Displaying One Session

Bilbao Auditorium (Hall 5) Proffered Paper session
Date
27.09.2019
Time
16:00 - 17:30
Location
Bilbao Auditorium (Hall 5)
Chairs
  • Paul M. Clement (Leuven, Belgium)
  • Martin J. Van den Bent (Rotterdam, Netherlands)
Proffered Paper – CNS tumours Proffered Paper session

390O - Efficacy and safety of ceritinib in ALK-positive non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM): Results from the phase II, ASCEND-7 study (ID 1638)

Presentation Number
390O
Lecture Time
16:00 - 16:12
Speakers
  • Fabrice Barlesi (Marseille, CEDEX 20, France)
Location
Bilbao Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
27.09.2019
Time
16:00 - 17:30

Abstract

Background

LM are seen in approximately 5% of ALK+ NSCLC patients (pts), and are associated with poor prognosis with standard treatment. Ceritinib is highly active in ALK+ NSCLC pts with previously reported intracranial/central nervous system activity. We report the efficacy and safety of ceritinib in ALK+ NSCLC pts with LM enrolled in the ASCEND-7 study (NCT02336451).

Methods

Pts with documented ALK + (FISH) NSCLC, CSF invasiveness with radiologically or cytologically confirmed LM, and ≥1 extracranial measurable lesion using RECIST v1.1 were eligible. The study objectives included evaluation of antitumor activity based on overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Data cut-off was Feb 6, 2019.

Results

Of the 18 LM pts enrolled, 14 pts (77.8%) also had brain metastases and 8 pts (44.4%) had measurable brain metastases at baseline. Majority of the pts (n = 16, 88.9%) had received prior crizotinib and 7 pts (38.9%) had received prior brain radiotherapy. Median duration of exposure to ceritinib was 18.1 weeks (range: 1.7–125.9). Whole body ORR by investigator assessment was 16.7% (95% CI: 3.6, 41.4) with median duration of response of 5.5 months (95% CI: 3.7, 9.9) and a clinically significant median PFS of 5.2 months (95% CI: 1.6, 7.2). Median duration of follow-up for PFS was 3.84 months (range: 0.5–13). Additional efficacy endpoints are included in the below Table. Adverse events (AEs, all grades, regardless of study drug relationship) were reported in all 18 pts. Grade 3/4 AEs occurring in ≥ 10% of pts were increased alanine aminotransferase (22.2%), hyperglycemia (16.7%), increased gammaglutamyltransferase (11.1%), pneumonia (11.1%), and increased lipase (11.1%). Table: Efficacy results

Endpoint per investigator assessmentArm 5 (ALK+ NSCLC pts with LM) N = 18
Whole body Response (RECIST v1.1)
ORR, % (95% CI)16.7 (3.6, 41.4)
DCR, % (95% CI)66.7 (41.0, 86.7)
Median DOR, (months) [95% CI]5.5 (3.7, 9.9)
Median PFS, (months) [95% CI]5.2 (1.6, 7.2)
Intracranial response* (modified RECIST v1.1)M = 8
ORR, % (95% CI)12.5 (0.3, 52.7)
DCR, % (95% CI)62.5 (24.5, 91.5)
Extracranial response (RECIST v1.1)
ORR, % (95% CI)22.2 (6.4, 47.6)
DCR, % (95% CI)72.2 (46.5, 90.3)
Median OS, months (95% CI)7.2 (1.6, 16.9)

In patients with measurable brain metastases M, number of patients with measurable brain metastases at baseline DCR, disease control rate; DOR, duration of response; NE, not estimable; ORR, overall response rate; OS, overall survival; PFS, progression free survival; RECIST, Response Evaluation Criteria in Solid Tumors.

Conclusions

Ceritinib demonstrated a clinically meaningful efficacy and a safety profile similar to earlier reported results in this largest reported set of ALK+ NSCLC pts with LM.

Clinical trial identification

NCT02336451.

Editorial acknowledgement

Aarti Kamaraj, Novartis Healthcare Pvt Ltd (Hyderabad, India).

Legal entity responsible for the study

Novartis Pharmaceuticals.

Funding

Novartis Pharmaceuticals.

