bluuebunny/crossref_metadata_2025 huggingface dataset:
CSIG-16. SEXUAL DIMPORHISM IN IRON ACQUISITION IN GLIOBLASTOMA
Authors: Pandya Bhavyata , Slagle-Webb Becky , Nesterova Darya , Zacharia Brad , Lathia Justin , Rubin Joshua , Berens Michael , Barnholtz-Sloan Jill S , Connor James
Published: December 2020

Glioblastoma (GBM) is the most aggressive brain cancer. Sex differences in incidence and clinical outcomes have been reported, however, our knowledge of contributing mechanisms is limited. Iron acquisition is key to robust tumor growth. Upregulation of Transferrin (Tf, iron transport protein)/Transferrin receptor (TfR) is found in multiple different cancers. We have identified H-ferritin (FTH1) as involved in iron transport and explore its uptake in GBM in this study. We interrogated iron uptake in a syngeneic orthotopic mouse model (GL261 cells) using male and female mice. After the tumors were established, radioactive 125I labeled Tf and FTH1 proteins were injected retro-orbitally in the mice. After 24 hours, tumors were removed, homogenized and analyzed for Tf and FTH1 uptake. There was a significant difference in Tf uptake into the tumor versus matched non-tumor tissue in both males and females and the uptake in the tumors was 1.5-fold higher in males than females. There was no significant difference in FTH1 uptake between male and female tumors nor between tumor and matched non-tumor brain tissue. Binding analyses were performed on homogenized samples of human male and female GBM tissue samples using 125I labeled Tf and FTH1. Tumors from males had increased binding of both proteins compared to tumors from females. We next queried the TCGA database and found in females, high TfR expression was associated with poor survival but not in males. TCGA database revealed a robust expression of Tim1, a putative receptor for FTH1, but its expression did not relate to survival. In summary, this study demonstrates FTH1 binding to GBMs and sexual dimorphism in iron acquisition via Tf and survival.
CSIG-18. CALCIUM COMMUNICATION IN GLIOMA: CRUCIAL PACEMAKER CELLS GOVERN TUMOR PROGRESSION
Authors: Hausmann David , Jung Erik , Azorin Daniel , Ratliff Miriam , Osswald Matthias , Wick Wolfgang , Winkler Frank
Published: December 2020

BACKGROUND

Gliomas form therapy-resistant multicellular networks, using neurite-like protrusions (called Tumor Microtubes [TMs]), and display intercellular calcium transients, that drive brain tumor malignancy.

METHODS

A refined in vitro model was established to study calcium communication and its molecular toolkit in patient-derived glioma cells. In vitro results were then validated with longitudinal in vivo two-photon calcium imaging in awake mice.

RESULTS

Here we first describe the discovery of a small subpopulation of glioma cells that display intrinsically active calcium oscillations and behave like pacemakers. Accordingly, these pacemaker-like glioma cells trigger synchronized calcium activity in tumor cells that are connected with them via TMs. The application of network theory shows that glioma cell networks follow a scale-free and small-world topology, governed by a subpopulation of highly connected hub cells. Interestingly, the pacemaker cells most often act as these hubs, hence communicating with many other network members. Graph theory predicts that such network design displays a high degree of robustness, making it resistant to random damage as seen after radio- and chemotherapy – but extremely vulnerable to selective damage to key hubs. In line with this theory, laser ablation of the pacemaker-like hub cells splintered the malignant tumor network into small isolated cell clusters and led to increased cell death, whereas laser ablation of random tumor cells showed no effect. Among others, KCNN4 channels, which are upregulated in gliomas, were identified as drivers of the pacemaker-like hub cells. Suppressing their pacemaking-abilities by KCNN4 inhibition strongly reduced calcium communication and tumor growth.

CONCLUSION

In summary, coordinated calcium communication in glioma drives brain tumor malignancy. A specific tumor cell subpopulation was identified that acts as hubs of the multicellular network and initiates global calcium activity. The network’s vulnerability to loosing these pacemaker-like hub cells suggests a novel targeted approach against the resistant networks of gliomas.
CSIG-19. THE DEUBIQUITINASE BRCC3 LINKS ALT TELOMERES TO SUPPRESSION OF INNATE IMMUNITY IN IDH1-MUTANT GLIOMA
Authors: Mukherjee Joydeep , Tang Yongjian , Johanessen Tor-Christian , Pandita Ajay , Ohba Shigeo , Cahill Daniel , Pieper Russell
Published: December 2020

Approximately 10% of tumors including all IDH1-mutant lower-grade glioma resolve telomeric shortening using Alternative Lengthening of Telomere (ALT) mechanism. Although the ALT process lengthens telomeres, it also generates small bits of extrachromosomal, telomere-containing DNA (ECTRs). These ECTRs can bind and activate cyclic GMP-AMP synthase (cGAS), the major cytosolic sensor of double-stranded DNA, which in turn can activate expression of stimulator of IFN genes (STING) and the interferon-based innate immune response. To limit the immune response, ALT cells inactivate the cGAS-STING pathway, although the mechanism by which this occurs is unknown. Here we show that the deubiquitinase BRCC3 links ALT telomeres to suppression of the cGAS-STING pathway and the innate immune response. Astrocytoma cells dependent on the ALT-mechanism (IDH1-mutant and ATRX-deficient genetically-modified human astrocytes and MGG119 PDX) contained ECTR and had reduced expression of the cGAS and the downstream components of the cGAS-STING pathway (STING, and IFN-β) relative to matched non-ALT (isogenic ATRX WT astrocytes and MGG152 PDX) cells lacking ECTRs. Decreased levels of cGAS in ALT cells were in turn associated with deubiquitiantion and destabilization of cGAS. The telomere-derived ECTR in ALT-dependent cells lacked two proteins normally found in ALT telomeres (TRF2 or PARP), but retained two other proteins, Mre11 and its binding partner, normally nuclear deubiquitinase BRCC3. Furthermore, either pharmacologic inhibition or genetic suppression of BRCC3 levels had no effect on ECTR levels but stabilized cGAS and activated the cGAS-STING pathway. This cGAS-mediated activation could be blocked by exogenous expression of WT BRCC3, but not by expression of a mutant BRCC3 incapable of deubiquitination. These results show that BRCC3 translocated along with ECTRs to the cytoplasm degrades cGAS and protects ALT-dependent cells from activating the innate immune response. The BRCC3-controlled cGAS-STING pathway may therefore represent a therapeutically targetable means to enhance the immune response in IDH1-mutant lower grade glioma.
CSIG-22. CANCER-ASSOCIATED MISSENSE SINGLE NUCLEOTIDE VARIANTS REGULATE THE STABILITY AND SUBCELLULAR LOCALIZATION OF NF2/MERLIN
Authors: Eaton Charlotte , Bisignano Paola , Raleigh David
Published: December 2020

