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Displaying One Session

Mini Oral session
Date
Sat, 10.09.2022
Time
16:30 - 18:00
Location
7.3.U - Urval Auditorium
Chairs
  • Enrico Franceschi (Bologna, Italy)
  • Patrick Roth (Zurich, Switzerland)
  • Monika E. Hegi (Lausanne, Switzerland)
Session Type
Mini Oral session
Mini Oral session

281MO - Quality of life and neurocognitive function in patients with active brain metastases of HER2-positive breast cancer treated with trastuzumab-deruxtecan: Secondary endpoint analysis of the prospective single-arm phase II TUXEDO-1 trial

Presentation Number
281MO
Speakers
  • Angelika M. Starzer (Vienna, Austria)
Lecture Time
16:30 - 16:35
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00

Abstract

Background

Maintaining quality-of-life (QoL) and neurocognitive function is a main goal in the setting of brain metastases (BM) in HER2-positive breast cancer (BC) patients (pts). TUXEDO-1 investigated QoL and neurocognitive function during trastuzumab-deruxtecan (T-DXd) therapy in HER2-positive BC BM pts.

Methods

TUXEDO-1 is a prospective, open-label, single-arm phase II trial and enrolled adult HER2-positive BC pts with newly diagnosed BM or progressive BM with no immediate need for local therapy. T-DXd was administered every three weeks at standard dose until disease progression, unacceptable side-effects or consent withdrawal. A secondary endpoint of the trial was QoL and pts completed the EORTC QLQ-C30 questionnaire at cycle 1, 3, 5 and every 9 weeks thereafter. A final assessment was performed at first survival follow-up three months after end-of-treatment. Linear mixed-effect models were used to analyze changes in QoL scores (sub-domains global QoL score, cognitive/emotional/physical function scores; scores range from 0-100) over time (slope). TUXEDO-1 is registered with EU Clinical Trials Register (EudraCT 2020-000981-41) and ClinicalTrials.gov (NCT04752059) and enrollment is closed.

Results

Fifteen pts (14 females, 1 male; 12/15 luminal B) were enrolled and received at least one dose of T-DXd. Median age at inclusion was 69 (range 30-76) years. Pts received a median of two (range 1-5) prior systemic therapies for metastatic BC and 9/15 (60%) pts received prior local therapy (whole brain radiotherapy, stereotactic radiotherapy or neurosurgery) for BM. Neurologic symptoms at inclusion were present in 6/15 (40%) of pts. Median follow-up time was 11 months. The QLQ-C30 global QoL (slope -0.13 per follow-up visit, p=0.953), the physical (0.52, p=0.363), emotional (-0.24, p=0.835) as well as the cognitive functioning scores (-0.79, p=0.429) were all maintained over the duration of T-DXd therapy.

Conclusions

TUXEDO-1 showed maintained QoL and neurocognitive function during T-DXd therapy in HER2-positive BC BM pts. Our data support first-line systemic therapy with T-DXd in pts with active BM.

Clinical trial identification

EU Clinical Trials Register (EudraCT 2020-000981-41) and ClinicalTrials.gov (NCT04752059).

Legal entity responsible for the study

The authors.

Funding

Daiichi Sankyo.

