Proffered Paper session : Immunotherapy Proffered Paper session

2O - A phase Ib/II study of APG-115 in combination with pembrolizumab in patients with unresectable or metastatic melanomas or advanced solid tumors (ID 173)

Presentation Number
2O
Lecture Time
14:30 - 14:45
Speakers
  • A. Tolcher
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
25.02.2019
Time
14:05 - 15:20
Authors
  • A. Tolcher
  • D. Fang
  • Y. Li
  • Y. Tang
  • J. Ji
  • H. Wang
  • R. Karim
  • C. Rosas
  • Y. Huang
  • Y. Zhai

Abstract

Background

Emerging evidence suggests that p53 participates in the regulation of tumor immunity. TP53 activation in the myeloid linage suppresses alternative (M2) macrophage polarization and attenuates tumor development and invasion. Retrospective clinical analyses suggested that MDM2 amplification is associated with hyper-progression. Targeting MDM2-p53 pathway may represent a novel strategy for reversing immunosuppression and enhancing antitumor immunity of PD-1/PD-L1 blockade. APG-115 is a potent and orally active small-molecule MDM2 protein inhibitor. Binding to MDM2 protein, APG-115 restores p53 expression, activates p53 - mediated apoptosis in tumor cells retaining wild-type p53. Preclinical studies demonstrated that APG-115 promoted the production of proinflammatory cytokines in T cells, enhanced CD4+ T cell activation, and increased PD-L1 expression on tumor cells. Enhanced antitumor activity was demonstrated in syngeneic tumor models after APG-115 combined with PD-1 blockade.

Methods

APG-115 has been evaluated as a single agent in a Phase I study in US (NCT02935907). In this study, total six dose levels (10 mg, 20 mg, 50 mg, 100 mg, 200 mg and 300 mg) have been tested. The preliminary results suggested a favorable safety and tolerability profile. APG-115 exhibited an approximately dose proportional increase in exposure in PK analyses. A Phase Ib/II study of APG-115 in combination with pembrolizumab for treatment of patients with metastatic solid tumor is ongoing. Pembrolizumab is administrated as a fixed dose of 200mg IV on d1 of a 21-d cycle. Safety, tolerability, and determination of the MTD and RP2D are primary objectives of phase Ib.

Results

The second cohort (APG 115 at 100 mg) has enrolled, no DLT was observed, and evidence of antitumor activity has been observed. Biomarker studies are ongoing to identify potential selection criteria. Updated clinical data will be presented.

Conclusions

This represents one of the first clinical trials to evaluate MDM2-mediated resistance to immunotherapy.

Clinical trial identification

NCT03611868.

Legal entity responsible for the study

Ascentage Pharma Group Corp Limited.

Funding

Ascentage Pharma Group Corp Limited.

Disclosure

A.W. Tolcher: Research funding: AbbVie, ADC Therapeutics, Adagene, Aminex, Acentage, Asana, Birdie, C Stone, Arrys, GlaxoSmithKline, Inhibrx, Innate, Kiromic, NatureWise, NextCure, Nitto BioPharma, Pfizer, Pieris, Deciphera, Syndax, Symphogen, Tizona, Mersana, Zymeworks; Consultancy (includes travel funding): AbbVie, Adagene, ADC Therapeutics, Agenus, Ascentage, AxImmune, Bayer, Bioinvent, Birdie, Boston Biomedical (Syneos), EMD Serono, Forbius (Formerly Formation Biologics), Gilde Healthcare Partners, HBM Partners, Ignyta, Immunome, ImmunoMet, Innate, Jazz Pharmaceuticals, Mekanistic, Nanobiotix, NBE Therapeutics, Nuvalent, Pelican, Pierre Fabre, Ridgeway, Scitemex, Sesen (formerly EBIO), Seattle Genetics, Symphogen, Syneos. D.D. Fang, Y. Li, Y. Tang, J. Ji, H. Wang, Y. Huang, Y. Zhai: Employee of Affiliates of Ascentage Pharma Group Corp Limited (“Ascentage Pharma”); Stock ownership: Ascentage Pharma. All other authors have declared no conflicts of interest.

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Proffered Paper session : Immunotherapy Proffered Paper session

3O - Applicability of the lung immune prognostic index (LIPI) in patients with metastatic solid tumors when treated with immune checkpoint inhibitors (ICI) in early clinical trials (ID 184)

Presentation Number
3O
Lecture Time
14:05 - 14:20
Speakers
  • A. Varga
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
25.02.2019
Time
14:05 - 15:20
Authors
  • A. Varga
  • A. Bernard-Tessier
  • E. Auclin
  • L. Mezquita Pérez
  • C. Baldini
  • D. Planchard
  • A. Marabelle
  • A. Hollebecque
  • B. Besse
  • C. Massard

Abstract

Background

Lung Immune Prognostic Index (LIPI) is a score that combines pretreatment dNLR (neutrophils/ (leucocytes-neutrophils) and lactate dehydrogenase (LDH) and is correlated with outcomes of patients treated with Immune Checkpoint Inhibitors (ICI) by tumor type. It has been shown for melanoma patients, NSCLC, SCLC, HNSCC, or TNBC but not in an all tumor type population.