BACKGROUND

Alterations in the NF2 tumor suppressor gene lead to meningiomas and schwannomas, but the tumor suppressor functions of the NF2 gene product, Merlin, are incompletely understood. To address this problem, we performed a structure-function analysis of Merlin by expressing cancer-associated missense single-nucleotide variants (mSNVs) in primary cancer cells for biochemical and cell biology experiments.

METHODS

All NF2 mSNVs were assembled from cBioPortal and COSMIC, and modelled on the FERM, a-helical, and C-terminal domains of Merlin (PDB 4ZRJ) using comparative structure prediction on the Robetta server and visually inspected using Pymol. mSNV hotspots were defined from sliding windows with at least 10 mutations within 5 residues in either direction. mSNVs from hotspots in meningiomas, schwannomas, or both, were selected for in vitro mechanistic analyses using immunofluorescence and immunoblotting of whole cell, plasma membrane, cytoskeletal, cytoplasmic, nuclear, and chromatin subcellular fractions from M10G meningioma cells and HEI-193 schwannoma cells.

RESULTS

We identified the following cancer-associated hotspot mSNVs in NF2, which were over-expressed for mechanistic studies: L46R, S156N, W191R, A211D, V219M, R418C and R462K. Endogenous Merlin was detected in all subcellular compartments, but was enriched in the nucleus. L46R and A211D mapped to hydrophobic pockets in the FERM domain, destabilized Merlin, and excluded Merlin from all subcellular compartments except the cytoskeleton. S156N, W191R and V219M also mapped to the FERM domain, but did not affect Merlin stability, and V219M attenuated chromatin localization, suggesting this motif may be involved in binding events that regulate subcellular localization. R418C and R463K mapped to the a-helical domain, but only R418C destabilized Merlin.

CONCLUSION

Our results suggest that cancer-associated mSNVs inactive the tumor suppressor functions of NF2 by altering the stability, subcellular localization, or binding partners of Merlin. Further work is required to identify and understand the impact of binding partners and subcellular localization on Merlin function.
CTIM-12. RANDOMIZED PHASE 2 STUDY OF NIVOLUMAB (NIVO) PLUS EITHER STANDARD OR REDUCED DOSE BEVACIZUMAB (BEV) IN RECURRENT GLIOBLASTOMA (rGBM)
Authors: Ahluwalia Manmeet , Peereboom David , Rauf Yasmeen , Lathia Justin , Alban Tyler , Schilero Cathy , Ciolfi Marci , LaForest-Roys Corey , Nayak Lakshmi , Lee Eudocia , Wen Patrick , Reardon David
Published: December 2020

BACKGROUND

Trials with anti-PD1 in rGBM have shown limited efficacy. VEGF is highly upregulated proangiogenic growth factor in GBM contributing to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF may be a promising approach in rGBM.

METHODS

90 patients with first-recurrent GBM were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) and bevacizumab at standard (10 mg/kg; Arm A) or low dose (3 mg/kg; Arm B) IV Q2 weeks. Eligibility also required KPS≥ 70% and dexamethasone ≤ 4 mg/day. Stratification included extent of resection, age, performance status and MGMT methylation status. Single cell RNA sequencing with CITE-seq was used to analyze blood samples from pre- and 8 weeks post-treatment among 8 responders and 8 non-responders.

RESULTS

90 patients were enrolled (May 2018- Jan 2020) and median follow-up is 7.5 months. Characteristics in 2 arms were comparable. Median age was 60.5 years (range 27–86), median KPS was 80. 35 patients were MGMT methylated, 53 unmethylated and 2 indeterminate. Estimated progression free survival (PFS) and median overall survival (OS) in arm A are 6.13 and 10.85 months and 4.59 and 9.61 months in Arm B, respectively. Single cell RNA sequencing with CITE-seq was used to analyze blood samples from 16 patients, baseline and 8 weeks post treatment. Standard dose bevacizumab treated patients had decreased myeloid derived suppressor cells and an inflammatory response gene signature at 8 weeks. Most frequent toxicities included fatigue (52.8%), headache (32.6%), diarrhea (31.5%), proteinuria (25.8) and hypertension (23.6%). Toxicity was comparable between 2 arms, except hypertension was more common in arm A.

CONCLUSIONS

PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared to historical benchmarks of bevacizumab monotherapy. Ongoing response evaluation and immunocorrelative data will be presented.
CTIM-24. AUTOLOGOUS CD34+ ENRICHED HEMATOPOIETIC PROGENITOR CELLS GENETICALLY MODIFIED FOR HUMAN INTERFERON-α2, ARE WELL TOLERATED & RAPIDLY ENGRAFT IN PATIENTS WITH GLIOBLASTOMA MULTIFORME (TEM-GBM_001 STUDY)
Authors: Finocchiaro Gaetano , Gentner Bernhard , Eoli Marica , Francesca Farina , Anghileri Elena , Girlanda Stefania , Carrabba Matteo , Cuccarini Valeria , DiMeco Francesco , Legnani Federico , Pollo Bianca , Bruzzone Maria Grazia , Saini Marco , Ferroli Paolo , Capotondo Alessia , Paterra Rosina , Garramone Mariagrazia , Mazzoleni Stefania , Zambanini Andrew , Russo Carlo , Naldini Luigi , Ciceri Fabio
Published: December 2020