Disclosure

F. Barlesi: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology; Honoraria (self): F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda; Research grant / Funding (institution): Abbvie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis; Non-remunerated activity/ies, Principal investigator: AstraZeneca, BMS, Merck, Pierre Fabre and F. Hoffmann-La Roche, Ltd, sponsored trials (or ISR); Research grant / Funding (institution): Takeda. D. Kim: Research grant / Funding (institution): Alpha Biopharma, AstraZeneca/Medimmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan. E.M. Bertino: Advisory / Consultancy: Takeda; Speaker Bureau / Expert testimony: Pfizer. M.J. van den Bent: Honoraria (self): Celgene, Agios, Boehringer, BMS, Abbvie; Research grant / Funding (institution): Abbvie. H. Wakelee: Honoraria (self): Novartis, AZ; Advisory / Consultancy, Compensated: AstraZeneca, Xcovery, Janssen; Advisory / Consultancy, Not compensated: Merck, Takeda, Genentech/Roche; Research grant / Funding (institution): ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bayer (under Suki and not me), BMS, Celgene, Clovis Oncology, Exelixis,, Genentech/Roche, Gilead, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, Xcovery; Travel / Accommodation / Expenses: AstraZeneca; Officer / Board of Directors: International Association for the Study of Lung Cancer (IASLC). P.Y. Wen: Advisory / Consultancy: Agios, AstraZeneca, Beigene, Eli Lily, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines, Tocagen; Speaker Bureau / Expert testimony: Merck, Prime Oncology; Research grant / Funding (institution): Agios, AstraZeneca, Beigene, Eli Lily, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines. P. Garrido Lopez: Advisory / Consultancy: Roche, MSD, BMS, Boerhinger Ingelheim, Pfizer, Abbvie, Guardant Health, Novartis, Lilly, AstraZeneca, Jansen, Sysmex, Blueprint Medicines, Takeda; Speaker Bureau / Expert testimony: Roche, MSD, BMS, Pfizer, Novartis, Boerhinger Ingelheim, Rovi; Research grant / Funding (institution), Financial support for clinical trials: Roche, MSD, BMS, Takeda, Lilly, Pfizer, Novartis, Pharmamar, Celgene, Sanofi, GSK, Theradex Oncology, BluePrint Medicines; Research grant / Funding (institution), Financial support for contracted research: Guardant Health, Sysmex. M. Majem: Advisory / Consultancy: Roche, MSD, AstraZeneca, Boehringer, Tesaro, Takeda, Pierre Fabre; Speaker Bureau / Expert testimony: Roche, BMS, MSD, AstraZeneca, Boehringer, Hellsin, Pierre Fabre, Amgen; Research grant / Funding (self): BMS; Travel / Accommodation / Expenses: BMS, MSD, AstraZeneca, Lilly. M. McKeage: Advisory / Consultancy: Novartis, Pfizer; Research grant / Funding (institution): Novartis, Pfizer, Roche. C. Yu: Honoraria (self): Roche, AstraZeneca, Ono pharma, Boehringer-Ingelheim; Advisory / Consultancy: Roche, AstraZeneca, Ono pharma, Boehringer-Ingelheim. F.K. Hurtado: Shareholder / Stockholder / Stock options: Novartis Pharmaceuticals Corp.; Full / Part-time employment: Novartis Pharmaceuticals Corp. P. Cazorla Arratia: Shareholder / Stockholder / Stock options: Novartis Pharmaceuticals Corporation; Full / Part-time employment: Novartis Pharmaceuticals Corporation. Y. Song: Shareholder / Stockholder / Stock options, Restricted Stock Unit: Novartis Pharmaceutical Corporation; Full / Part-time employment: Novartis Pharmaceutical Corporation. F. Branle: Shareholder / Stockholder / Stock options: Novartis AG; Full / Part-time employment: Novartis AG. M. Shi: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis Pharmaceuticals Corporation. L.Q. Chow: Advisory / Consultancy: Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/Medimmune, Pfizer, Seattle Genetics, Novartis, Dynavax Inc., Alkermes, Amgen, Sanofi-Genzyme, Takeda; Research grant / Funding (institution): Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/Medimmune, Pfizer, Seattle Genetics, Novartis, Dynavax Inc. and Alkermes,Incyte, VentiRx and Lily/Imclone. All other authors have declared no conflicts of interest.