Methods

dNLR and LDH were retrospectively collected from 360 patients with metastatic disease treated since September 2015 to November 2017 at Gustave Roussy, in the Drug Development Department. LIPI portrays 3 groups: good group (GG) if dNLR< 3 and normal LDH, intermediate group (IG) if dNLR> 3 or LDH> upper limit of normal (ULN), and poor group (PG) if dNLR>3 and LDH>ULN. ICI benefit was analyzed according to overall survival (OS) and progression free survival (PFS).

Results

From the 360 patients treated with ICI in early clinical trials, 353 (98%) were ICI naïve, 214 (59%) were male, 209 (58%) had a performance status of 1 with a median age at ICI treatment of 60 (range, 25-88), 322 (89%) received either a PD-1 or PD-L1 inhibitor and 268 (74%) as combination therapy. The most frequent tumor types were: NSCLC (14%), colorectal (14%), bladder (13%), renal (8%), breast (7%), HNSCC (7%) and cervix (6%). The median follow-up duration was of 14.1 months (m) [95%CI 12.9-16.1]. LIPI stratified the population into good group with 160 patients (44%), intermediate group with 161 patients (44%) and poor group with 39 patients (11%). The median OS was 17.8m [95%CI 13.1-not reached (NR)] vs. 11.68m [95%CI 8.8-15.3] vs. 3.9m [95%CI 2.1-6.4] for good, intermediate and poor group while the median PFS was of 4.6m [95%CI 4.0-6.2] for GG vs. 2.8m [95%CI 2.5-3.6] for IG vs. 1.4m [95%CI 1.2-2.0] for PG (both p < 0.0001).

Conclusions

Poor LIPI score, combining dNLR>3 and LDH>ULN is associated with a poorer outcome in patients treated with ICI. Calculating LIPI prior starting ICI therapy can be useful in identifying patients that will not benefit from such a treatment choice.

Legal entity responsible for the study

Drug Development Department, Gustave Roussy.

Funding

Has not received any funding.

Disclosure

A. Varga: Courses, trainings: Astra Zeneca, MSD, Roche; Travel funds: Boehringer Ingelheim, Clovis Oncology. L. Mezquita Pérez: Consulting, advisory role:  Roche Diagnostics; Lectures and educational activities: Bristol-Myers Squibb, Tecnofarma, Roche, AstraZeneca; Travel, Accommodations, Expenses: Chugai. C. Baldini: Research Grants: Roche, Amgen, Pfizer, Abbvie, BMS; Travel and accommodation expenses: Roche, Amgen, Pfizer; Paid expert testimony: Abbvie, BMS. D. Planchard: Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel, Accommodations, Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. A. Marabelle: Research Grants: Merus, BMS, Boehringer Ingelheim, Transgene; Member of Committee/Board: GSK, AstraZeneca, Oncovir, Merck Serono, eTheRNA, Lytix pharma, Kyowa Kirin Pharma, Bayer, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, Pfizer, Seattle Genetics, Flexus Bio, Roche/Genentech, OSE immunotherapeutics, Transgene, Gritstone, Merck (MSD), Cerenis, Innate pharma, Protagen, Partner Therapeutics, Servier; Teaching/Speaker activities: Roche/Genentech, BMS, Merck (MSD), Merck Serono, Astra Zeneca/Medimmune, Amgen, Sanofi; Consulting: Roche, Pierre Fabre, Onxeo, EISAI, Bayer, Genticel, Rigontec, Daichii Sankyo, Imaxio, Sanofi, BioNTech, Corvus, GLG, Deerfield, Guidepoint Global, Edimark, SYSTEM ANALYTICS, imCheck, Sotio, Bioncotech. A. Hollebecque: Consultant/Advisory role: Amgen, Spectrum Pharmaceuticals, Lilly Travel and accommodation expenses: Servier, Amgen, Lilly; Courses, trainings: Bayer. C. Massard: Consultant/Advisory fees: Amgen, Astellas, Astra Zeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, Novartis, Pfizer, Roche, Sanofi, Orion; Principal/sub-Investigator of Clinical Trials: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Exelixis, Forma, Gamamabs, Genentech, Inc., Gilead Sciences, Inc, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Inc, Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Iris Servier, Janssen, Kura Oncology, Kyowa Kirin Pharm, Lilly, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Rigontec Gmbh, Roche, Sanofi Aventis, Sierra Oncology, Taiho Pharma, Tesaro, Inc, Tioma Therapeutics, Inc., Xencor; Research Grants: Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-financial support (drug supplied): AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. B. Besse: Sponsored Research at Gustave Roussy Cancer Center: Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. All other authors have declared no conflicts of interest.

