Patients (pts) with glioma who had NGS at seven Spanish institutions were included between Jan 2018 and Dec 2022. For predictive associations, pts were classified into Tier1/2, Tier3/4 or wild type (WT) group according to their ESCAT score. Groups were compared using Kruskal-Wallis or Chi-squared tests. To explore prognostic markers, pts with grade 4 glioblastoma (GBM) IDH WT tested within 1 year from diagnosis who had TERT or TP53 genomic results were analyzed. Overall survival (OS) was estimated using the Kaplan-Meier method and Cox hazard ratio were fitted.
Results
Of 580 pts included, 567 pts (98%) underwent NGS testing. A total of 395/567 (71%) had a diagnosis of GBM and 165 (29%) harbored a Tier 1/2 MA. Median age was 51y (IQR: 39-61), 381 (67%) had ECOG ≥1, 223 (40%) were women, and 148 (26%) were 40 or younger. Most common MAs in the entire cohort were PI3KCA (29%), CDKN2A/B loss (28%), EGFR gain (26%), IDH1 (22.4%), EGFRvIII and ATRX (both 17%). Tier 1/2 MAs were more prevalent in younger pts (56% vs 10% in <40y vs >40y), non-GBM (65% vs 9% in non-GBM vs GBM), and TP53 mut (52% vs 24% in mutant vs WT) [all p<0.001]. Meanwhile, Tier 3/4 MAs were more typical for grade 4 gliomas with EGFR MAs (57% vs 2% in WT), TERT mut (55% vs 33% in WT) and CDKN2A/B loss (43% vs 13% in WT) [all p<0.001]. Among pts with grade 4 GBM-IDH WT, 53% had TERT mut and 26% had TP53 mut. In this subset of pts, median OS in case of incomplete resection (R1) was 29.5 months [95%CI 20-40.3] for those with TERT WT and 17 months [95% CI 14-22] in TERT mut pts (p=0.01), but no differences in OS were found in TP53 mut vs WT pts.
Conclusions
Most common actionable MA were IDH, PIK3CA, EGFR, ATRX, suggesting NGS value for identifying potential candidates for targeted treatment. TERT mut was prognostic of worse OS in pts with grade 4 GBM-IDH WT after incomplete tumor resection.
Legal entity responsible for the study
VHIO.
Funding
Has not received any funding.
Disclosure
O. Mirallas: Financial Interests, Personal, Invited Speaker: ROVI; Financial Interests, Institutional, Writing Engagement: Roche, Merck; Other, , Other, Travel Expenses: Kyowa Kirin, Almirall; Other, Travel Expenses and Conference Fee: Sanofi. T. Gorria: Other, Personal, Other, travel expenses: Bristol Myers Squibb, MSD. M.A. Vaz Salgado: Financial Interests, Personal, Advisory Board: Novocure; Financial Interests, Personal and Institutional, Coordinating PI: Pfizer. A. Hernandez Gonzalez: Financial Interests, Personal, Invited Speaker: Roche, Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Roche, Sanofi; Financial Interests, Institutional, Other, Research Funding: Janssen. M. Gonzalez Rodriguez: Financial Interests, Personal, Invited Speaker: MSD, Pfizer, Roche, AstraZeneca; Financial Interests, Personal, Other, Review clinical cases: Bayer. 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. J. Carles Galceran: Financial Interests, Personal, Advisory Board: Astellas Pharma, AstraZeneca, Bayer, Johnson & Johnson, MSD Oncology, Novartis (AAA), Roche, Sanofi; Financial Interests, Institutional, Local PI: Janssen-Cilag International NV, Lilly, S.A, MedImmune, Novartis Farmacéutica, S.A, Sanofi-Aventis, S.A; Other, Member of the Comission: Catalan Program of Ambulatory Medication Comission (CAHMDA). E. Pineda: Financial Interests, Personal, Advisory Board: Novocure. R. Dienstmann: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Boehringer Ingelheim, Ipsen, Libbs, Lilly, Merck Sharp & Dohme, Roche, Sanofi, Servier, GSK, Takeda, Janssen, Foundation Medicine; Financial Interests, Personal, Advisory Board: Bayer, Roche; Financial Interests, Personal, Full or part-time Employment, Oncoclínicas is a private healthcare provider in Brazil. I work part time as Medical Director of the Precision Medicine and Big Data Initiative. We develop molecular tests (pathology and genomics) that are offered to patients treated in the organisation as part of support programs sponsored by pharmaceutical companies and I coordinate research activities with real-world clinico-genomics cohorts: Oncoclínicas; Financial Interests, Personal, Stocks/Shares: Trialing; Financial Interests, Personal, Research Grant: Merck. M. Vieito Villar: Non-Financial Interests, Principal Investigator: Roche, Bristol Myers Squibb, Taiho, Hutchinson Pharma, Novartis, Mundipharma, Enterome, Debiopharm. All other authors have declared no conflicts of interest.