Disclosure

A.M. Starzer: Financial Interests, Personal, Other, Travel support: PharmaMar; Financial Interests, Personal, Invited Speaker: AstraZeneca. A.S.S. Berghoff: Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Roche; Financial Interests, Personal, Invited Speaker: Roche, Bristol Myers Squibb, Merck, Daiichi Sankyo; Financial Interests, Personal, Other, Travel support: Roche, Amgen, Daiichi Sankyo, AbbVie. Z. Bago-Horvath: Financial Interests, Personal, Advisory Board: MSD, Roche; Financial Interests, Personal, Other, Travel support: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: MSD, Daiichi Sankyo. A. Ilhan-Mutlu: Financial Interests, Personal, Advisory Board: MSD, Servier, BMS; Financial Interests, Personal, Invited Speaker: Eli Lilly, Servier, BMS, MSD; Financial Interests, Personal, Advisory Role: Astellas, MSD; Financial Interests, Personal, Other, Travel support: BMS, Roche, Eli Lilly, Daiichi Sankyo. C. Minichsdorfer: Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, MSD, Amgen; Financial Interests, Personal, Other, Travel grant: MSD, Merck Darmstadt. T. Fuereder: Financial Interests, Personal, Advisory Role: MSD, Merck, BMS, Boehringer Ingelheim, Roche, Pfizer, Sanofi, Amgen, Janssen, Takeda; Financial Interests, Personal, Research Grant: MSD, Merck. M. Preusser: Financial Interests, Personal, Invited Speaker: Bayer, Bristol Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck, Sharp & Dome, Tocagen; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Bristol Myers Squibb, Roche, Daiichi Sankyo, Merck Sharp & Dome, Novocure, GlaxoSmithKline, AbbVie. R. Bartsch: Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi, Eisai, Eli Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Puma, Roche, Seagen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Celgene, Eli Lilly, Novartis, Pfizer, Pierre Fabre, Roche, Seagen; Financial Interests, Institutional, Research Grant: Daiichi, MSD, Novartis, Roche. All other authors have declared no conflicts of interest.

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Mini Oral session

282MO - Brain metastases: Real-life treatment patterns, survival and patient-reported outcomes – Results from a population-based, prospective study in 914 patients

Presentation Number
282MO
Speakers
  • Olav E. Yri (Oslo, Norway)
Lecture Time
16:35 - 16:40
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00

Abstract

Background

Radiotherapy (RT) is frequently used in brain metastases (BM) treatment. RCTs show equal survival after stereotactic RT (SRT) and whole-brain RT (WBRT) in patients with favorable prognostic factors (i.e. ≤4 BM, good performance status [PS]), while WBRT may not improve survival in patients with more advanced cancer. We investigated what type of anticancer treatments pts were offered at the time of primary BM diagnosis. Patients were grouped according to anticancer treatments and known prognostic criteria. Survival and patient-reported outcomes (PROs) were compared between groups in this “real-life cohort” of consecutive, unselected BM pts.

Methods

A population-based prospective observational study at 5 hospitals in Norway (covering ≈70% of the Norwegian population). Clinical data were collected every 3 months, PROs monthly for 1 year.

Results

914 patients were included (46 % male, median age 69 [21-96]). Most frequent primary cancers were lung (non-small cell, 41%), melanoma (16%), breast (14%) and colorectal (10%). 31% had ≥5 BM, 82% were symptomatic, 41% had ECOG PS ≥2, 80% had extracranial metastases (ECM). Primary BM treatments were: Surgery 17%; SRT 34%; WBRT 40%, systemic treatments 3%; best supportive care (BSC) 6%. Median OS (mOS) after BM diagnosis for all was 6 months (surgery: 13, SRT: 9, systemic: 8, WBRT: 3, BSC: 1). In patients treated with WBRT, 71% had ≥5 BM, 50% ECOG 2-4, 87% ECM, 50% were ≥70 years. mOS for WBRT patients with ECOG 0, 1, 2 and 3-4 was 9, 4, 2 and 2 months, respectively. At inclusion, patients in the WBRT group reported significantly poorer scores for physical functioning (PF) and global quality of life (QoL) compared to those in the surgery and SRT groups. After 2 months, PF, QoL and fatigue scores significantly worsened in the WBRT group, with no change after surgery or SRT.

Conclusions

Clinical data (ECOG, ECM status) and PROs indicate a need for more careful selection of patients offered WBRT. Due to particularly short survival, patients with ECOG 3-4, and perhaps controversially also ECOG 2, may not be able to profit from WBRT. These patients should instead be considered for BSC alone.

Clinical trial identification

NCT03346655.