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Proffered Paper session : Immunotherapy Proffered Paper session

29O - The 18-year-old clinical trial inclusion limit is a major barrier in the access to immunotherapies and targeted therapies for adolescents and young adults (AYAs) with cancer (ID 196)

Presentation Number
29O
Lecture Time
14:55 - 15:10
Speakers
  • T. De Rojas
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
25.02.2019
Time
14:05 - 15:20
Authors
  • T. De Rojas
  • A. Neven
  • M. Garcia-Abos
  • L. Moreno
  • N. Gaspar
  • J. Peron

Abstract

Background

The 18-years-old age limit for inclusion in clinical trials constitutes a major hurdle for adolescents and young adults (AYAs) with cancer that the main stakeholders are advocating to overthrow. The purpose of this study was 1) to analyze the access for adolescents with cancer to targeted therapies and immunotherapies and to innovation (measured in number of mechanisms of action –MoA-), when compared to young adults; and 2) to describe the time lapse between the first adult trial for a specific drug and the first trial recruiting adolescents for that same drug.

Methods

ClinicalTrials.gov was searched to identify all the clinical trials including patients with malignancies relevant for AYAs (Hodgkin lymphoma, anaplastic large cell lymphoma, extracranial germ cell tumors, medulloblastoma, rhabdomyosarcoma, synovial sarcoma, Ewing sarcoma, osteosarcoma, melanoma, thyroid cancer), starting between Jan/2007-Jul/2018. Only trials investigating immunotherapies and/or targeted therapies were included. The trials, drugs, and MoA were categorized as “available for adolescents” (including patients 12-18 years old) and “available for young adults” (18-25 years).

Results

Out of 2765 identified trials, 1369 were included: 1352 (99%) available for young adults vs 233 (17%) available for adolescents. A total of 384 novel drugs (target therapies or immunotherapies) were investigated, all 384 available for young adults vs 108 (28%) for adolescents. All 184 investigated MoA were accessible for young adults vs 61 (33%) for adolescents. Out of the 108 drugs investigated in adolescents for the included malignancies, 59 were investigated first in adults, with a median delay of 35 months (IQR 23-60). No time trend in this delay was observed over the years of the study.

Conclusions

There is a major gap in the access to novel drugs and innovation between adolescents and young adults, with the 18-years-old limit posing a large barrier. There is also a prominent delay in the opening of trials for adolescents, with no improvement observed over the last decade. Greater efforts are needed to improve clinical research for AYAs with cancer.

Legal entity responsible for the study

EORTC.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper session: New and early developments with new concepts Proffered Paper session

7O - Phase I study of CC-90011 in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma (R/R NHL) (ID 127)

Presentation Number
7O
Lecture Time
11:25 - 11:40
Speakers
  • A. Hollebecque
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
11:00 - 12:15
Authors
  • A. Hollebecque
  • J. De Bono
  • R. Plummer
  • N. Isambert
  • P. Martin-Romano
  • E. Baudin
  • S. Mora
  • E. Filvaroff
  • M. Lamba
  • Z. Nikolova

Abstract

Background

CC-90011 is a potent, selective, reversible oral inhibitor of the epigenetic target, lysine-specific demethylase 1A (LSD1) that has demonstrated anti-proliferative activity against cancer cells in vitro and in patient-derived xenograft models.

Methods

CC-90011-ST-001 is a phase I, first-in-human study of CC-90011 in patients (pts) with advanced unresectable solid tumors and R/R NHL. Pts received oral CC-90011 once/wk (QW) in 28-d cycles. Primary endpoints included safety, maximum-tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to measure preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD).

Results

As of September 4, 2018, 50 pts were enrolled. All had advanced solid tumors except 1 pt with R/R NHL; 26 pts had neuroendocrine neoplasms (NENs). Pts received escalating doses of CC-90011 at 1.25 (n = 4), 2.5 (n = 5), 5 (n = 6), 10 (n = 4), 20 (n = 5), 40 (n = 6), 60 (n = 6), 80 (n = 10), or 120 mg (n = 4). The non-tolerated dose was established as 120 mg QW, the MTD as 80 mg QW, and the RP2D as 60 mg QW. The median age was 61 y (range, 22–75), 52% were male, and pts had received a median of 3 (range, 1–4) prior systemic anticancer regimens. Thrombocytopenia, an on-target effect, was the only dose-limiting toxicity. The most common grade 3/4 treatment-related adverse events (AEs) were thrombocytopenia (16%) and neutropenia (8%; occurring in the context of thrombocytopenia at the highest doses). Serious AEs occurred in 40% of pts; 6% were treatment-related. Peak plasma concentrations occurred 2-4 h post-dose and average terminal half-life was ∼60 h; exposure was dose proportional. PD analysis showed decreased CgA and MMD in response to CC-90011, correlating with clinical benefit. One pt achieved a complete response (CR) and 22 had stable disease (SD). Prolonged SD ≥ 4 months occurred in 7 pts, 5 with bronchial NEN and 2 with prostate NEN.

Conclusions

CC-90011 is well-tolerated with promising antitumor activity in solid tumors and R/R NHL, including a CR and prolonged SD in pts with NENs. PD and PK data showed sufficient target engagement. Taken together, the preliminary clinical data provides the rationale for dose expansion of CC-90011 in pts with NENs.