GBM with an unmethylated MGMT gene promoter is associated with very poor prognosis. A subset of tumor associated macrophages expressing the angiopoietin receptor Tie2 (TEMs) can be genetically modified for local & tumor restricted release of interferon-α2 (IFN). IFN has antitumor effects, inhibits angiogenesis & modulates the immune system. Temferon consists of autologous HSPCs transduced ex-vivo with an LVV encoding an IFN gene & expression control sequences for TEMs. TEM-GBM is an open-label, Phase I/IIa study (Part A: 3x3x3 dose escalation; Part B: n=12), & Temferon (single dose) is given to patients with first diagnosis of GBM & unmethylated MGMT promoter. Part A 3rd cohort is ongoing & completes dosing in September 2020. Eight patients completed screening; one patient died (disease progression) before Temferon was administered. Six patients received Temferon (3 women, 3 men, mean age 52.3 years). Cohort 1 received Temferon 0.5x106 cells/kg & Cohort 2, 1x106 cells/kg. Neutropenia & thrombocytopenia occurred as expected following conditioning & hematologic recovery (HR) occurred median D+13. Transduced PBMCs were identified by vector copy number (VCN) on myeloid cells at HR & at later timepoints. In general, a dose-ordered increase in VCN was observed (mean VCN D+30 CD14+ Cohort 1: 0.094, cohort 2: 0.125); 1 patient in each cohort had low VCNs. VCN remained detectable up to recent follow up visits (≤ D+180). No dose-limiting toxicities have been reported. Four SAEs occurred in 3 patients who received Temferon (pneumonia, pulmonary embolism, febrile neutropenia, fatigue) but these events were not attributed to Temferon, resolved, & may have been related to the conditioning regimen (carmustine & thiotepa). Disease progression has been confirmed in 3 patients who received Temferon. These preliminary results indicate feasibility of engrafting a pre-determined fraction of Temferon cells in the bone marrow of GBM patients without, so far, causing dose-limiting toxicity.
CTIM-31. USE OF A SINGLE PEPTIDE CHECKPOINT INHIBITOR FOR TREATMENT OF CENTRAL NERVOUS SYSTEM TUMORS
Authors: Moertel Christopher , Xiong Zhengming , Zellmer David , Pluhar Elizabeth , Neil Elizabeth , Greengard Emely , Olin Michael
Published: December 2020

Cancer immunotherapy has revolutionized clinical management of malignancies by generating long-term, durable control of tumors. Unfortunately, these therapies often cause serious immune-related adverse events. In addition, only a small percentage of solid tumors respond to these therapies and there is little efficacy in CNS tumors. Our research is focused on the CD200 immune checkpoint, which modulates the immune system through the inhibitory receptor (CD200R1) and activation receptors (CD200AR). We demonstrated that targeting the CD200AR with a checkpoint peptide ligand (CD200AR-L) activates the immune system and renders it impervious to the inhibitory effects of CD200. In a pre-clinical canine spontaneous high-grade glioma trial, CD200AR-L, with autologous tumor lysate vaccination, resulted in a 20% two-year progression-free survival; no toxicities or adverse effects were observed. We suggest this result was due to the ability of the CD200AR-L to modulate multiple immune checkpoints. During the characterization of the CD200AR-L, we discovered signaling molecules are shared by the CD200 and PD-1/PD-L1 checkpoint pathways, suggesting these immune checkpoints are connected. Our preliminary studies demonstrated that the inhibitory CD200R1 and PD-1 mediate immune checkpoint signaling activities through the SHIP1/2. Moreover, CD200AR-L overpowers the suppressive effects of CD200 and PD-L1, which are both shed by tumors, by downregulating the inhibitory CD200R1 and PD-1 on both antigen-presenting cells (APC) and T-cells. In addition, CD200AR-L downregulates PD-1 on APCs and inhibits the upregulation of PD-L1 and CTLA4. These studies led to the discovery that the novel peptide modulates the CD200, PD-1/PD-L1 and CTLA-4 pathways, providing the basis for the translatable development of a CD200-directed peptide for clinical use against multiple tumors including gliomas. These studies led to FDA approval of this peptide for the first in human phase I single center, open-label, dose-escalation clinical trial in adult and pediatric trial for children with recurrent malignant brain tumors.
CTNI-04. ACTIVITY OF LAROTRECTINIB IN TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION CANCER PATIENTS WITH CENTRAL NERVOUS SYSTEM (CNS) METASTASES
Authors: Patel Jyoti D , Farago Anna F , Hong David S , Lassen Ulrik N , Leyvraz Serge , Park Keunchil , Sohal Davendra P S , Solomon Benjamin , Reeves John A , Dima Laura , Brega Nicoletta , Drilon Alexander
Published: December 2020

BACKGROUND

NTRK gene fusions occur in a range of tumor types, including those with CNS metastases. Larotrectinib, a highly selective FDA- and EMA- approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% across various cancers (Hong et al. Lancet Oncol. 2020). We report data on patients with TRK fusion cancer with CNS metastases treated with larotrectinib.

METHODS

Patients with solid tumors with CNS metastases at baseline harboring an NTRK gene fusion enrolled in two clinical trials (NCT02122913 and NCT02576431) were identified. Response was assessed by the investigator per RECIST v1.1.

RESULTS

As of July 15, 2019, 14 patients with CNS-metastases were enrolled: lung cancer (n=7), thyroid cancer (n=4), melanoma (n=2), and non-secretory breast cancer (n=1). Median age was 53 years (range 25–76). Including all sites of disease, the ORR was 71% (95% CI 42–92%): ten patients had a partial response (PR), two had stable disease (SD), and two had progressive disease (lung and melanoma). Of the three patients with measurable intracranial disease at baseline, the best intracranial response was 1 complete response, 1 PR, and 1 SD. Median duration of response for all patients was 14.8 months (range 1.9+ to 17.4+), median progression-free survival was 9.9 months (range 1.4 to 19.3+), and median overall survival was 27.8 months (range 1.4+ to 27.8). Treatment duration ranged from 1.4 to 25.0 months; six patients continued treatment beyond progression (lasting between 0.1+ and 8.5 months). Treatment-emergent adverse events (TEAEs) were mainly Grade 1 and 2; Grade 3 TEAEs occurred in seven patients (50%), with one (myalgia) attributed to larotrectinib (7%). There were no Grade 4 TEAEs.