Legal entity responsible for the study

Oslo University Hospital.

Funding

The Norwegian Cancer Society. South-East Health Care Region of Norway.

Disclosure

O.E. Yri: Non-Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca. All other authors have declared no conflicts of interest.

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Mini Oral session

283MO - Leptomeningeal disease (LMD) in patients (pts) with metastatic melanoma (MM): Survival analysis of a contemporary cohort

Presentation Number
283MO
Speakers
  • Isabella C. Glitza (Houston, United States of America)
Lecture Time
16:40 - 16:45
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00

Abstract

Background

Previous review of the overall survival (OS) of 178 pts with LMD from MM diagnosed between 1999-2015 showed a dismal OS of only 3.5 months (mos). Here we present a contemporary analysis to assess if outcomes had improved with the many changes in systemic therapies for MM pts with LMD since 2015.

Methods

Clinical characteristics, treatment (tx) and OS data were collected for MM pts diagnosed with LMD from 2015-2020. The Kaplan-Meier method was used to estimate OS and multivariable Cox proportional hazards regression modeling was used to evaluate associations with OS.

Results

172 melanoma pts were identified. LMD diagnosis was confirmed with CSF cytology in 53% (n=44) of the 83 pts that underwent analysis, with MRI brain in 128 (74%) pts and MRI spine in 69 (40%) pts. Median age at LMD diagnosis was 53 years (range: 20-79 years), and most pts were male (n=103, 60%). 93 (54%) had a history of primary cutaneous melanoma; the majority had a BRAF mutation (n=113, 66%). With a median follow-up of 4.0 mos (range: 0.1-65.3 mos), the median OS from LMD diagnosis for all pts was 4.9 mos (95% CI: 3.4, 6.5). The majority of patients (n=142; 83%) received at least one LMD directed tx following LMD diagnosis. Systemic tx for LMD was used in 118 (69%) pts. The median OS from LMD diagnosis was 7.9 mos for all pts who received any systemic tx; 10.2 mos for those receiving immunotherapy alone (n=57, 48%), 8.0 mos for pts receiving targeted therapy alone (n=60, 51%), and 5.6 mos for those receiving chemotherapy alone (n=30, 25%). Forty-two (24%) pts received intrathecal (IT) immunotherapy tx. Median OS for pts receiving IT tx was 8.0 mos. 92 (64%) pts received radiation therapy (RT) for LMD, whole-brain RT (n=71, 49%), spine RT (n=23, 16%), and stereotactic RT (n=9, 6%). Improved OS was observed in pts with negative baseline CSF cytopathology (hazard ratio (95% CI): 0.52 (0.27, 0.99); p=0.046), normal LDH (0.47 (0.30, 0.73); p<0.001) and no tx with WBRT (0.20 (0.09, 0.44); p<0.001).

Conclusions

Despite overall poor OS even with available contemporary MM tx, a subset of MM pts with LMD achieve better survival. Further investigation of this specific pts population is needed, as it might guide management and to inform the design of future clinical trials for this population.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

I.C. Glitza: Non-Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb. R. Amaria: Financial Interests, Personal, Advisory Board: Iovance Biotherapeutics, Novartis, Bristol Myers-Squibb; Financial Interests, Institutional, Invited Speaker: Merck, Bristol Myers Squibb, Novartis, Iovance. M. Davies: Financial Interests, Personal and Institutional, Other, Consultant: Bristol Myers Squibb, Pfizer, Novartis; Financial Interests, Institutional, Principal Investigator: Merck. A. Diab: Financial Interests, Personal, Advisory Board: Nektar Therpaeutics, Apexigen, Idera Pharmaceuticals. J. Mcquade: Financial Interests, Personal and Institutional, Other, Consultant: Merck; Financial Interests, Personal and Institutional, Other, Honorarium: Bristol Myer Squibb. S. Patel: Financial Interests, Personal, Invited Speaker, Peer discussion group leader for melanoma (non-promotional speaker / leader): Merck; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: TriSalus; Financial Interests, Personal, Advisory Board: Cardinal Health; Financial Interests, Personal, Other, Independent Data Monitoring Committee: Immunocore; Financial Interests, Institutional, Invited Speaker: Provectus, Lvgen, Bristol Myers Squibb, InxMed, Foghorn Therapeutics, Ideaya. H.A. Tawbi: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Novartis, Genentech, Eisai, Karyopharm, Iovance, Pfizer; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, Merck, Novartis, Genentech; Financial Interests, Institutional, Funding: GSK, Eisai. M. Wong: Financial Interests, Personal and Institutional, Advisory Board: Merck, Pfizer, Bristol Myers Squibb. All other authors have declared no conflicts of interest.