Editorial acknowledgement

Editorial assistance was provided by Johna Van Stelten, Ph.D., of BioConnections LLC, funded by Celgene Corp.

Clinical trial identification

NCT02875223 and EUDRACT 2015-005243-13.

Legal entity responsible for the study

Celgene Corp.

Funding

Celgene Corp.

Disclosure

A. Hollebecque: Honoraria: Merck Serono; Consultant or advisor: Gritstone Oncology; Travel funding: Amgen. J.S. de Bono: Advisor: AstraZeneca, Genentech, Pfizer, Merck Sharp & Dohme, Bayer, Merck Serono, Janssen, Astellas, Seattle Genetics; Research funds: AZ, Sanofi, Genentech, GSK, Daiichi Sankyo, Taiho Oncology, Merck Serono, Merck Sharp & Dohme, Sierra Oncology; Speaker bureau: AZ. R. Plummer: Honoraria: Novartis, BristolMyers Squibb; Research funding: Merck, Genmab, AstraZeneca, Menarini; Patents: with Clovis Oncology; Travel funding: Merck Sharp & Dohme, Bristol Myers Squibb. S. Mora: Travel funding: Celgene; Employment and equity ownership: Celgene. E. Filvaroff: Employee: Celgene; Stock or equity ownership: Celgene, Amgen, Gilead, Genentech, Roche; Patents/royalties: Celgene and Genentech. M. Lamba: Employee, equity ownership, research funding: Pfizer, Celgene; Patents/royalties: Pfizer. Z. Nikolova: Employee, equity ownership, travel funding: Celgene. All other authors have declared no conflicts of interest.

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Proffered Paper session: New and early developments with new concepts Proffered Paper session

8O - 89Zr-labeled anti-PD-L1 CX-072 PET imaging in human xenograft and syngeneic tumors (ID 155)

Presentation Number
8O
Lecture Time
11:00 - 11:15
Speakers
  • D. Giesen
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
11:00 - 12:15
Authors
  • D. Giesen
  • L. Broer
  • M. Lub-De Hooge
  • I. Popova
  • B. Howng
  • O. Vasiljeva
  • E. De Vries
  • M. Pool

Abstract

Background

Immune checkpoint inhibiting antibodies have antitumor activity across several tumor types, but can also elicit immune-mediated adverse events (imAEs). CX-072 is an investigational antibody prodrug (Probody™ therapeutic), reactive to the murine and human programmed death-ligand 1 (PD-L1) immune checkpoint. CX-072 can be activated to a fully avid antibody by tumor-associated proteases that remove the masking peptides blocking the antigen-binding domain, which may limit peripheral PD-L1 binding and therefore imAEs. CX-072 was radiolabeled with zirconium-89 (89Zr) to study its biodistribution and tumor- versus lymphoid tissue-targeting properties using positron emission tomography (PET).

Methods

CX-072, non-specific Probody™ therapeutic control (PbCtrl) and CX-072 parental antibody (CX-075) were radiolabeled with 89Zr. Human PD-L1-expressing MDA-MB-231 tumor-bearing BALB/c nude mice received 10 μg 89Zr-CX-072, 89Zr-PbCtrl or 89Zr-CX-075 (∼5 MBq) supplemented with 0, 40 or 240 µg of respective unlabeled antibody. Biodistribution was also evaluated in C57BL6/J mice bearing PD-L1-expressing MC38 syngeneic colon adenoma tumors. Mice underwent PET scans 1, 3 and 6 days post intravenous injection (pi), followed by ex vivo analysis.

Results

In MDA-MB-231 tumors, 89Zr-CX-072 and 89Zr-CX-075 showed comparable uptake of 8.7 ± 1.0%ID/g and 8.8 ± 2.9%ID/g respectively for the 10 µg total protein dose, which is 2.3-fold higher compared to 89Zr-PbCtrl. Autoradiography showed 89Zr-CX-072 localization in PD-L1-positive tumor tissue areas on immunohistochemistry. Activated CX-072 was detected by capillary electrophoresis immunoassay mainly in MDA-MB-231 tumor, with limited amounts found in spleen. Flow cytometry confirmed PD-L1 expression in lymphoid tissues of C57BL6/J mice, while 89Zr-CX-072 uptake in these tissues was similar to 89Zr-PbCtrl and significantly lower compared to 89Zr-CX-075.

Conclusions

89Zr-CX-072 accumulates in PD-L1-expressing tumors with minor uptake in murine peripheral lymphoid tissues, confirming that the CX-072 structure limits uptake in non-tumor, PD-L1-expressing tissues. We developed clinical grade 89Zr-CX-072 to study its whole-body distribution in patients.

Legal entity responsible for the study

Dept. of Medical Oncology, University Medical Center Groningen (UMCG), The Netherlands.

Funding

CytomX Therapeutics Inc.

Disclosure

I. Popova, B. Howng, O. Vasiljeva: Employee: CytomX Therapeutics Inc. E.G.E. de Vries: Research funding: CytomX was made available to her institution (UMCG); Advisory boards: Pfizer, Daiichi Sankyo; Other funding: Amgen, Bayer, Chugai, G1 Therapeutics, Genentech/Roche, Nordic Nanovector, Regeneron, Synthon, all payments to UMCG. All other authors have declared no conflicts of interest.

