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Mini Oral session
Date
18.09.2020
Chairs
  • Jayesh Desai (Melbourne, VIC, Australia)
  • Ulrik N. Lassen (Copenhagen, Denmark)
  • Elena Garralda (Barcelona, Spain)
Mini Oral - Developmental therapeutics Mini Oral session

Open & welcome

Speakers
  • Jayesh Desai (Melbourne, VIC, Australia)
Mini Oral - Developmental therapeutics Mini Oral session

529MO - Activity, safety and circulating tumour DNA (ctDNA) dynamics of paradox breaker BRAF inhibitor PLX8394 in patients with advanced cancer

Presentation Number
529MO
Speakers
  • Mohamed A. Gouda (Houston, United States of America)

Abstract

Background

PLX8394, a second generation BRAF inhibitor, does not induce paradoxical activation and blocks signaling from both monomeric BRAFV600 and dimeric BRAFnon-V600 alterations.

Methods

A phase I/II study of oral PLX8394 with or without an oral CYP3A4 inhibitor, cobicistat (150 mg daily) to enhance systemic exposure, enrolled patients (pts) with advanced solid tumours to establish recommended phase II dose (R2PD) and dose-limiting toxicities (DLT). Dynamic changes in plasma ctDNA using droplet digital PCR (ddPCR) and targeted next-generation sequencing (NGS) were compared to treatment outcomes.

Results

69 pts (BRAFV600, 43; BRAFnon-V600, 17; non-BRAF, 9; colorectal cancer, 30%; melanoma, 14%) were treated with escalating doses of PLX8394 (450-1,800 mg BID) with or without cobicistat. Grade 3 (G3) AST elevation (900 mg BID) was the only DLT. Other >G3 toxicities occuring in more than 1 pt included ALT (4), AST (2), bilirubin (3), and diarrhea (2). The RP2D was declared at 900 mg BID. Coadministration of cobicistat resulted in 2-3-fold increase in PLX8394 systemic exposure, with dose dependent increase. Partial responses (-32% to -100%) lasting up to 56 months were observed in 10 pts (BRAFV600, 9; BRAF fusion, 1; prior BRAF and MEK inhibitors, 2) of 46 pts with BRAF alterations. Dynamic changes in BRAFV600-mutant ctDNA in 11 pts with available serial samples for ddPCR testing demonstrated that the median variant allele frequency (VAF) was lower at baseline, on day 21 of cycle 1 and at the first restaging in pts without progression vs. those with progression (p=0.02, p=0.05, p=0.02, respectively). Pts with detectable ctDNA at any timepoint had a shorter median progression-free survival (p<0.04). Increase in ctDNA VAF preceded or co-occurred with progression in 6 pts (67%). Targeted NGS of serially collected ctDNA samples from 16 pts detected broad spectrum somatic alterations in 14 samples and clonal evolution corresponded with the clinical course.

Conclusions

PLX8394 and cobicistat demonstrated a favorable safety profile and encouraging activity in patients with advanced cancers with BRAF class I and II alterations. Dynamic changes in ctDNA were predictive of clinical outcomes.

Clinical trial identification

NCT02428712.

Legal entity responsible for the study

Plexxikon.

Funding

Plexxikon.