CONCLUSIONS

Larotrectinib was highly active and well tolerated in TRK fusion cancer patients with CNS metastases. These results support testing for NTRK gene fusions across all cancers, including in patients with CNS metastases.
CTNI-05. NRG ONCOLOGY / RTOG 1119: PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY / STEREOTACTIC RADIOSURGERY WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN METASTASES FROM HER2-POSITIVE BREAST CANCER
Authors: Ah Kim In , Winter Kathryn , Sperduto Paul , De Los Santos Jennifer , Peereboom David , Ogunleye Tomi , Boulter Daniel , Cho Kwan Ho , Shin Kyung Hwan , Zoberi Imran , Choi Serah , Palmer Joshua , Liem Ben , Kim Yong Bae , Anderson Bethany , Thakrar Anupama , Muanza Thierry , Kim Michelle , Choi Doo Ho , White Julia , Mehta Minesh
Published: December 2020

Trastuzumab/pertuzumab improved outcomes for patients (pts) with HER2+ breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of these agents apparently contributes to increased incidence of brain metastases (BM). Lapatinib (L) crosses the BBB and demonstrates activity against BM. Based upon pre/early clinical data, it’s hypothesized that L + whole brain radiotherapy (WBRT) or Stereotactic Radiosurgery (SRS) would improve intracranial control compared to WBRT/SRS (RT) alone. This randomized phase II trial included HER2+ breast cancer pts with ≥ 1 measurable, unirradiated parenchymal BM. Pts were randomized 1:1 to WBRT (37.5 Gy/3 weeks) or SRS +/- concurrent L (1000 mg dailyx6 weeks), andwere stratified by graded prognostic assessment (GPA), use of non-CNS penetrating anti-HER2 therapies, and previous SRS/resection. The primary endpoint was intracranial complete response (CR) rate 12weeks (wk) after RT. Secondary endpoints included objective response rate (ORR), lesion-specific response rate, CNS progression-free survival, and overall survival. 114 of 143 pts were evaluable for 12-wk CR (52 RT, 62 RT+L). Rate of grade 3 and 4 adverse events were 8% and 0% for RT and 29% and 6% for RT+L. 92% and 90% pts received concurrent and adjuvant L per protocol/acceptable variation. There were no significant differences in 12 or 4wk CR rates (p=0.97 and p=0.77); 5.8% and 0% at 12wk and 3.6% and 1.5% at 4wk for RT and RT+L, respectively. The ORR at 4 wk was 42% and 56% (p=0.059, RECIST), 40% and 58% (p=0.027, WHO) in the RT and RT+L, respectively. Although the addition of lapatinib to WBRT/SRS did not improve the 12wk CR rate, it showed meaningful clinical benefit by demonstrating a trend toward improvement of 4 wk ORR. Results of ongoing central review of MRIs using RECIST1.1, WHO and RANO-BM criteria including secondary endpointswill be reported. Support: NCI grants U10CA180868, U10CA180822, UG1CA189867, and Novartis
CTNI-14. A 3-ARM, PHASE IIA TRIAL OF SAFETY & EFFICACY OF OLINVACIMAB, A MONOCLONAL ANTIBODY TO VEGFR2 IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME WITH IMAGING AND PK/PD ASSESSMENTS: FINAL REPORT
Authors: Cher Lawrence , Nowak Anna , Iatropoulos George , Bowyer Samantha , Gan Hui , Long Anne Poh , Bynevelt Michael , Jackson Graeme , Lee Seon Young , Lee Weon Sup , Yoo Jin-San
Published: December 2020

The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF signalling. Olinvacimab (TTAC-0001) is a fully humanised VEGFR2 Mab that binds and inhibits the receptor. This report assesses the safety, dosing schedules and efficacy of Olinvacimab in recurrent GBM. We conducted a two-site, 3 arm, open-label study of Olinvacimab in recurrent GBM. Eligible patients were ≥18 years with RANO-measurable lesion, KPS ≥ 80, and had completed chemoradiotherapy without prior bevacizumab therapy. We assessed three arms, 8 mg/kg and 12mg/kg weekly for 3 of every 4 weeks, and 12 mg/kg weekly. Three patients were treated in arms 1 and 2 and 6 in arm 3. Safety assessments were performed prior to dose escalation. The main toxicity was development of grade 1 (67%) and 2 (8%%) cutaneous haemangiomas. Common toxicities seen with other VEGF directed therapies, including hypertension, impaired wound healing, and proteinuria were not seen in this cohort. Efficacy was assessed by MRI using RANO criteria. 6 month PFS was 17%, with disease control in 25%, with steroid dose reduction. The longest response was 15 months. On DCE MRI, there was no significant difference in perfusion parameters between baseline and 1st follow-up MRI comparing those with SD and PD. However, 6 of 12 patients showed decreased Ktrans > 20 % of baseline, consistent with an anti-angiogenic effect of Olinvacimab. Pharmacokinetics showed a decreased clearance rate and increased half-life of Olinvacimab compared to the prior Phase I study. Pharmacodynamic studies showed significantly higher levels of angiogenic markers, particularly VEGF-A in those treated at 12mg/kg vs arm 1. VEGF-A, C and D levels were elevated in patients with SD compared to those with PD. Conclusion: Olinvacimab was well tolerated with a different toxicity profile to other VEGFR directed therapies. There were promising responses in 25% of patients.
CTNI-23. IDH1/2wt ANAPLASTIC GLIOMAS OF THE EORTC RANDOMIZED PHASE III INTERGROUP CATNON TRIAL: OVERALL SURVIVAL RELATED TO TREATMENT, MGMT STATUS AND MOLECULAR FEATURES OF GLIOBLASTOMA
Authors: Tesileanu C Mircea S , French Pim , Erridge Sarah , Vogelbaum Michael , Nowak Anna , Sanson Marc , Brandes Alba , Wick Wolfgang , Clement Paul , Baurain Jean , Mason Warren , Wheeler Helen , Weller Michael , Aldape Kenneth , Wesseling Pieter , Kros Johan M , Golfinopoulos Vassilis , Gorlia Thierry , Baumert Brigitta , van den Bent Martin
Published: December 2020

BACKGROUND

The phase III CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant TMZ. Here, we present the molecular analysis of the IDH1/2wt subgroup, and associations between molecular characteristics and patient outcomes.