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Proffered Paper session: New and early developments with new concepts Proffered Paper session

25O - Use of CTTA to predict treatment response in patients with EGFR T790M+ NSCLC treated with osimertinib (ID 138)

Presentation Number
25O
Lecture Time
11:50 - 12:05
Speakers
  • Q. Ng
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
11:00 - 12:15
Authors
  • W. Tan
  • T. Tran Nguyen
  • T. Koh
  • T. Priyanthi Hennedige
  • C. Yip
  • S. Tan
  • D. Tan
  • C. Thng
  • D. Lim
  • Q. Ng

Abstract

Background

Computed tomography textural analysis (CTTA) can be used to quantify intra-tumour heterogeneity, which is linked to adverse tumour biology. We aimed to evaluate if CTTA can predict treatment response in metastatic epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (mNSCLC) with T790M mutations (T790M+) treated with osimertinib, after prior tyrosine kinase inhibitors.

Methods

We did a retrospective analysis of 39 consecutive patients with T790M+ mNSCLC on osimertinib. Treatment response was independently assessed on CT scans by RECIST 1.1. Routine contrast-enhanced CT images were acquired for each patient pre-osimertinib. Contiguous regions of interest (ROIs) were drawn by a radiologist around all measurable lesions and encompassing the entire axial tumour volume to assess tumour heterogeneity. Acquired image data was evaluated with an in-house program developed for analysing textures using Matlab (MathWorks, Natick, MA). Four textural variables – skewness, kurtosis, entropy and standard deviation (SD) were computed based on voxel histogram statistics, quantifying the distribution and relationship of voxel gray levels in each CT image. Each variable was assessed for association with objective response rates. Patients who had partial or complete response were “responders” (Rs), those with stable disease or disease progression were “non-responders” (NRs).

Results

There were 23 Rs and 16 NRs (ORR 59%). Patient characteristics were similar between Rs and NRs. SD (which reflects degree of variability) was significantly higher in NRs: average SD was 35.8 (28.67, 38.91) in NRs vs. 31.2 (23.82, 33.28) in Rs; p = 0.04. Except for skewness, there was a trend towards higher entropy (measure of irregularity) and lower kurtosis (peakedness of the histogram) in NRs. Average entropy was 5.93 (5.667, 6.177) in NRs vs. 5.71 (5.434, 5.888) in Rs; p = 0.06, and average kurtosis was 3.27 (2.505, 4.189) in NRs vs. 4.14 (3.043, 5.223) in Rs; p = 0.08. Findings were consistent with greater tumour heterogeneity in NRs compared to Rs.

Conclusions

Texture parameters of SD, entropy and kurtosis derived from pre-treatment CT images of T790M+ mNSCLC may reflect tumour heterogeneity and have potential to predict for response to osimertinib.

Legal entity responsible for the study

Centralised Institutional Review Board - SingHealth Research.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Selected Poster Presentation Poster Display session

4P - Novel applications of MVA to improve outcomes in immunooncology (ID 143)

Presentation Number
4P
Lecture Time
17:30 - 17:35
Speakers
  • C. Heery
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
17:30 - 18:00
Authors
  • C. Heery
  • C. Pico-Navarro
  • T. Adams
  • L. Bauman
  • J. Medina
  • M. Hinterberger
  • A. Heiseke
  • H. Lauterbach
  • H. Hochrein

Abstract

Background

Our understanding of the interaction between the host immune system and cancer has evolved rapidly over the previous 10 years due to the clinical success induced by checkpoint inhibition. Previous immunologic work can now be realized in combination strategies. Modified Vaccinia Ankara (MVA) offers significant opportunities due to its natural induction of innate and adaptive immunity, large payload, and excellent safety profile.

Methods

MVA vectors were administered subcutaneously (SC), intravenously (IV) or intratumorally (IT) into tumor-bearing mice. Cytokine secretion profile in serum was assessed by Luminex analysis. NK and T cell infiltration and activation in various organs and cytolytic activity against target cells were determined by flow cytometry-based assays. PD-1 immune checkpoint blockade (ICB), low dose cyclophosphamide, tumor-targeting Abs or 15 Gy radiotherapy were administered along with IV MVA.

Results

Recombinant MVA (rMVA) in which tumor antigens and costimulatory molecules are encoded can be customized for maximal effect by route of administration. rMVA administered intravenously (IV) causes superior induction of antigen specific T cells, cytokines and NK cells than previously seen with subcutaneous or intramuscular routes. Encoding CD40L in addition amplifies the effects and efficacy improves in relevant models. This is dependent on T cells and NK cells, indicating a potential solution to one tumor-resistance mechanism, MHC loss and/or mutation. Furthermore, the combination of rMVA with tumor targeting antibodies, checkpoint inhibition, radiotherapy or chemotherapy often showed additional synergistic therapeutic effects. Administration of MVA alone intratumorally (IT) causes innate immune activation through toll like receptors (TLRs) as well as the cGAS / STING pathway. Recombinant antigen encoding rMVA improves systemic and local antigen-specific T cell responses. These effects can be bolstered by encoding certain costimulatory molecules.