Disclosure

E.J. Sherman: Advisory/Consultancy, Research grant/Funding (institution): Regeneron; Advisory/Consultancy: Eisai; Advisory/Consultancy: Novartis; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Lilly. A. Parikh: Advisory/Consultancy: Natera; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy: Puretech; Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Guardant Health; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Array; Research grant/Funding (institution): Tesaro. S. Kummar: Advisory/Consultancy: Bayer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: HarbourBioMed; Advisory/Consultancy: Genome & Company; Advisory/Consultancy: Springworks Therapeutics; Advisory/Consultancy: Corvus Pharmaceuticals; Advisory/Consultancy: Varian; Leadership role, Co-Founder: PathomIQ . C. Zhang: Leadership role, Full/Part-time employment: Plexxikon. P. Severson: Full/Part-time employment: Plexxikon. K. Inokuchi: Full/Part-time employment: Plexxikon. M. Silverman: Advisory/Consultancy: Plexxikon. G. Bollag: Leadership role, Full/Part-time employment: Plexxikon. F. Janku: Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): BioMed Valley Discoveries; Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Piqur; Research grant/Funding (institution): Symphogen; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): FujiFilm Corporation; Research grant/Funding (institution): Astex; Research grant/Funding (institution): Asana; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Agios; Research grant/Funding (institution): Proximagen; Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: Asana; Advisory/Consultancy: Deciphera; Advisory/Consultancy: IFM Therapeutics; Advisory/Consultancy: Synlogic; Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Ideaya; Advisory/Consultancy: PureTech Health; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Cardiff Oncology; Advisory/Consultancy: Immunomet; Advisory/Consultancy: Jazz Pharmaceuticals; Advisory/Consultancy: Sotio. All other authors have declared no conflicts of interest.

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Mini Oral - Developmental therapeutics Mini Oral session

530MO - Clinical benefit in biomarker-positive patients (pts) with locally advanced or metastatic solid tumours treated with the PARP1/2 inhibitor pamiparib in combination with low-dose (LD) temozolomide (TMZ)

Presentation Number
530MO
Speakers
  • Emiliano Calvo (Madrid, Spain)

Abstract

Background

DNA damage caused by the alkylator TMZ can sensitize tumors to PARP inhibitors. Pamiparib, an investigational oral PARP1/2 inhibitor, has shown PARP-DNA complex trapping activity, brain penetration, and synergistic cytotoxicity with LD TMZ in nonclinical studies and preliminary antitumor activity in pts with solid tumors.

Methods

This ongoing phase Ib study consists of a dose-escalation (3+3 design) and dose-expansion phase. In dose escalation, pts received pamiparib 60 mg PO BID on Days 1-28 and LD TMZ at escalating doses PO QD on Days 1-7, 1-14, or 1-28 of each 28-day cycle. Dose-expansion pts, including pts with gastric cancer and SCLC with 1-2 prior lines of chemotherapy, were treated at the recommended phase II dose of pamiparib 60 mg PO BID on Days 1-28 and LD TMZ 60 mg PO QD on Days 1-7. Tumor assessments occurred every 8 weeks. Endpoints were safety/tolerability (CTCAE v4.03) and antitumor activity (RECIST v1.1). Biomarker assessments included determination of DDR mutational status (SNV/CNV homozygous loss) of 16 core DDR genes in circulating tumor DNA and genomic instability score (GIS) by the Myriad myChoice® HRD test. Herein, we present data from the biomarker analysis.

Results

As of 10 April 2020, 114 pts were enrolled (n=66, dose escalation; n=48, dose expansion). Median follow-up was 8.5 mo (range: 0.3, 26.5). Of 36 pts analyzed for GIS, 11 (31%) were GIS positive (GIS+ ≥33), with an ORR of 82% and disease control rate (DCR) of 91% across multiple tumor types. Antitumor activity was observed in BRCA m/GIS+ (n=5; ORR and DCR, 100%) and BRCA wt/GIS+ pts (n=6; ORR, 67%; DCR, 83%). Responses were observed in 3 GIS pts with pancreatic cancer, pheochromocytoma, and nonsquamous NSCLC (ORR=12%; DCR, 52%). Of 104 pts analyzed for DDR mutational status, 27 (26%) were DDR+, with an ORR of 26% and DCR of 52%. In DDR pts, ORR was 14% and DCR was 67%. Five pts were both GIS+ and DDR+.

Conclusions

In this limited subset of pts analyzed for GIS status, GIS+ pts derived superior benefit from pamiparib + LD TMZ, irrespective of BRCA status. GIS status appears to be the most robust biomarker to predict response to pamiparib + LD TMZ.