METHODS

CNV data and MGMT promoter methylation status were assessed from EPIC methylation array data. IDH1/2 and H3F3A mutation status were determined with a glioma tailored next-generation sequencing panel and TERT promoter mutation status using a SNaPshot assay. Overall survival (OS) was measured from date of randomization.

RESULTS

Of 654 assessed tumors, 211 (32%) were IDH1/2wt. An H3F3A mutation was present in 14 tumors (K27M: n=10; G34R: n=4). Of the remaining 197 patients, 154 tumors had molecular features of glioblastoma according to cIMPACT-NOW 3 criteria (‘IDH1/2wt astrocytomas WHO IV’), 39 tumors did not (‘IDH1/2wt astrocytomas WHO III’), and 4 had inconclusive molecular data. IDH1/2wt astrocytomas WHO III patients had significantly better survival than WHO IV patients: median OS of 2.83 yrs vs 1.43 yrs respectively [log-rank test: p< 0.001]. Of the 154 IDH1/2wt astrocytoma WHO IV, 55 (36%) were found MGMT promoter methylated. MGMT promoter methylation was prognostic in IDH1/2wt astrocytomas WHO IV patients, with a median OS of 1.86 yrs for methylated vs 1.34 yrs for unmethylated [HR 1.62, p=0.006]. In the IDH1/2wt astrocytomas WHO IV, no effect of concurrent and/or adjuvant TMZ was observed; the HR for OS after RT with any TMZ vs RT alone was 1.31 [95% CI 0.73–2.36, p=0.4] for MGMT promoter methylated and 0.90 [95% CI 0.55–1.45, p=0.7] for unmethylated glioma patients.

CONCLUSIONS

Our study validated the prognostic value of the cIMPACT-NOW 3 criteria. MGMT promoter methylation is prognostic but not predictive for outcome to TMZ treatment in this cohort of IDH1/2wt anaplastic gliomas with molecular features of glioblastoma.
CTNI-24. A PHASE 2 STUDY OF TRAMETINIB FOR PATIENTS WITH PEDIATRIC GLIOMA WITH ACTIVATION OF THE MAPK/ERK PATHWAY. TRAM-01
Authors: Perreault Sébastien , larouche Valérie , Tabori Uri , Hawkins Cynthia , Lippe Sarah , Ellezam Benjamin , Décarie Jean-Claude , Théoret Yves , Metras Marie-Élaine , Sultan Serge , Cantin Édith , Routhier Marie-Ève , Caru Maxime , Legault Geneviève , Bouffet Eric , Lafay-Cousin Lucie , Hukin Juliette , Erker Craig , Jabado Nada
Published: December 2020

BACKGROUND

Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway.

METHODS

This multicenter phase II included three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). Primary objective is to evaluate overall response rate after daily oral trametinib administration for 18 cycles each 28 days duration. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment.

RESULTS

As of June 1 2020, 37 patients have been enrolled (NF1: 7 patients, KIAA1549-BRAF fusion: 22, other: 8 (including 5 patients with FGFR1 alterations). Median age is 9.3 years (range 2.3–25.4). Median follow-up is 8.8 months (range 0–19.3). Twenty-eight patients are evaluable. Best response includes: 4 partial response (PR) (14%), 5 minor response (MR) (18%), 18 stable disease (64%), 1 progressive disease (3.5%). Median time to response is 2.8 months (range 2.4–11.3). Median duration of response is 8.0 months (range 0.6–16.8. Progression free survival at 12 months is 83.1% (95% CI 70.5–98.0%) and median progression free survival has not reached. Nine patients (24%) discontinued treatment: 3 for progressive disease, 4 adverse events (3 alanine aminotransferase increase, 1 paronychia), 2 for other reasons.

CONCLUSION

Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Overall treatment is well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.
CTNI-29. CODEL: PHASE III TRIAL OF RT ALONE, RT PLUS TMZ, OR TMZ ALONE FOR NEWLY-DIAGNOSED, 1p/19q CODELETED ANAPLASTIC OLIGODENDROGLIOMA. ANALYSIS FROM THE INITIAL STUDY DESIGN. (NCCTG N0577, ALLIANCE)
Authors: Jaeckle Kurt , Ballman Karla , van den Bent Martin , Giannini Caterina , Galanis Evanthia , Brown Paul , Jenkins Robert , Cairncross Gregory , Wick Wolfgang , Weller Michael , Aldape Kenneth , Dixon Jesse , Anderson S Keith , Cerhan Jane , Wefel Jeffrey S , Klein Martin , Grossman Stuart , Schiff David , Raizer Jeffrey , Dhermain Frederick , Nordstrom Donald , Flynn Patrick , Vogelbaum Michael
Published: December 2020

BACKGROUND

The original 3-arm CODEL design included a radiotherapy (RT)-alone control arm, an RT plus temozolomide (TMZ) arm, and an exploratory TMZ-alone arm. We report the analysis involving patients treated per the initial design.

METHODS

Adults (18+ years) with newly-diagnosed 1p/19q codeleted WHO grade III oligodendroglioma were randomized to RT (5940 cGy) alone (Arm A); RT with concomitant and adjuvant TMZ (Arm B); or TMZ alone (Arm C). Primary endpoint was OS, Arm A vs. B. Secondary comparisons were performed for OS and PFS, comparing pooled RT arms with the TMZ-alone arm.

RESULTS

36 patients were randomized equally to the three arms. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients had progressed, versus 37.5% (9/24) patients on the RT arms. PFS was shorter in TMZ-alone patients compared to RT-treated patients (HR=3.12; 95% CI: 1.26, 7.69; p=0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) of RT-treated patients. OS did not statistically differ between arms, although this comparison was underpowered. After adjustment for IDH status (mutated vs. wildtype) in a Cox regression model, with IDH status and RT treatment status as co-variables (Arm C vs pooled A and B), PFS remained shorter for patients not receiving RT (HR= 3.33; 95% CI: 1.31, 8.45; p=0.011), and OS differences remained non-significant ((HR = 2.78; 95% CI 0.58, 13.22, p=0.20). Grade 3+ adverse events occurred in 25%, 42% and 33% patients (Arms A, B and C, respectively). Neurocognitive assessments, comparing baseline and 3 month timepoints, showed no significant differences between arms.