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Mini Oral session

Invited Discussant 281MO, 282MO and 283MO

Speakers
  • Enrico Franceschi (Bologna, Italy)
Lecture Time
16:45 - 17:00
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00
Mini Oral session

284MO - Targeting the tumor microenvironment of glioblastoma multiforme using a macrophage-based treatment for the local delivery of immune-therapeutic payload: The TEM-GBM study (NCT03866109)

Presentation Number
284MO
Speakers
  • Gaetano Finocchiaro (Milan, Italy)
Lecture Time
17:00 - 17:05
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00

Abstract

Background

Bone marrow-derived macrophages account for a substantial Glioblastoma (GBM) tumor volume and contribute to the local inflammatory tumor microenvironment (TME), disease progression & treatment response.

Methods

We have developed a genetically modified, autologous hematopoietic stem cell-based platform designed to deliver IFNa, specifically into the TME via Tie-2 expressing monocytes (Temferon). TEM-GBM is an open-label, phase I/IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 21 newly diagnosed, unmeth-MGMT GBM patients. The patients will be assigned to 7 cohorts and will receive a single increasing dose of Temferon.

Results

As of April 2022, 4 doses of Temferon (0.5-3.0x106/kg) were tested across 16 patients assigned to 6 cohorts. Follow-up from surgery is 6–28mo (2–25mo after Temferon). To date, no DLTs have been identified. Temferon-derived progeny as defined by gene-marked cells were found within the hematopoietic system within 2-weeks of Temferon administration and persisted, albeit at lower levels, up to 18mo (longest time of analysis). Very low concentrations of IFNα were detected in plasma and CSF, indicating tight regulation of transgene expression. SAEs were mostly attributed to conditioning chemotherapy (infections) or disease progression (PD) (seizures). 1SUSAR (persistent GGT elevation) occurred. Median OS is 15mo from surgery. Transduced cells were detected in the 2nd surgery specimens of 3 out 4 pts belonging to low dose cohorts. Single-cell RNA seq of the TME highlighted a Temferon signature associated with the induction IFNa responsive genes and macrophage repolarization. Potential long-term benefit with Temferon was identified in a patient from C3, who had PD at D+120 with 2-distant enhancing lesions, and increased tumor necrosis. 1y following Temferon, with no 2nd-line therapy added, there was approximately 40% reduction in enhancing tumor volume compared to D+180 with a stable clinical and imaging picture thereafter.

Conclusions

The results provide initial evidence of Temferon’s potential to modulate GBM TME, and anecdotal evidence for long lasting effects of Temferon in prevention of PD.

Clinical trial identification

NCT03866109.

Legal entity responsible for the study

Genenta Science.

Funding

Genenta Science.

Disclosure

B. Gentner: Financial Interests, Personal, Stocks/Shares: Genenta Science; Financial Interests, Institutional, Research Grant: Genenta Science; Financial Interests, Personal, Advisory Role: Genenta Science. S. Mazzoleni: Financial Interests, Personal, Full or part-time Employment: Genenta Science. L. Naldini: Financial Interests, Personal, Stocks/Shares: Genenta Science; Financial Interests, Institutional, Research Grant: Genenta Science; Financial Interests, Personal, Advisory Role: Genenta Science. C. Russo: Financial Interests, Personal, Full or part-time Employment: Genenta Science; Financial Interests, Personal, Stocks/Shares: Genenta Science. All other authors have declared no conflicts of interest.