Clinical trial identification

NCT03150810.

Editorial acknowledgement

Writing and editorial assistance was provided by Regina Switzer, PhD, Cathy R. Winter, PhD, and Elizabeth Hermans, PhD (OPEN Health Medical Communications, Chicago. IL) and funded by the study sponsor.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd. The UK sites are supported as Experimental Cancer Medicine Centres by Cancer Research UK and Departments of Health.

Disclosure

M. Johnson: Research grant/Funding (institution): AbbVie, Acerta, Adaptimmune, Apexigen, Array Biopharma, AstraZenca, Atreca, BeiGene, Birdie, Boehringer Ingelheim, Checkpoint Therapeutics, Corvus Pharmaceuticals, CytomX, Daiichi Sankyo, Dynavax, Lilly, EMD Serono, Genentech/ Roche, Genmab, Genocea Bio; Advisory/Consultancy, Spouse: Astellas, Otsuka; Advisory/Consultancy, To institution: AbbVie, Achilles Therapeutics, AstraZenca, Atreca, Beohringer Ingelheim, Calithera Biosciences, Genentech, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Lilly, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Th; Travel/Accommodation/Expenses: AbbVie, Astellas, AstraZenca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, EMD Serono, BMS, Exelixis, Genentech/Roche, Incyte, Merck, Pfizer, Sysmex Inostics, Vapotherm, Janssen, Lilly, Novartis, Sanofi. S. Goel: Non-remunerated activity/ies, - I have a patent with a co-inventor, John Mariadason, Ph.D, entitled \"Method Of Determining The Sensitivity Of Cancer Cells To EGFR Inhibitors Including Cetuximab, Panitumumab And Erlotinib.\", Patent No. 20090258364: Patent. S.R. Chandana: Research grant/Funding (institution): BeiGene, Ltd.. M.D. Galsky: Shareholder/Stockholder/Stock options: Rappta Therapeutics; Advisory/Consultancy: Biomotiv, Janssen, Dendreon, Merck, GlaxoSmithKline, Lilly, Astellas Pharma, Genentech, BMS, Novartis, Pfizer, EMD Serono, AstraZenca, Seattle Genetics, Incyte, Aileron Therapeutics, Dracen, Inobio Pharmaceuticals, NuMab, Dragonfly Therapeutics; Research grant/Funding (institution): Janssen Oncology, Dendreon, Novartis, BMS, Merck, AstraZenca, Genentech/Roche; Non-remunerated activity/ies, Patent: Methods and compositions for treating cancer and related methods. Mount Sinai School of Medicine July 2012 Application number: 20120322792. E. Calvo: Advisory/Consultancy, Research grant/Funding (institution): Boehringer-Ingelheim, PsiOxus, Nanobiotix Janssen, AbbVie, Janseen-Cilag, Seattle Genetics, Pierre Fabre, Cerulean Pharma, EUSA, Celgene, AstraZeneca; Research grant/Funding (institution): Roche/Genentech, BMS, PharmaMar, PUMA, Sanofi, Lilly, Pfizer, Merck, Nektar, Amcure, Amgen, AstraZenca, Principia Bayer, CytomX, H3, Incyte, Kura, LOXO, Macrogenenics, Menarini, Merck Serono, Merus, Millenium, Rigontec, Tahio, Tesaro, BeiGene; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Leadership role, Full/Part-time employment, Officer/Board of Directors: START; Honoraria (self), Full/Part-time employment: HM Hospitals Group; Leadership role, Ownership: Oncoart Associated, International Cancer Consultants; Advisory/Consultancy: Nanobiotix, PsiOxus Therapeutics, AbbVie, Guidepoint Global, GLG, Pfizer, Servier, Amcure, ; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche Genentech; Officer/Board of Directors, President and founder: NPO Foundation Intheos (Investigational Therapeutics in Oncological Sciences). H. Park: Research grant/Funding (institution): BeiGene, Ambryx, Amgen Array BioPharma Bayer BeiGene BJ Bioscience Bristol-Myers Squibb Daiichi Pharmaceutical Eli Lilly EMD Serono Five Prime Therapeutics Genentech Gilead Sciences GlaxoSmithKline Hoffman-LaRoche Immunomedics Incyte MacroGenics Medimmune. T. Arkenau: Research grant/Funding (institution): Beigene, Roche, Bayer. A. Cervantes: Research grant/Funding (institution): Beigene, Genentech, Fibrogen, Amcure, Sierra Oncology, AstraZenca, Medimmune, B L. Fariñas-Madrid: Speaker Bureau/Expert testimony: MSD, AstraZenca; Advisory/Consultancy: Tesaro; Speaker Bureau/Expert testimony: Roche. S. Fu: Research grant/Funding (institution): NIH/NCI, NeuPharma, Inc, Novartis, OncoMed Pharmaceuticals, Parexel International, LLC, Sellas Life Sciences Group, Soricimed Biopharma, Inc, Tolero Pharmaceuticals; Research grant/Funding (institution): AstraZenca, Anaeropharma Science, Arrien Pharmaceuticals, BeiGene, BioAtla, LCC; Research grant/Funding (institution): Abbisko, Boehringer Ingelheim, Eli Lilly & Co, Hookipa Biotech, Huya Bioscience International, IMV, Inc, Innovent Biologics, Co, Ltd, Macrogenics, Medivir AB, Millennium Pharmaceuticals, Inc, Nerviano Medical Sciences. R. Plummer: Honoraria (self): BeiGene. J. Evans: Research grant/Funding (institution): BeiGene, AstraZeneca, Basilea, MiNa Therapeutics, Pfizer, Sierra, Lilly, Novartis, Bicycle Therapeutics, Halozyme, Johnson & Johnson, Vrtex, CytomX, Plexxikon, Boehringer, Athenex, Adaptimmune, Verastem, Immunocore, Iovance, Berg, BiolinerX; Honoraria (institution), Research grant/Funding (institution): Bayer, Celgene, BMS, Clovis, Eisai, Genentech, GlaxoSmithKline, Immunova, Nucana, Karus Therapeutics, Otsuka, Roche, MSD, Medivir. L. Horvath: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Connected Medical Solutions; Research grant/Funding (institution), Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: Janssen-Cilag; Honoraria (self), Shareholder/Stockholder/Stock options: Imagion Biosystems. A. Prawira: Research grant/Funding (institution): BeiGene, Arcusbio, Akesobio, Pfizer, Bayer, Mapkure, Roche/Genentech, BMS, Apollomics, CStone, Macrogenics, Five Prime, Henlius, Eli Lilly, Virogin, Janssen, AstraZenca, Bio Oncology, MSD, Eisai. K. Qu: Shareholder/Stockholder/Stock options, Full/Part-time employment: BeiGene, Ltd. R. Pelham: Full/Part-time employment: BeiGene, Ltd. All other authors have declared no conflicts of interest.