CONCLUSIONS

TMZ-alone treated patients experienced significantly shorter PFS than patients treated on the pooled RT arms, which remained significant when adjusting for IDH status. CODEL has been redesigned to compare the efficacy and toxicity of RT+PCV versus RT+TMZ. Clinicaltrials.gov Identifier: NCT00887146. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org.
CTNI-33. DEBIO1347, AN ORAL FGFR INHIBITOR: RESULTS FROM A SINGLE CENTER STUDY IN PEDIATRIC PATIENTS WITH RECURRENT/REFRACTORY FGFR ALTERED GLIOMAS
Authors: Farouk Sait Sameer , Rosenblum Marc , Bale Tejus , Haque Sofia , Gilheeney Stephen , Spatz Krisoula , Prince Daniel , Ibanez Katarzyna , Dunkel Ira , Karajannis Matthias
Published: December 2020

BACKGROUND

Oncogenic driver alterations in fibroblast growth factor receptors (FGFRs) are present in a subset of pediatric gliomas. Debio1347 is an orally available, highly selective FGFR 1–3 inhibitor with a favorable safety profile and encouraging preliminary clinical activity in an adult phase 1 study.

METHODS

We treated five children with progressive/refractory CNS tumors harboring an FGFR gene alteration with Debio1347 on single patient use protocols. Patients were treated using the 20 mg tablet formulation at the adult recommended phase 2 dose (80 mg/1.73 m2 ′ BSA once daily).

RESULTS

All adverse events (AEs) were grade 1–2. Most common treatment-related AEs were hyperphosphatemia, ALT elevation and hypoalbuminemia. Two patients met criteria for partial response and two patients had stable disease. A 13-month-old patient with a spinal cord high-grade glioma harboring two FGFR1 mutations had tumor reduction of 96.3% maintained for 11 months. A 26 month-old patient with a pilomyxoid astrocytoma harboring an FGFR1-TACC1 fusion had a tumor reduction of 74.5% maintained for 9 months. Prolonged disease stabilization and clinically significant improvement in visual function was noted in an eight year-old patient with metastatic suprasellar pilomyxoid astrocytoma harboring two FGFR1 mutations (14 months overall and sustained for 6 months off therapy) and in a 14 year-old patient with posterior fossa glioneuronal tumor harboring an FGFR3-TACC3 fusion (26 months and ongoing).

CONCLUSIONS

FGFR targeted therapy with Debio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with recurrent/refractory FGFR altered gliomas. Further studies in this population are warranted.
CTNI-34. INITIAL ANALYSIS OF PHASE-III TRIAL - STANDARD CHEMOTHERAPY VS. CHEMOTHERAPY GUIDED BY A CANCER STEM CELL TEST IN RECURRENT GLIOBLASTOMA (NCT03632135)
Authors: Ranjan Tulika , Chen Ricky , Aregawi Dawit , Chaudhary Rekha , Sengupta Soma , Lu-Emerson Christine , Moulding Hugh , Glass Jon , Schroeder Jason , Jubelirer Steven , Anderson Mark
Published: December 2020

BACKGROUND

ChemoID is a cancer stem cell (CSC) cytotoxicity assay for guiding personalized treatment in the clinical trial NCT03632135 using standard-of-care drugs for improving clinical outcomes. The ChemoID assay is a functional test that determines the response to chemotherapy treatments from a panel of FDA approved drugs or their combinations. The trial aims to determine the clinical utility of the ChemoID assay as a predictor of clinical response in recurrent glioblastoma (GBM).

METHODS

The study has been designed as a parallel group controlled clinical trial where participants with recurrent GBM amenable to surgery or biopsy are randomized at a ratio of 1:1 to either standard-of-care chemotherapy chosen by the physician or ChemoID-guided therapy. Response to therapy is measured by MRI imaging (RANO 1.1). The primary endpoint is median overall survival (OS) and secondary endpoints are OS at 6, 9, and 12 months, median progression-free survival (PFS), PFS at 4, 6, 9, and 12 months, objective tumor response, time to recurrence, and quality of life.

RESULTS

A total of 41 participants (29 males, 12 females) have been accrued to the trial thus far with a median age of 61yo. Data from 38 participants (27 males, 11 females) has reached maturity for analysis. 21 participants have been randomized to the assay-guided arm and 17 to the physician-choice arm. From an initial analysis, we observed that 71% (15/21) of the participants in the ChemoID-guided arm are alive and 29% (6/21) are deceased. We also observed that 41% (7/17) of the participants in the physician-choice arm are alive and 59% (10/17) are deceased. This gives the odds of death for the ChemoID-guided arm to be 72% lower than on the physician-guided arm (OR=0.28; (0.07–1.08); p=0.065).

CONCLUSIONS

Our preliminary results indicate that the ChemoID assay has the potential to improve survival of recurrent GBM patients.
CTNI-38. PAMIPARIB IN COMBINATION WITH RADIATION THERAPY (RT) AND/OR TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED (ND) OR RECURRENT/REFRACTORY (R/R) GLIOBLASTOMA (GBM); PHASE 1B/2 STUDY UPDATE
Authors: Piotrowski Anna , Puduvalli Vinay , Wen Patrick , Colman Howard , Campian Jian , Pearlman Michael , Butowski Nicholas , Cloughesy Timothy , Battiste James , Glass Jon , Schiff David , van den Bent Martin , Walbert Tobias , Ahluwalia Manmeet , Badruddoja Michael , Kalra Amandeep , Pelham Robert , Zhang Kathy , Wood Katie , Weller Michael , Shih Kent
Published: December 2020