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Proffered Paper – CNS tumours Proffered Paper session

391O - Prognostic role of the EANO ESMO classification of leptomeningeal metastases (ID 4648)

Presentation Number
391O
Lecture Time
16:12 - 16:24
Speakers
  • Emilie Le Rhun (Lille, CEDEX, France)
Location
Bilbao Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
27.09.2019
Time
16:00 - 17:30

Abstract

Background

The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) based on clinical (typical/atypical), cytological (positive/negative/equivocal) and MRI (A linear, B nodular, C linear + nodular, D normal or hydrocephalus only) presentation. Type I LM is defined by the presence of tumor cells in the cerebrospinal fluid (CSF) (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the correlation between EANO ESMO subtypes of LM and outcome to assess their clinical utility.

Methods

We collected data from 254 patients with newly diagnosed LM from different primary solid tumors. Survival curves were estimated using the Kaplan-Meier method and compared by Log-rank test.

Results

Median age at LM diagnosis was 56.5 years (range 20-82 years). The main primary tumors were breast cancer (n = 98, 45%), lung cancer (n = 65, 25.5%) and melanoma (n = 51, 13.5%). Typical clinical LM symptoms or signs were noted in 225 patients (88.5%); only 13 patients (5%) were clinically asymptomatic. The most common MRI subtype was A seen in 117 patients (46%). Types B (n = 33, 13%), C (n = 54, 21%) and D (n = 50, 19.5%) were less common. Tumor cells were observed in the CSF in 186 patients (73%) whereas the CSF was equivocal in 24 (9.5%) and negative in 44 (17.5%) patients. Assignment to EANO ESMO classes was as follows: type IA 86 (34%), IB 19 (7.5%), IC 39 (15.5%), ID 45 (17.5%), IIA 28 (11%), IIB 13 (5%), IIC 16 (6.5%), IID 8 (3%). LM was confirmed in 189 (74.5%), probable in 51 (20%) and possible in 14 (5.5%) patients. The median overall survival (OS) was 2.75 months (range 0.09-220 months). OS was inferior in type I compared with type II LM patients (p = 0.0024). EANO ESMO subtype IIA patients had the longest survival (p = 0.0103). Patients with MRI patterns A and D pooled had poorer survival than B and C patients pooled in the presence of tumor cells in the CSF (type I) (p = 0.0402), but longer survival in the absence of tumor cells in the CSF (type II) (p = 0.0273).

Conclusions

The presence of tumor cells in the CSF appears to have a greater prognostic role than the neuroimaging presentation. EANO ESMO LM subtypes are prognostic and should be considered in the design of clinical trials.

Legal entity responsible for the study

University Hospital of Zurich.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper – CNS tumours Proffered Paper session

Invited Discussant 390O and 391O (ID 6664)

Lecture Time
16:24 - 16:39
Speakers
  • Paul M. Clement (Leuven, Belgium)
Location
Bilbao Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
27.09.2019
Time
16:00 - 17:30
Proffered Paper – CNS tumours Proffered Paper session

392O - A phase 0/II clinical trial of a CDK4/6 inhibitor in aggressive meningioma patients (ID 4361)

Presentation Number
392O
Lecture Time
16:39 - 16:51
Speakers
  • Nader Sanai (Phoenix, United States of America)
Location
Bilbao Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
27.09.2019
Time
16:00 - 17:30

Abstract

Background

New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients.

Methods

Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily (900mg) for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04 µM) and >20% decrease in pRB levels, respectively, were enrolled into an exploratory phase 2 cohort.

Results

The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At one year, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria.

Conclusions

Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted.

Clinical trial identification

NCT02933736.

Legal entity responsible for the study

The authors.