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Mini Oral - Developmental therapeutics Mini Oral session

531MO - VHIO immune gene-expression signature (VIGex) to enrich patient selection in immunotherapy (IT) phase I clinical trials

Presentation Number
531MO
Speakers
  • Alberto Hernando-Calvo (Barcelona, Spain)

Abstract

Background

While the number of phase I clinical trials testing IT agents continues to increase exponentially, few trials include an enrichment strategy to optimize response. We have developed the VIGex test, a gene expression panel using RNA data, developed from a pan-cancer cohort of 649 tumor samples and a set of 51 immune-related genes (including genes related to interferon-γ signalling, T-cell exhaustion, Tregs, tumor associated macrophages (TAM) and antiinflammatory cytokines) (submitted ESMO2020).

Methods

We conducted a retrospective review of the pts treated with IT at VHIOś Phase 1 Unit from 2018-2019 who had VIGex performed prior to IT. 2 clusters (hot (HT) and cold (CT)) were defined by VIGex and correlated with clinical benefit rate (CBR) and progression free survival (PFS). A subset of CT enriched for TGFb signaling and TAMs associated genes was identified. CBR was defined as the sum of partial responses and stable disease (SD) for ≥4 months (m). The primary objective was to describe preliminary signs of predictive value from VIGex.

Results

Overall, 61 pts were identified, median age was 60 years, all ECOG ≤1, 30 treated with single IT agents (49%) and 31 with IT combinations (51%). Median prior lines were 2 (1-3) and median follow-up was 5.8 m. VIGex was performed on primary tumor (59%) or metastases (41%). In the whole cohort, CBR was 25% (5 pts (8%) achieved a partial response (PR) and 10 pts (17%) achieved a prolonged SD). Median PFS and OS were 1.7 m (CI95% 1.4 – 2.3) and 6.7 m (CI95% 4.5 – 9.5) respectively. VIGex algorithm classified 20 pts as HT and 41 pts as CT. CBR was 55% in the HT group and 18% for CT group (p= 0.016 Fisherś exact test). Interestingly, CT subgroup enriched for TGFb signaling and TAMs had a 0% CBR. Significantly longer progression free survival (PFS) was also observed for HT vs. CT clusters (HR: 0.5; 0.28 – 0.89; p = 0.02). Of note, significance was maintained after adjustment in a multivariate model for other prognostic variables (age, ECOG and single vs. combination IO treatments).

Conclusions

Our results suggest that VIGex may be a predictive marker of IT benefit in phase I clinical trials. With upcoming early phase IT treatments, VIGex could become a promising tool to enrich patientś selection and improve clinical outcomes.

Legal entity responsible for the study

Vall d'Hebron Institute of Oncology.

Funding

Comprehensive Program of Cancer Immunotherapy and Immunology (CAIMI) supported by the Banco Bilbao Vizcaya Argentaria Foundation (BBVA Foundation) (grant 89/2017). La Caixa Foundation (LCF/PR/CEO7/50610001). Cellex Foundation providing research facilities and equipment.