Pamiparib, an investigational, oral PARP 1/2 inhibitor, demonstrated preclinical brain penetration and synergistic cytotoxicity with TMZ. We report updated safety and antitumor data for pamiparib plus RT and/or TMZ in ND-GBM or R/R-GBM (SNO 2019, ACTR-39). This dose-escalation/expansion study includes three arms: A, pamiparib (2, 4, or 6 weeks) plus RT (6–7 weeks) in ND-GBM with unmethylated MGMT promoter (unmethylated-GBM); B, pamiparib (6 weeks) plus RT and increasing TMZ doses in Weeks 1 and 5 of RT in unmethylated ND-GBM; and C, pamiparib plus increasing TMZ doses in methylated/unmethylated R/R-GBM. Most patients in Arms A (expansion) and B received maintenance pamiparib plus TMZ after post-RT rest period at Arm C expansion. As of April 10, 2020, enrollment was complete (N=116; A, n=60; B, n=9; C, n=47). Median study follow-up was 11.3 mo (A/B) and 7.1 mo (C). Common grade ≥3 AEs were anemia (10%) in Arm A; decreased neutrophil and white blood cell count (each 22%) in B; anemia, fatigue, and decreased lymphocyte count (each 11%) in C. Brain edema (A) and pneumonia (C) (n=1 each) were fatal treatment-unrelated AEs. In ND-GBM, modified disease control rate (DCR following post-RT rest period) was 69.8% (95% CI, 55.7–81.7) overall, 68.8% (50.0–83.9) in A, and 80.0% (28.4–99.5) in B. Median duration of response was 5.1 mo (overall), 3.8 mo (A), and NE (B). In Arms A/B, median progression-free survival (PFS) and median overall survival (OS) were 4.4 mo and 12.7 mo, respectively; 12-mo OS rate, 54% (95% CI, 40–66). In R/R-GBM (Arm C), confirmed ORR was 9.1% (95% CI, 2.5–21.7); median PFS and OS were 1.9 mo and 7.3 mo, respectively; 6-mo PFS rate, 19% (95% CI, 9–32). These results showed a manageable safety profile for pamiparib +/- RT +/-TMZ; response and survival results support further evaluation of these combinations in GBM.
CTNI-42. FIRST-IN-HUMAN FLUORESCENCE GUIDED SURGERY OF HIGH-GRADE GLIOMAS USING PANITUMUMAB-IRDYE800
Authors: Zhou Quan , van den Berg Nynke , Nishio Naoki , Lu Guolan , Chirita Stefania , Raymundo Roan , Yi Grace , Vogel Hannes , Cayrol Romain , Rosenthal Eben , Li Gordon
Published: December 2020

INTRODUCTION

High-grade gliomas (HGGs) are malignant brain tumors with devastating prognosis. Extent of resection predicts survival in patients, but current neuroimaging approaches lack tumor specificity. The epidermal growth factor receptor (EGFR) is a biomarker heterogeneously expressed in HGGs. We assessed the feasibility of imaging HGGs using a near-infrared fluorescent anti-EGFR antibody.

METHODS

Nine patients with contrast enhancing HGGs on presurgical MRI scan were systemically infused with a flat dose of either 50mg (n = 4) or 100mg (n = 5) panitumumab-IRDye800, 1–5 days before surgery. Near-infrared fluorescence imaging of tumor and histologically normal brain tissues was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratio (TBR) were calculated by comparing MFIs of tumor and histologically uninvolved tissue. Immunohistopathological staining of EGFR was performed on formalin fixed paraffin embedded tissue sections.

RESULTS

Both MFI and TBR were positively correlated to panitumumab-IRDye800 dose per body weight (R2 = 0.59 and 0.07, P < 0.0001 and P = 0.046 respectively). The TBR was higher at a 100 mg dose than at 50 mg (2.1 vs. 1.5). The smallest detectable tumor volume in a closed-field setting was 21 mg with 50 mg of dye and 12 mg with 100 mg. On sections of paraffin embedded tissues, positive EGFR protein expression was observed in 88.9% ± 12.4% of tumor tissues and positively correlated with fluorescence. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (93%) and specific (81%) for viable tumor tissues while normal brain tissues showed minimal fluorescence. No adverse events related to the imaging probe was observed.

CONCLUSION

This first-in-human study demonstrates the feasibility and safety of antibody based imaging for contrast enhancing high-grade gliomas.
CTNI-43. ANLOTINIB COMBINED WITH STUPP REGIMEN IN TREATING PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME: A PHASE II PILOT STUDY
Authors: Lai Shuzhen , Chen Yuanyuan
Published: December 2020

PURPOSE

Anlotinib, an orally multi-target tyrosine kinase inhibitor, inhibits tumor angiogenic and proliferative signal pathways. We performed a phase II trial of anlotinib in combination with the STUPP regimen in patients with newly diagnosed glioblastoma multiforme（GBM）to determine whether the combination therapy would safely improve outcomes in this group of patients. An initial pilot study assessed interim safety and tolerability.

METHODS AND MATERIALS

Ten newly diagnosed GBM patients were included in this study. All patients received standard radiation of 60 Gy in 30 fractions starting within 4–6 weeks after surgery with concurrent TMZ (daily, 75 mg/m2) and anlotinib (8mg per day, from day 1 to 14, every 3 weeks). After a 4-week break, adjuvant therapy including 6 cycles of TMZ (150–200 mg/m², from day 1 to 5, every 4 weeks) and 8 cycles of anlotinib (8mg per day, from day 1 to 14, every 3 weeks) was given. For patients completing adjuvant therapy, anlotinib alone (8mg per day, from day 1 to 14, every 3 weeks) was administrated until disease progression.

RESULTS

All patients completed concurrent chemo-radiotherapy without interruption. One patient developed grade 3 weight loss at 56th week and grade 3 presumed radiation-induced cognitive disturbance at 60th week. Fatigue and hypertension were frequently observed during treatment, which potentially be related to the treatment. No severe toxicity was observed in other patients. Up to this writing, none of these patients developed disease progression.