504MO - Validation of a spectroscopic liquid biopsy for the earlier detection of brain cancer
- James M. Cameron (Glasgow, United Kingdom)
Abstract
Background
Brain cancer has a very high fatality rate with only one third of patients surviving five years or more after a diagnosis. Early referral for brain imaging is crucial, but existing symptom-based referral guidelines inadequately stratify patients for brain imaging. Delayed detection leads to 62% of brain tumor patients receiving a diagnosis when they present to the emergency department (ED). A liquid biopsy could rapidly triage the symptomatic population in primary care. The most at-risk patients would be fast-tracked for urgent brain imaging, whereas those with a negative result can be monitored with routine follow-up.
Methods
We initially recruited 988 patients prospectively with non-specific symptoms associated with a brain tumor in NHS Lothian (Edinburgh, UK). Patient blood serum samples were analyzed using the Dxcover® Brain Cancer liquid biopsy. This technology utilizes infrared spectroscopy combined with a diagnostic algorithm to predict the presence of intracranial disease. Sensitivity analysis explored cost-effectiveness across possible combinations of sensitivity and specificity defined by the receiver operating characteristic (ROC) curve. Thereafter, an additional 500 patients were recruited for a verification study, in preparation for an EU-IVDR Performance Evaluation trial. In this clinical performance study, multiple sites across the UK and Europe will collect and analyze patient samples for clinical validation of the test.
Results
In our initial feasibility studies, the liquid biopsy reported an area under the ROC curve of 0.8. The algorithm detected 96% of the patients with brain tumors, and the diagnostic models can be tailored towards higher sensitivity (or specificity) depending on clinical priorities. We will also present the results of our verification study, the cost-effectiveness analysis and an interim analysis of the EU-IVDR trial at the meeting.
Conclusions
This simple, non-invasive blood test facilitates the triage and radiographic diagnosis of brain tumor patients, while providing reassurance to healthy patients. By decreasing the time to diagnosis, the morbidity from treatment can be reduced, which in turn would improve the quality of life of brain cancer patients.
Legal entity responsible for the study
Dxcover Limited.
Funding
Dxcover Limited.
Disclosure
J.M. Cameron, A. Sala, J.J.A. Conn, G. Antoniou: Financial Interests, Personal, Full or part-time Employment: Dxcover Limited. D.S. Palmer: Financial Interests, Personal, Full or part-time Employment: Dxcover Limited; Financial Interests, Personal, Leadership Role: Dxcover Limited; Financial Interests, Personal, Stocks or ownership: Dxcover Limited; Financial Interests, Personal, Advisory Role: Dxcover Limited; Financial Interests, Personal, Research Funding, Dxcover Ltd, GSK, Endophotonics: Dxcover Limited. M.J. Baker: Financial Interests, Personal, Leadership Role: Dxcover Limited; Financial Interests, Personal, Full or part-time Employment: Dxcover Limited; Financial Interests, Personal, Stocks or ownership: Dxcover Limited.
Invited Discussant 502MO, 503MO and 504MO
- Joan Seoane (Barcelona, Spain)
505MO - A phase 0/Ib study of AZD1390 plus radiotherapy in recurrent glioblastoma patients
- Nader Sanai (Phoenix, United States of America)
Abstract
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
Results
In 12 patients treated to date, AZD1390 was consistently measured in the Gd-non-enhancing tumor region. All patients (n=12) 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 (median 2.1% vs 34.8%, average 94% reduction, p<0.01). Median 6-month progression-free survival has not been reached at a median clinical follow-up of 4.4 months.
Conclusions
AZD1390 is well-tolerated in recurrent GBM patients, achieving pharmacologically relevant concentrations in non-enhancing tumor tissue, and substantially suppressing induction of pRAD50 levels
Clinical trial identification
NCT05182905.
Legal entity responsible for the study
Neurotrials.
Funding
Barrow Neurological Foundation, Ben and Catherine Ivy Foundation.
Disclosure
A. Tovmasyan: Financial Interests, Personal, Royalties: Biomimetix. All other authors have declared no conflicts of interest.