Conclusions

IV and IT recombinant MVA may offer off the shelf solutions to resolve many of the host – tumor immunity interactions that result in lack of efficacy of checkpoint inhibition alone in most patients. Bavarian Nordic plans to initiate clinical trials with existing agents in 2019 applied IV and IT and will create novel constructs to maximize clinical effect, planned to initiate in 2020 and beyond.

Legal entity responsible for the study

Bavarian Nordic, Inc.

Funding

Bavarian Nordic, Inc.

Disclosure

C. Heery: Employee and shareholder: Bavarian Nordic, Inc. C. Pico-Navarro, T. Adams, L. Bauman, J. Medina, M. Hinterberger, A. Heiseke, H. Lauterbach, H. Hochrein: Employee of Bavarian Nordic.

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Selected Poster Presentation Poster Display session

9P - Safety profile and therapeutic efficacy of one cycle of [177Lu]prostate-specific membrane antigen (PSMA) in end stage metastatic castration-resistant prostate cancer patients with low performance status (ID 79)

Presentation Number
9P
Lecture Time
17:40 - 17:45
Speakers
  • M. Gupta
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
17:30 - 18:00
Authors
  • M. Gupta
  • P. Choudhury
  • S. Rawal
  • H. Goel
  • V. Talwar
  • K. Dutta
  • A. Singh

Abstract

Background

Prostate cancer patients with distant metastasis have poor prognosis and develop resistance to all standard drugs at various time intervals. Therapeutic options which can alleviate symptoms and prolong survival are required for these patients. [177Lu]prostate-specific membrane antigen ([177Lu]PSMA) is a novel drug based on a theranostic concept. Here, we have presented the safety and efficacy profile of one cycle of [177Lu]PSMA in metastatic castration-resistant prostate cancer (mCRPC) patients who have exhausted all standard therapeutic options.

Methods

Twenty two patients treated with at least first line anti-androgens and docetaxel were treated with one cycle of [177Lu]PSMA therapy on a compassionate basis. Haemoglobin, total leukocyte counts, platelets and serum creatinine for toxicity profile while prostate specific antigen (PSA), Eastern Cooperative Oncology Group (ECOG) performance status, visual analogue scale (VAS) and analgesic quantification scale (AQS) for therapeutic efficacy were recorded pre and 8 weeks post therapy. Wilcoxon signed-rank and ANOVA tests were used for statistical analysis.

Results

Partial response (PR), stable disease (SD) and progressive disease (PD) for PSA were seen in 5 (22.7%), 13 (59.1%) and 4 (18.2%) patients, respectively, treated with mean 6.88GBq dose of [177Lu]PSMA. 8/22 (36.4%) patients showed ≥ 30% drop in PSA. Grade 3 haemoglobin toxicity was seen in 5/22 (22.7%) patients. No patient developed grade 4 haemoglobin toxicity. No patients had grade 3 or 4 leukocytopenia or thrombocytopenia. Wilcoxon signed-rank test showed statistically significant (p < 0.05) difference in pre- and post-treatment ECOG, VAS, AQS scores while it was not significant for PSA (P > 0.05). ANOVA test showed a statistically significant difference in mean doses of [177Lu]PSMA used in the three PSA response groups while the difference was non-significant for other variables.

Conclusions

We conclude that [177Lu]PSMA therapy delivers adequate pain palliation in all end-stage mCRPC patients and it has a potential to become an effective therapeutic option in properly selected patients.

Legal entity responsible for the study

Manoj Gupta.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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30P - Dynamic change in the distribution of cancer types in oncology phase I trials (ID 161)

Presentation Number
30P
Lecture Time
17:50 - 17:55
Speakers
  • J. Sato
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
17:30 - 18:00
Authors
  • J. Sato
  • K. Itahashi
  • T. Shimizu
  • T. Koyama
  • S. Kondo
  • Y. Fujiwara
  • N. Yamamoto

Abstract

Background

Insufficient information is available on cancer types among patients enrolled in all-comer phase I oncology trials. We evaluated the global trends in cancer types of patients in these trials, including time-dependent changes and regional differences among North America, Europe, and Asia.

Methods

The PubMed database was searched to identify single-agent phase I trials published between 1991 and 2015, which enrolled patients with any type of solid tumor. The inclusion and exclusion criteria were predefined for article selection; trials recruiting from specific patient populations were excluded from the analysis.