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Mini Oral session

285MO - The combination of lomustine and antibody-based targeted TNF (L19TNF) as a promising treatment for recurrent glioblastoma

Presentation Number
285MO
Speakers
  • Tobias Weiss (Zurich, Switzerland)
Lecture Time
17:05 - 17:10
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00

Abstract

Background

Glioblastoma is a poorly immunogenic cancer and treatment options for recurrent glioblastoma are limited. Therefore, there is an urgent need for effective treatment strategies against recurrent glioblastoma. Here, we investigated a new treatment combination based on the tumor-stroma targeting antibody-cytokine fusion protein L19TNF and the alkylating chemotherapy lomustine in preclinical glioma models and patients with recurrent glioblastoma.

Methods

Orthotopic immunocompetent mouse glioma models were used to study the anti-glioma activity of L19TNF in combination with anti-PD1, bevacizumab or lomustine. Tumor-infiltrating immune cells were characterized by microscopy and flow cytometry and the MHC immunopeptidome was analyzed by MHC immunoaffinity purification and subsequent mass spectrometry. Subsequently, we translated the most efficient treatment combination to patients with recurrent glioblastoma within a phase I/II clinical trial (NCT04573192).

Results

The combination of L19TNF and lomustine demonstrated strong synergistic anti-tumor activity in two immunocompetent orthotopic glioma models curing the majority of tumor-bearing mice, whereas the other mono- or combination therapies had only limited anti-glioma activity. The combination of L19TNF and lomustine led to the strongest increase in tumor-infiltrating lymphoid cells as demonstrated by flow cytometry and microscopy and to the highest number of peptides presented in the context of MHC-I. The anti-tumor activity was also abrogated in immune-deficient mouse models. Furthermore, the treatment was well tolerated in the first patients treated within a phase I/II clinical trial and we observed partial tumor responses and long-lasting disease stabilizations even in patients with an unfavorable unmethylated MGMT promoter.

Conclusions

The combination of L19TNF and lomustine demonstrated promising anti-glioma activity. Patients are currently recruited within a phase I/II clinical trial for patients with recurrent glioblastoma.

Clinical trial identification

NCT04573192.

Legal entity responsible for the study

Philogen S.p.A.

Funding

Philogen S.p.A.

Disclosure

T. Weiss: Financial Interests, Personal and Institutional, Principal Investigator: Philogen S.p.A.; Financial Interests, Personal and Institutional, Advisory Role: Philogen S.p.A. E. Puca, T. Hemmerle, R. Stucchi: Financial Interests, Personal, Full or part-time Employment: Philogen S.p.A. R. De Luca: Financial Interests, Institutional, Full or part-time Employment: Philochem AG. D. Neri: Financial Interests, Personal, Full or part-time Employment: Philogen S.p.A.; Financial Interests, Personal, Ownership Interest: Philogen S.p.A. M. Weller: Financial Interests, Personal and Institutional, Advisory Role: Philogen S.p.A. All other authors have declared no conflicts of interest.

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Mini Oral session

286MO - Radiomics-based prediction of lymphocyte infiltration in IDH-wildtype glioblastoma

Presentation Number
286MO
Speakers
  • Maximilian J. Mair (Vienna, Austria)
Lecture Time
17:10 - 17:15
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00

Abstract

Background

In glioblastoma, the benefit of immunotherapy is limited to a small, yet to be defined subgroup. Due to the immunological diversity and as tissue availability remains a challenge, clinically practicable biomarkers are urgently needed.