CONCLUSION

Anlotinib combined with the STUPP regimen is a potential choice for newly diagnosed GBM patients. It is well tolerated and the toxicity is manageable. It’s acceptable to continue enrolling of this Phase II study.
CTNI-47. PHASE II STUDY OF ABEMACICLIB IN RECURRENT GBM PATIENTS WITH CDKN2A/B LOSS AND INTACT RB
Authors: Lee Eudocia , Muzikansky Alona , Arrillaga-Romany Isabel , Chukwueke Ugonma , Cloughesy Timothy , Colman Howard , Daras Mariza , de Groot John , Mcfaline-Figueroa Jose , Nayak Lakshmi , Prins Robert , Reardon David , Taylor Jennie , Ligon Keith , Wen Patrick
Published: December 2020

Deregulation of the cyclin-dependent kinases (CDK) 4 and 6 (cdk4/6)–cyclin D-INK4—retinoblastoma protein (Rb) signaling pathway is among the most common aberrations found in glioblastoma (GBM) with more than 80% of patients estimated to be affected. We conducted an open label, multi-center, phase II trial of abemaciclib in participants with recurrent glioblastoma (GBM) at their first relapse and with documented evidence of CDKN2A/B loss and intact RB from archival tissue. A total of 32 patients enrolled on the non-surgical arm of the study with 13 women (40.63%) and median KPS 90 [range 60–100]. The PFS6 rate was 9.37% [95% CI, 2.4%, 22.27%], median PFS 55 days [95% CI, 49, 56], and median OS 384 days [95% CI, 228, 488]. Out of 31 evaluable patients, best response was PR 1 (3.2%), SD 11 (35.5%), and PD 19 (61.3%). The most common grade 3 or higher toxicities at least possibly related to abemaciclib included leukopenia (21.9%), neutropenia (18.6%), lymphopenia (9.4%), and thrombocytopenia (6.3%). Abemaciclib has minimal activity in this preselected recurrent GBM population. Correlative studies from the surgical arm of this study are pending.
CTNI-48. NOVEL TREATMENT OF END STAGE RECURRENT GLIOBLASTOMA TREATED WITH A NONINVASIVE ONCOMAGNETIC DEVICE USING OSCILLATING MAGNETIC FIELDS – A NEW AND POWERFUL NONINVASIVE THERAPY
Authors: Helekar Santosh , Sharpe Martyn , Pichumani Kumar , Ijare Omkar , Nguyen Lisa , Baskin David
Published: December 2020

Noninvasive treatment with alternating electric fields at 200 kHz (Optune therapy) has been approved for recurrent and newly diagnosed glioblastoma (GBM). We have recently tested and confirmed in vitro, and in patient derived xenografted mouse models, the oncolytic potential of powerful newly developed device generating oscillating magnetic fields (OMF) using rotating magnets. This device is completely different and has different mechanisms of action than Optune therapy. We report the successful treatment of an endstage recurrent GBM in a 53-year-old man. The patient had undergone radical surgical excision and standard of care chemoradiotherapy, as well as experimental gene therapy for a left frontal tumor. 18 months after this treatment, there was recurrence with progressive enlargement and leptomeningeal spread, making the patient’s condition not suitable for further treatment. We conducted a 5-week treatment (followed by a pause of one week) consisting of daily exposure (on weekdays) with intermittent OMF. The patient tolerated the treatment well. At 4 weeks there was a progressive reduction of the contrast-enhanced tumor (CET) volume to less than 60% of the pre-treatment volume on magnetic resonance imaging scans. Caregiver report indicated mild subjective improvement in speech and cognitive function. The daily decrease in volume was correlated with the amount of daily treatment, with longer treatments showing an increase in shrinkage of the CET volume. After the treatment pause in the 6th week, there was an apparent increase in CET volume. However, a marked reduction in the choline peak and an increase in the lipid peak on a proton magnetic resonance spectrogram of the tumor at this timepoint documented that this represented necrotic tissue. We are excited about this new and powerful treatment for glioblastoma and will present the details of treatment and imaging studies during therapy.
CTNI-54. LONG-TERM USE OF EVEROLIMUS PLUS OCTREOTIDE FOR RECURRENT INTRACRANIAL OR SPINAL MENINGIOMA: A SINGLE INSTITUTION EXPERIENCE
Authors: Youssef Michael , Pham Lily , Demirhan Mehmet , Harrison Rebecca , Loghin Monica , Johnson Jennifer , Alfaro-Munoz Kristin , Bhat Krishna , Yeboa Debra , Prabhu Sujit , Raza Shaan , de Groot John , Demonte Franco , Kamiya-Matsuoka Carlos
Published: December 2020

BACKGROUND

Selection of systemic therapy for recurrent meningiomas with progression after resection and/or radiation therapy represents a challenge. The combination of everolimus, an mTOR inhibitor, plus octreotide long-acting repeatable (LAR), a somatostatin agonist, suggests synergistic activity in preclinical studies. Its long-term clinical impact in recurrent meningiomas warrants further study.

METHODS

We reviewed the records of adult patients with recurrent intracranial or spinal meningioma (WHO grade I, II, or III), not candidates for further surgery or radiation therapy, who were treated with everolimus and octreotide, between 1/1/2015 and 06/1/2020 at MD Anderson Cancer Center. Patients received everolimus (10 mg PO daily) each 28-day cycle and octreotide 30 mg SC once monthly. Molecular features were determined by next generation sequencing (T-200–1, Oncomine).

RESULTS

A total of 18 patients were identified, including WHO grade I tumors (n=4), grade II (n=10), and grade III (n=4); furthermore, 8 patients harbored NF2 mutation, followed by mutations in CREBBP (n=2), NOTCH2 (n=1), MHL1 (n=1), PTEN (n=1), SETD2 (n=1), and TP53 genes (n=1). One patient had spinal meningioma. The 6- and 12-month PFS were 77.8% and 61.1%, 6- and 12-month OS were 94.4% and 83.3% respectively. Seven (38.9%) patients had tolerated treatment for more than 12 cycles, 3 (16.7%) remain on treatment for more than 24 cycles and 1 patient is still on treatment for 31 cycles. Only 1 patient required dose reduction to 7.5 mg daily due to pneumonitis, otherwise there is an acceptable toxicity profile. Four patients had resolution of trigeminal neuralgia.

CONCLUSIONS

In our patient population, combination treatment with everolimus and octreotide seems to have antitumor activity and proved to be safe without major side effects from long-term exposure. It also contributed to control of neuralgia. Further tissue analysis of the role of mTOR pathway and SSTR2A expression is ongoing.