Results

We identified 866 eligible clinical trials, which enrolled a total of 29,112 patients with advanced solid tumors. The selected trials were conducted mainly in North America (55.5%), Europe (27.8%), and Asia (10.5%). The distribution of cancer types in phase I trials was considerably different from cancer-related incidence and mortality. Colorectal cancers (n = 7,510, 25.8%) were the most prevalent in phase I trials, followed by lung cancer (n = 3,212, 11.0%), sarcoma (n = 1,756, 6.0%), breast cancer (n = 1,623, 5.6%), renal cancer (1589, 5.5%), and ovarian cancer (1473, 5.1%). The proportion of patients with either colorectal or lung cancer decreased with time. The proportion of trials, in which patients with either of these two cancers accounted for ≥50% of the total enrolled patients in each trial, had also decreased as follows: 31/67 trials (46.3%) from 1991 to 1995, 58/142 (40.8%) from 1996 to 2000, 59/223 (26.5%) from 2001 to 2005, 38/189 (20.1%) from 2006 to 2010, and 41/245 (16.7%) from 2011 to 2015. These trends were consistent across the three regions, with an increase in the proportion of various types of cancer enrolled in phase I trials.

Conclusions

The distribution of cancer types among patients enrolled in all-comer phase I trials has changed dramatically. Patients with common types of cancer, with poor general condition and vital organ dysfunction after multiple lines of therapy, are likely not to participate in phase I trials.

Legal entity responsible for the study

Noboru Yamamoto.

Funding

Has not received any funding.

Disclosure

T. Shimizu: Consulting: Takeda Oncology; Honoraria: ONO, ONO Pharma Taiwan, Boehringer Ingelheim, Taiho, Chugai; Research funding: Takeda Oncology, PharmaMar, BMS Japan, Daiichi Sankyo, SymBio, Five Prime Therapeutics, 3D Medicine. S. Kondo: Research funding: AstraZeneca, Eli Lilly, Pfizer. Y. Fujiwara: Consulting: ONO, BMS Japan; Participation in speakers’ bureau: ONO, BMS Japan, MSD, Taiho; Research funding: AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Lilly Japan, Novartis, BMS Japan, MSD, Merck Serono, Abbvie, Incyte. N. Yamamoto: Consulting: Eisai, Takeda, Otsuka, OncoTherapy; Speakers’ bureau: BMS, Pfizer, AstraZeneca, Lilly, ONO, Chugai; Funding: Chugai, Taiho, Eisai, Quintiles, Astellas, Novartis, Daiichi Sankyo, Boehringer, Takeda, Kyowa Kirin, Bayer, Pfizer, BMS, ONO.

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1P - PIWI proteins play oncogenic functions in pancreatic cancer (ID 142)

Presentation Number
1P
Lecture Time
18:00 - 18:05
Speakers
  • W. Li
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • W. Li
  • J. Martinez Useros
  • M. Fernández-Aceñero
  • N. García Carbonero
  • J. García-Foncillas

Abstract

Background

Human homologues of PIWI proteins identified are PIWIL1, PIWIL2, PIWIL3 and PIWIL4 (Sasaki et al. 2003). Aberrant expression of these proteins has been associated with hallmarks of cancer, and have also a potential prognostic and diagnostic markers for different cancers (Suzuki et al. 2012). However, their functional and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unknown. The purpose of this study was to dissect the role of PIWI proteins and their prognostic relevance.

Methods

PIWI proteins expression were analyzed by western blot in human PDAC derived cell lines and one non-transformed pancreatic cell line. Functional experiments were performed with PIWIL3 and/or PIWIL4 downregulated PDAC derived cell lines and one non-transformed cell line. Immunohistochemistry was performed to evaluate expression of PIWI proteins in 124 PDAC samples from Fundacion Jimenez Diaz Hospital, and with 124 validation cohort from TGCA. Then, association between PIWI proteins expression and survival was assessed.

Results

Only PIWIL3 and PIWIL4 showed differential expression in PDAC cell lines. Both wound-healing and transwell assay showed a decrease in migration ratio after PIWIL3 and/or PIWIL4 downregulation (P < 0.05). Furthermore, both PIWIL3 and/or PIWIL4 are necessary for the maintenance of undifferentiated phenotype highlighted by a reduction in size and number of pancreatic spheres after PIWIL3 and/or PIWIL4 downregulation (P < 0.05). On the other hand, PIWIL1 associated with shorter survival (P = 0.056), and this finding was validated in the TGCA cohort (P = 0.021). PIWIL2 associated significantly to shorter survival (P = 0.046) in our training set, and validation set exhibited a high trend toward significance (P = 0.051). Although PIWIL3 and PIWIL4 did not show association with survival in our training set, validation set revealed a statistically significant association of PIWIL4 with shorter overall survival (P = 0.027).

Conclusions

The present study demonstrate that PIWIL3 and PIWIL4 regulates PDAC aggressiveness by inhibiting cell migration and regulate undifferentiated phenotype of cancer cells. Furthermore, PIWIL1, PIWIL2 and PIWIL4 are potential prognostic biomarkers in PDAC.

Legal entity responsible for the study

Fundación Instituto de Investigación Sanitaria - Fundación Jiménez Díaz (G-85874949).

Funding

Spanish Ministry of Economy and Competitiveness.

Disclosure

All authors have declared no conflicts of interest.