Methods

Patients treated for newly diagnosed isocitrate dehydrogenase (IDH)-wildtype glioblastoma were included. Tumor-infiltrating lymphocytes (TILs) were analyzed by immunohistochemistry for CD3, CD8 and PD-1 and quantified using tissue phenomics software. Extraction of quantitative radiomics parameters was performed using PyRadiomics on preprocessed preoperative MRI images of (A) contrast-enhancing tumor tissue and (B) T2-hyperintense signal abnormalities as a surrogate for non-enhancing tumor tissue and perifocal edema. TIL parameters were predicted by ElasticNet models, and correlations between predicted and quantified values were used to evaluate prediction accuracy.

Results

In total, 133 patients (39.1% female, median age 62 (range: 20-80) years) were included. O6-methylguanine-methyltransferase (MGMT) promoter methylation status was known in 96 tumors, of whom 42 (43.8%) were methylated. Median percentages of TILs based on total cells were 0.95% (range: 0.08%-5.47%) for CD3+, 0.40% (0.05%-2.78%) for CD8+, and 0.19% (0.02%-0.84%) for PD1+ cells. Median densities were 73.0 cells/mm2 (3.1-450.7) for CD3+, 28.0 cells/mm2 (5.2-104.4) for CD8+, and 13.2 cells/mm2 (1.6-61.4) for PD1+ TILs. In the contrast-enhancing tumor region, PD-1+ TIL densities which were predicted based on radiomics parameters correlated with actual values (r = 0.444, p < 0.001). In contrast, there was no predictive value of radiomic features for CD3+ and CD8+ TIL densities or percentages in contrast-enhancing tumor tissue (r < 0.2, p > 0.05). However, in non-enhancing T2-hyperintense tissue, a weak predictive power for the absolute number of CD3+ (r = 0.315, p = 0.003) and CD8+ (r = 0.274, p = 0.017) TILs was detected.

Conclusions

These provisional results may serve as a proof of concept for further investigations on “immuno-radiomic” parameters as possible immune biomarkers in brain tumors. Validation of these results in an independent cohort is ongoing.

Legal entity responsible for the study

The authors.

Funding

Austrian Federal Ministry for Digital and Economic Affairs; National Foundation for Research, Technology and Development; Christian Doppler Research Association.

Disclosure

M.J. Mair: Financial Interests, Personal, Other: Pierre Fabre. M. Preusser: Financial Interests, Personal, Advisory Board: Bayer, Bristol Myers Squibb, Novartis, Gerson Lehrman, CMC Contrast, Glaxo Smith Kline, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dohme, Tocagen, Adastra, Gan & Lee Pharmaceuticals; Financial Interests, Institutional, Research Grant, Clinical Trials and research: Boehringer-Ingelheim, Bristol Myers Squibb, Roche, Daiichi Sankyo, Merck Sharp & Dohme, Novocure, Glaxo Smith Kline, AbbVie; Non-Financial Interests, Leadership Role, Brain Tumor Group Chair: EORTC; Non-Financial Interests, Leadership Role, EANO President: EANO. A.S.S. Berghoff: Financial Interests, Personal, Invited Speaker: Roche, Bristol Myers Squibb, Merck, AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Roche. All other authors have declared no conflicts of interest.

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Mini Oral session

Invited Discussant 284MO, 285MO and 286MO

Speakers
  • Monika E. Hegi (Lausanne, Switzerland)
Lecture Time
17:15 - 17:30
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00
Mini Oral session

287MO - A phase 0 ‘trigger’ trial of pamiparib in newly diagnosed and recurrent glioblastoma patients

Presentation Number
287MO
Speakers
  • Nader Sanai (Phoenix, United States of America)
Lecture Time
17:30 - 17:35
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00

Abstract

Background

This phase 0 study evaluates glioblastoma (GBM) pharmacokinetics (PK) and pharmacodynamics (PD) of pamiparib, a PARP1/2-selective inhibitor, graduating patients to a therapeutic expansion phase of drug plus radiotherapy when high unbound drug concentrations are present in nonenhancing tumor.