Disclosure

A. Hernando-Calvo: Travel/Accommodation/Expenses: Kyowa Kirin. I. Braña: Advisory/Consultancy: Orion Pharma; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: AstraZenca ; Speaker Bureau/Expert testimony: Merck Serono; Advisory/Consultancy: Rakutan Pharma; Speaker Bureau/Expert testimony: Roche. O. Saavedra Santa Gadea: Travel/Accommodation/Expenses: Kyowa Kirin; Travel/Accommodation/Expenses: MSD. M. Vieito: Advisory/Consultancy: Debio; Advisory/Consultancy: Roche; Advisory/Consultancy: TFS; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Merck Serono. A.B. Azaro Pedrazzoli: Advisory/Consultancy: Orion Pharma; Advisory/Consultancy: Ambcure GmbH; Research grant/Funding (self): Ambcure GmbH. I. Matos: Research grant/Funding (self), ESMO Research Fellowship: Roche. C. Saura: Advisory/Consultancy: AstraZenca; Advisory/Consultancy: Celgene; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: F-Hoffmann La Roche Ltd; Advisory/Consultancy: Genomic Health; Advisory/Consultancy, Research grant/Funding (institution): Merck, Sharp and Dhome España S.A; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Odonate Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Philips Healthwork; Advisory/Consultancy: Pierre Fabre ; Advisory/Consultancy: priME Oncology; Advisory/Consultancy, Research grant/Funding (institution): Puma; Advisory/Consultancy: Synthon ; Advisory/Consultancy: Sanofi Aventis; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Eli Lilly and Company; Research grant/Funding (institution): Genetech; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Piqur Therapeutics; Research grant/Funding (institution): Zenith Pharma; Research grant/Funding (institution): Roche. G. Argiles Martinez: Advisory/Consultancy, Research grant/Funding (institution): Hoffman La-Roche; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Servier; Advisory/Consultancy: Amgen; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Menarini; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Boston Pharmaceuticals; Research grant/Funding (institution): Genentech. E. Elez: Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Hoffman La-Roche; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Bristol Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Servier; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Serono; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Array; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Honoraria (institution): MSD; Honoraria (institution): AbbVie; Honoraria (institution): GSK; Honoraria (institution): AstraZeneca; Honoraria (institution), Advisory/Consultancy: Novartis; Honoraria (institution): Boehringer Ingelheim. E. Munoz Couselo: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck Sharp and Dohme; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self): Sanofi. E. Felip: Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Janssen; Speaker Bureau/Expert testimony: Medscape; Advisory/Consultancy: Merck KGaA; Advisory/Consultancy: Merck Sharp and Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Speaker Bureau/Expert testimony: priME; Advisory/Consultancy: Roche; Advisory/Consultancy: Samsung; Advisory/Consultancy: Takeda; Speaker Bureau/Expert testimony: Touchime; Advisory/Consultancy: GSK; Advisory/Consultancy: Bayer; Research grant/Funding (institution): Grant for Oncology Innovation; Research grant/Funding (institution): Fundación Merck Salud. J. Seoane: Leadership role, Research grant/Funding (institution): Mosaic Biomedical; Research grant/Funding (institution): Northern Biologics; Research grant/Funding (institution): Roche/Glycart; Research grant/Funding (institution): Hoffmann La Roche. J. Tabernero: Advisory/Consultancy: Array Biopharma ; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: BeiGene; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Chugai; Advisory/Consultancy: Genentech; Advisory/Consultancy: Genmab A/S; Advisory/Consultancy: Halozyme; Advisory/Consultancy: Imugene Limited; Advisory/Consultancy: Inflection Biosciences Limited; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Kura Oncology; Advisory/Consultancy: Lilly; Advisory/Consultancy: MSD; Advisory/Consultancy: Menarini; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Merus; Advisory/Consultancy: Molecular Partners; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pectomyc; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Pharmacyclics; Advisory/Consultancy: ProteoDesign SL; Advisory/Consultancy: Rafael Pharmaceuticals; Advisory/Consultancy: F. Hoffmann-La Roche Ltd; Advisory/Consultancy: Sanofi; Advisory/Consultancy: SeaGen; Advisory/Consultancy: Seattle Genetics. A. Vivancos: Advisory/Consultancy: Sysmex; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Merck; Advisory/Consultancy: Roche; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Bayer; Licensing/Royalties: Ferrer; Research grant/Funding (institution): Debio; Advisory/Consultancy: Sysmex; Research grant/Funding (institution): Cellestia Biotech; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Chittern. E. Garralda: Research grant/Funding (institution): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Thermo Fisher; Advisory/Consultancy: Hoffmann La Roche; Research grant/Funding (institution): Ellipses Pharma; Advisory/Consultancy: Neomed Therapeutics; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Janssen Global Services; Advisory/Consultancy: SeaGen; Advisory/Consultancy: TFS; Research grant/Funding (institution): Alkermes; Advisory/Consultancy, Research grant/Funding (institution): Bristol Mayers Squibb; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck Sharp and Dohme; Travel/Accommodation/Expenses: Menarini; Travel/Accommodation/Expenses: Glycotope. All other authors have declared no conflicts of interest.

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Mini Oral - Developmental therapeutics Mini Oral session

Invited Discussant 529MO, 530MO and 531MO

Speakers
  • Jayesh Desai (Melbourne, VIC, Australia)
Mini Oral - Developmental therapeutics Mini Oral session

532MO - A phase Ib study of TQB2450 in combination with anlotinib in patients with advanced solid tumour

Presentation Number
532MO
Speakers
  • Ying Cheng (Changchun, Jilin, China)

Abstract

Background

Anlotinib, an antiangiogenic multi-target tyrosine kinase inhibitor, significantly improved clinical benefit in many solid tumours. TQB2450 is an engineered anti-programmed death-ligand 1 antibody. This study aimed to assess the safety and effect of TQB2450 plus anlotinib in patients with advanced solid tumour.