506MO - A phase I dose-expansion cohort of SYHA1813, a vascular endothelial growth factor receptor (VEGFR) 1-3 /colony-stimulating factor 1 receptor (CSF1R) inhibitor, in patients (pts) with recurrent meningioma
- Wenbin Li (Beijing, China)
Abstract
Background
SYHA1813 is a highly potent inhibitor, mainly against VEGFR1-3/CSF1R, and exerts synergistic anti-tumor effects by blocking tumor angiogenesis and modulating tumor microenvironment. Here, we report early findings from pts treated with SYHA1813 in the recurrent meningioma cohort.
Methods
Adult pts (Karnofsky performance status ≥ 60) with recurrent histologically confirmed meningioma not amenable to surgery or radiotherapy were enrolled and treated with 15mg or 20mg SYHA1813 once daily. The primary endpoints were objective response rate (ORR) and the 6-month progression-free survival rate (PFS-6) per Response Assessment in Neuro-Oncology Criteria for meningioma. The secondary endpoints included incidence, type, and severity of adverse events, graded by Common Terminology Criteria for Adverse Events (Version 5.0).
Results
As of Apr. 12, 2023, 11 eligible pts (5 males) with a median age of 50 (range 34-76) were enrolled, including 1 with World Health Organization (WHO) grade I tumor, 6 WHO grade II, and 4 WHO grade III. The median number of prior surgeries were 2 (range 1-4). With a median treatment duration of 1.45 months (range 0.23-6.24), ORR was 45.5% [95% confidence interval (CI) 16.8%–76.6%], with 1 partial response (PR), 2 minor response (MR), 1 unconfirmed PR and 1 unconfirmed MR. Tumor regression in target lesions was observed in 10 out of 11 pts, of which 6 reached ≥ 25% reductions in tumor size. PFS-6 was 75.8% (95% CI 30.5%-93.7%). All pts experienced treatment-emergent adverse events (TEAEs), of which 6 (54.5%) were ≥ grade 3, and all of them were recovered within 7 days. Of these ≥ grade-3 TEAEs, hypertension occurred in ≥ 2 patients. One patient with a complex surgery history developed a serious TEAE, grade-4 intracranial hemorrhage, which was resolved quickly after interventions. No grade-5 TEAEs were reported.
Conclusions
SYHA1813 showed encouraging objective responses with a well-tolerated safety profile in pts with recurrent meningioma.
Clinical trial identification
ChiCTR2100045380.
Legal entity responsible for the study
CSPC Pharmaceutical Group Limited.
Funding
CSPC Pharmaceutical Group Limited.
Disclosure
W. Pu, X. Yang, J. Lin, M. Liu: Financial Interests, Institutional, Full or part-time Employment: CSPC Pharmaceutical Group Limited. All other authors have declared no conflicts of interest.
Invited Discussant 505MO and 506MO
- Andreas F. Hottinger (Lausanne, Switzerland)
507MO - REGOMA-OS: A large Italian multicenter, prospective, observational study analyzing regorafenib efficacy and safety in recurrent glioblastoma patients
- Giuseppe Lombardi (Padova, Italy)
Abstract
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 treatment. We performed a large multicenter, prospective and observational study to confirm REGOMA data in a real-world setting.
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 the 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. The 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 was 34.7% (95%CI 27.2-42.4); median PFS was 2.6ms (95%CI 2.3-2.9), 6ms-PFS was 14.3%. The 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 real-world trial confirmed the results in terms of overall survival with a good toxicity profile of REG in recurrent GBM PTS.
Clinical trial identification
NCT04810182.
Legal entity responsible for the study
Veneto Institute of Oncology IOV-IRCCS.
Funding
Veneto Institute of Oncology IOV-IRCCS.
Disclosure
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. E. Franceschi: Non-Financial Interests, Advisory Role, Non reimbursed role in the advisory board: Incyte. All other authors have declared no conflicts of interest.
508MO - Spatial remodeling of the immune tumor microenvironment after radiotherapy and CXCL12 inhibition in glioblastoma in the phase I/II GLORIA trial
- Julian Philipp Layer (Bonn, Germany)
Abstract
Background
Radiotherapy (RT) causes upregulation of CXCL12, a chemokine facilitating recruitment of tumor-associated macrophage (TAM) precursors promoting neovasculogenesis and the formation of an immunosuppressive tumor microenvironment (TME). Here, we report an in-depth analysis of the immune TME (iTME) in patients of the multicentric phase 1/2 GLORIA trial (NCT04121455) which combines RT and CXCL12 inhibition with the RNA-Spiegelmer NOX-A12.