Methods

Newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID). Tumor tissue (enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug > 5-fold biochemical IC50 in nonenhancing tumor determined eligibility for the therapeutic expansion phase. PARP inhibition was assessed via 10 Gy ex vivo radiation of tumor tissue and quantification of PAR levels compared to non-radiated control. Newly-diagnosed, MGMT-unmethylated and recurrent GBM patients, irrespective of MGMT-status, exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance dosing of study drug plus TMZ.

Results

In Arms A (n=20) and B (n=14), the mean unbound concentrations of pamiparib in Gd-nonenhancing tumor region were 171.5 nM and 162.5 nM, respectively and in Arm C (n=4) the mean unbound concentration of olaparib was 11.0 nM. All patients in Arms A and B, but only one in Arm C, exceeded the PK threshold to qualify for the expansion phase of the study. Progression onto the expansion phase occurred in 12/20 (60%), 7/14 (50%), and 1/4 (25%) patients in Arms A, B, and C, respectively. Radiation-induced PAR expression was 2.44 fold in untreated control vs 1.16 in Arm A, 0.82 in Arm B and 1.11 in Arm C patients, respectively. The median progression-free survival was 5.8 (Arm A), 3.1 months (Arm B) (n=6), and 1.9 months (Arm C) (n=1), respectively.

Conclusions

Pamiparib was generally well-tolerated, achieved pharmacologically-relevant concentrations in nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation.

Clinical trial identification

NCT05076513.

Legal entity responsible for the study

Nader Sanai, St. Joseph's Hospital and Medical Center, Phoenix.

Funding

Ivy Brain Tumor Center at Barrow Neurological Institute, Phoenix, AZ.

Disclosure

All authors have declared no conflicts of interest.

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Mini Oral session

288MO - Brain-only oligometastatic cancer patients present with longer overall survival than patients with extracranial involvement

Presentation Number
288MO
Speakers
  • Ariane Steindl (Vienna, Austria)
Lecture Time
17:35 - 17:40
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00

Abstract

Background

The incidence of brain-only oligometastatic diseases have been described to be increasing. Therefore, we aimed to investigate the clinical course of patients with BM as the only site of metastatic disease.

Methods

6083 patients with BM from different solid tumors treated between 1989-2021 at the Medical University of Vienna were identified from the Vienna Brain Metastasis Registry. Patients with one BM as the only metastatic site were classified as brain-only oligometastatic, whereas patients with extracranial and intracranial metastatic lesions were classified as poly-metastatic. A retrospective analyses was performed.

Results

1299/6083 (21.4%;[56.4% male; 43.6% female; median age 62 years]) patients presented with brain-only oligometastatic disease at time of BM diagnosis. Brain-only oligometastatic disease was most frequently observed in lung cancer (67.0%) followed by breast cancer (9.0%),melanoma (4.3%), cancer of unknown primary (4.5%), colorectal cancer (4.3%), renal cell carcinoma (3.2%), and others (7.7%) (p>0.001; chi-square test). The single BM as the only metastatic site was synchronously diagnosed with the primary tumor in 43.8% (569/1299) of patients. The median time from diagnosis of primary tumor to diagnosis of BM was significantly longer in poly-metastatic patients than in brain-only oligometastatic patients (25 vs. 17 months; p-value <0.001; log-rank test). Patients with brain-only oligometastatic disease showed a significantly longer median overall survival from diagnosis of BM compared to poly-metastatic patients (11 vs. 6 months; p< 0.001; log-rank test). Furthermore, 22.0% (286/1299) of patients with brain-only oligometastatic disease had long-term survival of >24 months, while only 11.0% (526/4784) of poly-metastatic patients presented with similar favorable survival (p<0.001; chi-square test).