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5P - Establishment and application of a panel of PBMC-humanized mouse tumor models in cancer immunotherapy (ID 132)

Presentation Number
5P
Lecture Time
18:10 - 18:15
Speakers
  • L. Bourre
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • L. Zhang
  • S. Qi
  • H. Wu
  • L. Zhao
  • X. An
  • W. Tan
  • X. Fu
  • M. Qiao
  • Q. Shi
  • W. Yang

Abstract

Background

To meet the rapidly growing I/O market, the demands for fast, relevant and cost effective mouse tumor model systems are also increasing. We developed a panel of straightforward humanized tumor models, designated as MiXeno platform.

Methods

CrownBio has established a sizable collection of MiXeno models where human PBMCs were reconstituted in the mouse system for the evaluation in vivo activity of immune checkpoint inhibitors or immune-modulators. These MiXeno models were characterized with tumor response to anti-PD-1 and anti-CTLA4 antibodies, and onset of possible graft versus host disease (GVHD) or graft versus tumor response (GVT) under different settings. To engage both host immune system and tumor antigens, we have developed some specific Mixeno tumor models by inoculating tumor cells over-expressing specific anti-tumor antigens (e.g. EGFR, CD47, Braf or PD-L1) into PBMC-humanized immunocompromised mice. Moreover, to improve capacity and consistency of MiXeno platform, we are conducting studies to characterize and validate commercialized frozen PBMCs for MiXeno model establishment.

Results

Models with over-expression of a variety of tumor antigens (e.g. EGFR, CD47, Braf, PD-L1...) were used to develop specific Mixeno tumor models. Meanwhile, in order to overcome the limitation of PBMC shortage, commercialized PBMC has been purchase and implanted into several xenograft models, and exhibit consistent tumor growth with fresh PBMC, as well as human immune component reconstitution. Up to date, a variety of test articles of different categories, including checkpoint inhibitors, T cell modulators and bispecific T cell engagers (e.g. EpCam-CD3, CD47/CD3, BCMA/CD3) have been evaluated using this platform. Merchandized I/O drugs, such as Pembrolizumab, are being tested in commercialized PBMC implanted immunocompromised mice.

Conclusions

MiXeno platform are valid model system for the human immuno-modulatory drugs including bispecific antibodies evaluation and will be optimized by introduction of specific Mixeno tumor models, commercial PBMC and B2M mice.

Legal entity responsible for the study

CrownBio.

Funding

CrownBio.

Disclosure

L. Bourre, L. Zhang, S. Qi, H. Wu, L. Zhao, X. An, M. Qiao, Q. Shi, W. Yang: Employee: CrownBio. All other authors have declared no conflicts of interest.

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6P - Prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ID 197)

Presentation Number
6P
Lecture Time
18:20 - 18:25
Speakers
  • S. Amaral
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • S. Amaral
  • M. Casal Moura
  • J. Carvalho
  • A. Chaves
  • E. Jesus
  • G. Sousa

Abstract

Background

Immunotherapy with programmed death receptor-1 (PD-1) antibodies has changed the paradigm of advanced NSCLC treatment. These checkpoint inhibitors showed better outcomes compared with standard treatment but reliable predictive markers are still lacking. High pre-treatment NLR and PLR have been associated with poor prognosis in several tumor types and recent studies suggest a potential role also in NSCLC. We thus conducted this study to evaluate the prognostic significance of NLR and PLR in our patients.

Methods

All patients with locally advanced and metastatic NSCLC treated with nivolumab and pembrolizumab from February 2016 to October 2018 were enrolled. NLR and PLR were determined by the division of neutrophils and platelets by lymphocytes in peripheral blood. Kaplan Meier method and Cox proportional hazardous analysis were conducted to assess the impact of NLR, PLR and other clinical factors on overall survival (OS) and progression free survival (PFS).

Results

Thirty-two patients were treated, 20 with nivolumab and 12 with pembrolizumab. Median age was 61 (40-82); 63% were male; 91% had an ECOG PS ≤ 2; 37% received ≥ 2 prior systemic therapies and 78% had stage IV disease. Increased NLR or PLR values above mean were independent predictive factors for decreased PFS (11 vs. 6 months, HR 3.33 95%CI 0.97 - 11.3, p = 0.056 and 12 vs. 6 months, HR 3.9 95%CI 1.19 - 12.8, p = 0.025, respectively). NLR and PLR values higher than percentil 25 were predictive factors, when used in combination, for decreased OS (21 vs. 11 months, HR 12.363 95% CI 1.303 - 117.291, p = 0.028 and 13 vs. 11 months, HR 3.9 95%CI 1.19 - 12.8, p = 0.025, respectively). Other clinical factors (i.e. histology, tobacco use, age, gender, ECOG PS, metastatic sites) did not present any implication for OS and PFS, as determined by multivariate analyses.

Conclusions

Elevated pre-treatment NLR and PLR are associated with shorter OS and PFS in our cohort independently of other prognostic factors. Our results reinforce the potencial role of these markers as a predictive factor of poor prognosis for NSCLC patients. Prospective studies are warranted to validate these findings.

Legal entity responsible for the study

Susana Rocha Amaral.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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