Methods

This phase Ib study, which included a dose-escalating phase and an expansion phase, enrolled patients with advanced or metastatic solid tumour who had standard treatment failure or no standard treatment between June 2019 and January 2020. Eligible patients were firstly enrolled into sequential dose-escalating cohorts including 10mg and 12mg anlotinib plus TQB2450 following the conventional 3+3 design. If the starting dose of 10mg anlotinib led to ≥2 dose-limiting toxicities (DLTs), 8mg anlotinib would be administered. After the dose-escalating phase completed, eligible patients were enrolled into the expansion cohort. The primary outcomes were safety and objective response rate (ORR).

Results

In the dose-escalating phase, the first 3 eligible patients received 10mg anlotinib plus TQB2450 had no DLTs in the first cycle, neither did the 3 patients who received 12mg anlotinib plus TQB2450. Then the expansion phase started, 16 patients were enrolled and received 12mg anlotinib plus TQB2450. Of the 22 patients included, there are 6 patients with small cell lung cancer (SCLC), 8 patients with non-small cell lung cancer, 2 patients with colorectal cancer, 2 patients with breast cancer, 2 patients with ovarian cancer, 1 patient with thymic carcinoma and 1 patient with cervical cancer. Of Those patients, ORR was 32.8% and Disease control rate was 81.8%. Four SCLC patient had PR and 1 SCLC patient had stable disease. Ten ≥3 grade AEs were observed (Table).

The ≥3 grade AEs

≥3 grade AEs 10mg anlotinib plus TQB2450, n=3 12mg anlotinib plus TQB2450, n=19
Hypertriglyceridemia 1 4
Dyspnea 1
Pericardial effusion 1
Oropharyngeal and gingival pain 1
Decreased lymphocyte count 1
Elevation of γ-glutamyltransferase 1

Conclusions

12mg anlotinib plus TQB2450 showed an acceptable safety profile and promising results in patients with advanced solid tumour. The phase Ib study is ongoing to investigate the safety and effect.

Clinical trial identification

NCT03897283.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Mini Oral - Developmental therapeutics Mini Oral session

533MO - Phase Ib study of BI 836880, a VEGF/Ang2-blocking nanobody®, in combination with BI 754091, an anti-PD-1 antibody: Initial results in patients (pts) with solid tumours

Presentation Number
533MO
Speakers
  • Nicolas Girard (Paris, France)

Abstract

Background

Preclinical studies have shown that combining anti-VEGF/Ang2 with anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumour cell destruction. BI 836880 is a humanized bispecific nanobody® that targets VEGF and Ang2, and BI 754091 is an anti-PD-1 antibody. Dose-finding trials of BI 836880 and BI 754091 in advanced solid tumours determined the recommended phase II dose (RP2D) for monotherapy as 720 mg q3w and 240 mg q3w, respectively. Here, we report results from a phase Ib study assessing BI 836880 in combination with BI 754091.

Methods

In part 1 (dose escalation), pts with locally advanced or metastatic (m) non-squamous NSCLC who progressed during/after completion of ≥2 cycles of platinum-based chemotherapy (CT) ± a checkpoint inhibitor (CPI) received BI 836880 plus fixed-dose BI 754091. RP2D was determined as BI 836880 720 mg plus BI 754091 240 mg q3w. In Part 2 (expansion phase), patients are recruited to one of 7 cohorts: mNSCLC after CPI monotherapy; mNSCLC after CT + CPI; mSCLC after CT ± CPI; immunotherapy-resistant m-melanoma; recurrent glioblastoma after 1st-line CT; HCC after prior sorafenib or lenvatinib; and previously untreated/unresectable HCC.