Conclusions

Patients with brain only oligometastatic disease present with a more favorable survival prognosis than patients with additional extracranial involvement. Multidisciplinary treatment planning should be encouraged in patients with brain-only oligometastatic disease to address the high proportion of patients surviving more than 24 months.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Steindl: Financial Interests, Personal, Other: Lilly. M. Preusser: Financial Interests, Personal, Advisory Board: Bayer, Bristol Myers Squibb, Novartis, Gerson Lehrman, CMC Contrast, Glaxo Smith Kline, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dohme, Tocagen, Adastra, Gan & Lee Pharmaceuticals; Financial Interests, Institutional, Research Grant, Clinical Trials and research: Boehringer-Ingelheim, Bristol Myers Squibb, Roche, Daiichi Sankyo, Merck Sharp & Dohme, Novocure, Glaxo Smith Kline, AbbVie; Non-Financial Interests, Leadership Role, Brain Tumor Group Chair: EORTC; Non-Financial Interests, Leadership Role, EANO President: EANO. A.S.S. Berghoff: Financial Interests, Personal, Invited Speaker: Roche, Bristol Myers Squibb, Merck, AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Roche. All other authors have declared no conflicts of interest.

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Mini Oral session

289MO - Next-generation sequencing (NGS) for identifying actionable molecular alterations in newly diagnosed and recurrent IDHwt-glioblastoma (GBM) patients: A large mono institutional experience

Presentation Number
289MO
Speakers
  • Marta Padovan (Padova, Italy)
Lecture Time
17:40 - 17:45
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00

Abstract

Background

NGS panels allow the identification of alterations within hundreds of cancer-related genes and can guide a personalized strategy in glioma treatment.

Methods

From Nov 2019 to Jan 2022 at Veneto Institute of Oncology, Padua, Italy, a large cohort of IDHwt-GBM tissues was analyzed by NGS (FoundationOne®CDx). We identified all potential actionable molecular alterations at diagnosis and/or at recurrence. High tumor mutational burden (TMB) was defined as ≥10 mutations/megabase.

Results

We analyzed 429 IDHwt-GBM samples: NGS profile was available for 419 samples (97.7%); sample failures in 10 cases (2.3%). 351 (84%) and 68 (16%) GBM samples derived from surgery at diagnosis and recurrence, respectively. All patients received radiotherapy and/or temozolomide as first line therapy. Among all the analyzed samples, the most frequent actionable molecular alterations were: CDKN2A (57%), CDKN2B (53%), EGFR amplification (39%), EGFR mutation (24%), PTEN loss (27%), RB1 (23%), NF1 (18%), PIK3CA (18%), CDK4 (15%), MDM2 (10%), PDGFRA (8%), BRCA1-2 (7%), FGFR1-3 (7%), Myc (6%), JAK (6%), ROS1 (5%), METmut (2%), METampl (2%), BRAF V600E (2%). No NTRK1/2/3 druggable alterations were observed. High TMB was found in 18 samples. The incidence of alteration of EGFR (ampl/mut), RB1, PIK3CA was statistically different between the two subgroups of newly diagnosed and relapsed GBM samples (Fisher test). To date, 10% of patients received a personalized treatment as compassionate use, off-label use or in clinical trials (9 Dabrafenib/Trametinib, 8 Alpelisib, 3 Erdafitinib, 2 Ipatasertib, 1 Alectinib, 1 Capmatinib, 1 Palbociclib, 1 Entrectinib, 1 Pamiparib). Activity analysis is still ongoing.

Conclusions

NGS is feasible in GBM samples. Potentially, a high rate of patients could receive a personalized treatment. The activity analysis is ongoing. However, the incidence of actionable molecular alterations may differ between diagnosis and recurrent GBM samples.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Mini Oral session

Invited Discussant 287MO, 288MO and 289MO

Speakers
  • Patrick Roth (Zurich, Switzerland)
Lecture Time
17:45 - 18:00
Location
7.3.U - Urval Auditorium, Paris Expo Porte de Versailles, Paris, France
Date
Sat, 10.09.2022
Time
16:30 - 18:00