Funding

The Ben and Catherine Ivy Foundation.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper – CNS tumours Proffered Paper session

393O - Is immuno-oncology therapy effective in hypermutator glioblastoma with somatic or germline mutations? (ID 1170)

Presentation Number
393O
Lecture Time
16:51 - 17:03
Speakers
  • Carlos Kamiya-Matsuoka (Houston, United States of America)
Location
Bilbao Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
27.09.2019
Time
16:00 - 17:30

Abstract

Background

Immuno-oncology (IO) is an effective strategy for the management of non-glioma tumors and it may be enhanced in hypermutators. Hypermutator glioblastoma (HmGB) is seen as initial tumor diagnosis or at recurrence after temozolomide (TMZ) treatment. We describe clinical and molecular features of HmGB treated with IO.

Methods

Retrospective review at MD Anderson between Feb, 2012 through Feb, 2017 identified 312 gliomas with tissue analyzed by next-generation sequencing (T200-1, Oncomine, FoundationOne). HmGB was defined as histologically proven GB with tumor mutational burden (TMB-30) of 30 or more mutations (mut) per Mb, or displaying mut in mismatch repair (MMR) or DNA polymerase (Pol) genes.

Results

30 (9.6%) patients had HmGB. From those, 9 (30%) received IO. 5 (55%) were men. Median age at HMGB diagnosis was 38 years (31-66). 7 (78%) had mut in MMR and 2 (22%) in Pol gene. 5 cases had IDH1 mut. 5 MGMT were umethylated. HmGB was found as initial diagnosis in 5 (56%) cases, the rest after TMZ. Of those patients with initial HmGB, 3 had MMR mut and 2 Pol mut. 8 had somatic mut and only 1 had germline MMR mut (Lynch Syndrome, MSH2, c.652C>T [p.Gln218*]). For post-treatment/recurrent HmGB, the most common alteration was MMR mut (N = 4). 8 HmGB patients received either CPI off protocol or cellular therapy (T-cells or NK cells) at recurrence of HmGB after TMZ, only 1 patient received CPI at initial HmGB diagnosis, concurrently with standard of care. In HmGB with somatic mut, OS from initial brain tumor and HmGB diagnosis was 39 and 22 months. PFS and 6m-PFS after starting IO was 72 days and 0% respectively. The PFS after TMZ, in those treated with CPI, reactive T-cells and natural killer cells was 51, 41 and 175 days, respectively, whereas the PFS in the one with newly diagnosed HmGB was 96 days. The median cumulative dose of pembrolizumab was 720 mg per patient. The patient with germline HmGB is on pembrolizumab and is the only one with stable disease for more than 12 months.

Conclusions

IO seems to be ineffective in HmGB with somatic mut regardless the onset of diagnosis (newly/recurrent) or type of Hm phenotype. However, germline HmGB may have durable responses to IO. Further investigation is needed to determine the potential antitumor immune response in this population.

Legal entity responsible for the study

The authors.

Funding

This work was supported in part by the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, and the MD Anderson Cancer Center Support grant (P30 CA016672) MD Anderson Cancer Center.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper – CNS tumours Proffered Paper session

394O - Health-related quality of life (HRQoL) evaluation in the REGOMA trial: A randomized, phase II clinical trial analyzing regorafenib activity in relapsed glioblastoma patients (ID 1688)

Presentation Number
394O
Lecture Time
17:03 - 17:15
Speakers
  • Giuseppe Lombardi (Padova, Italy)
  • Mario Caccese (Padova, Italy)
Location
Bilbao Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
27.09.2019
Time
16:00 - 17:30

Abstract

Background

REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in patients (pts) with relapsed GBM with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point.

Methods

HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P = 0.01 (2-sided).

Results

Of 119 randomized pts, 117 participated in the HRQoL evaluation, and 114 had a baseline assessment (n = 56 REG; n = 58 LOM).

No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD = 28.6) vs 7.6 (SD = 16.0); p = 0.0081). The rate of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively; p = 0.02).

Conclusions

In the REGOMA trial, HRQoL did not change during regorafenib treatment. Pts treated with regorafenib and lomustine reported no significant difference in HRQoL.

Legal entity responsible for the study

Giuseppe Lombardi.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper – CNS tumours Proffered Paper session

Invited Discussant 392O, 393O and 394O (ID 6665)

Lecture Time
17:15 - 17:30
Speakers
  • Juan M. Sepulveda Sanchez (Madrid, Spain)
Location
Bilbao Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
27.09.2019
Time
16:00 - 17:30