Methods
We analyzed tumor tissue of 10 GLORIA patients with newly diagnosed, incompletely resected (n=8) or biopsied (n=2) GBM with ECOG≤2 lacking MGMT promoter methylation. All patients received standard RT and escalating dose levels of continuous (24/7) i.v. infusions of NOX-A12. Two patients underwent re-surgery, whereas one was diagnosed with pseudoprogression (PsP) and one with recurrence. To characterize the iTME, we used highly multiplexed immunofluorescence (mIF) imaging. As a comparison to the GLORIA cohort, we investigated the pre/post-therapeutic iTME of reference patients receiving standard-of-care (n=7) treatment.
Results
In all samples analyzed, CXCL12 co-localized with endothelial cells. Unlike in the reference cohort, matched pre-/post-treatment tissue analysis of the patient with PsP revealed endothelial and gliomal CXCL12 depletion following treatment with NOX-A12, confirming the mode of action of the drug. Both post-treatment GLORIA samples showed intralesional clustering of activated CD8+ T cells. In the non-responder diagnosed with recurrence, a pro-tumorigenic spatial rearrangement of the iTME was observed, characterized by a presence of M2-like TAMs in the proximity of the perivascular T cell clusters, confirmed by nearest neighbor analysis. None of the reference patients showed similar alterations of the iTME.
Conclusions
m IF of matched pre-/post-therapy tissue samples from the ongoing GLORIA trial supports the proposed modes of action of RT and NOX-A12 counteracting vasculogenesis and modulating the iTME reflected through its spatial rearrangement. This opens up the question of a targetable, compartment-specific role of CXCL12 to be further assessed.
Clinical trial identification
NCT04121455.
Legal entity responsible for the study
TME Pharma.
Funding
TME Pharma.
Disclosure
S. Leonardelli: Financial Interests, Personal, Funding, Travel Reimbursemen: TME Pharma; Financial Interests, Personal, Advisory Role: AlphaSights Ltd; Financial Interests, Institutional, Funding: TME Pharma. J.P. Layer: Other, Personal, Full or part-time Employment: MVZ Venusberg gGmgh; Financial Interests, Personal, Stocks/Shares: BioNtech, Siemens Healthineers, Bayer, TME Pharma; Financial Interests, Institutional, Funding: TME Pharma; Financial Interests, Personal, Funding, Travel reimbursement: TME Pharma; Financial Interests, Personal, Advisory Role: Siemens Healthineers. C. Schaub: Financial Interests, Personal, Stocks/Shares: Bayer. E. Sperk: Financial Interests, Personal, Financially compensated role, + Travel expenses: Zeiss Meditech. M. Glas: Financial Interests, Personal, Financially compensated role: Novocure, Roche, Novartis, AbbVie, Seagan, TME Pharma, Daiichi Sankyo Pharmaceutical, Merck; Financial Interests, Personal, Advisory Role: Novocure, Seagan, AAA HealthCare; Financial Interests, Personal, Research Funding: Novocure; Financial Interests, Personal, Funding, Travel Reimbursement: Novocure. C. Seidel: Financial Interests, Personal, Advisory Role: Seagen; Financial Interests, Personal, Financially compensated role: Seagen . U. Herrlinger: Financial Interests, Personal, Advisory Role: Janssen, Bayer; Financial Interests, Personal, Speaker’s Bureau: Medac. F.A. Giordano: Financial Interests, Personal, Advisory Role: Cureteq, Carl Zeiss Meditec, Targeted Medical Education, Inc.; Financial Interests, Personal, Funding: Carl Zeiss Meditec, TME Pharma; Financial Interests, Personal, Expert Testimony: Carl Zeiss Meditec; Financial Interests, Personal, Royalties, Patent: US10857388B2; Financial Interests, Personal, Other: Federal Joint Committee (G-BA); Financial Interests, Personal, Stocks/Shares: TME Pharma; Financial Interests, Personal, Financially compensated role: AstraZeneca, Carl Zeiss Meditec, Medac, TME Pharma, Cureteq; Financial Interests, Personal and Institutional, Research Funding: Carl Zeiss Meditec, TME Pharma. M. Hölzel: Financial Interests, Personal, Financially compensated role: Bristol Myers Squibb, Novartis; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Novartis; Financial Interests, Personal and Institutional, Research Funding: TME Pharma; Financial Interests, Personal, Funding, Travel reimbursement: TME Pharma. All other authors have declared no conflicts of interest.
Invited Discussant 507MO and 508MO
- Emeline Tabouret (Marseille, France)