Results

At data cut-off (April 2020), 18 pts had received BI 836880 plus BI 754091 (14 in Part 1, 4 in Part 2); 11 males; median age 59 years, 13 had received prior CPI. Seven pts remain on treatment (including 1 treated for >12 months). 16 pts experienced an adverse event (AE; any-cause), most commonly (all%/G3%) hypertension (50/28), asthenia (33/6), vomiting, nausea and cough (each 33/0). No G4 AEs were reported; 2 G5 AEs occurred (1 general physical health deterioration and 1 tracheal haemorrhage). 6 pts had immune-related AEs (including G2 hypothyroidism; G2 pruritus, G2 vomiting, G1 papular rash). To date, 3 pts have achieved confirmed partial response (two NSCLC pts in Part 1, one 2nd-line HCC pt in Part 2), 10 pts had stable disease, 3 had progressive disease; data were not available for 2 pts.

Conclusions

The combination of BI 836880 and BI 754091 had a manageable safety profile, and preliminary antitumor activity was observed. Expansion cohorts are ongoing.

Clinical trial identification

NCT03468426.

Editorial acknowledgement

Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Jane Saunders, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this abstract.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

N. Girard: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy: MSD; Advisory/Consultancy: Takeda; Advisory/Consultancy: GSK; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Pharmamar; Travel/Accommodation/Expenses: MSD Oncology. M. Wermke: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Honoraria (self): Merck; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Kite Pharma; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Heidelberg Pharma; Travel/Accommodation/Expenses: Glenmark. F. Barlesi: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): BMS; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Lilly; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self): Merck Serono; Honoraria (self), Advisory/Consultancy: MSD Oncology; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Takeda; Advisory/Consultancy: Merck; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): ACEA Bioscience; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Eisai. D-W. Kim: Research grant/Funding (institution): Alpha Biopharma; Research grant/Funding (institution): AstraZenca/Medimmune; Research grant/Funding (institution): Boehringer-Ingelheim; Research grant/Funding (institution): Hanmi; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Merus; Research grant/Funding (institution): Mirati Therapeutics; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): ONO Pharmaceutical; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): TP Therapeutics; Research grant/Funding (institution): Xcovery; Research grant/Funding (institution): Yuhan; Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Daiichi Sankyo. F. Ghiringhelli: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Astra; Honoraria (self): Merck Serono; Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self), Travel/Accommodation/Expenses: Amgen; Honoraria (self): Bayer; Honoraria (self), Travel/Accommodation/Expenses: Servier. H.T. Landsteiner: Full/Part-time employment: Boehringer Ingelheim. G. Jayadeva: Full/Part-time employment: Boehringer Ingelheim. J. Alt: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Takeda. B. Hackanson: Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self): Takeda; Honoraria (self): Pfizer.

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Mini Oral - Developmental therapeutics Mini Oral session

534MO - First in human study of ONO-4578, a PGE2-receptor EP4 antagonist, in monotherapy and combination with PD-1 checkpoint inhibitor nivolumab in patients with advanced or metastatic solid tumours

Presentation Number
534MO
Speakers
  • Noboru Yamamoto (Chuo-ku, Japan)

Abstract

Background

Prostaglandin E2 (PGE2) contributes to immunosuppression in the tumour microenvironment through PGE2 receptor 4 (EP4). ONO-4578 is a novel, potent, and highly selective small-molecule antagonist of EP4. Our preclinical data showed that ONO-4578 promoted anti-tumour immunity and a combination of ONO-4578 and anti-PD-1 antibody resulted in enhanced anti-tumour effects in syngeneic mouse models compared with anti-PD-1 monotherapy. ONO-4578 in combination with Nivolumab may be useful in the treatment of cancer patients (pts).

Methods

This is a first-in-human, dose-escalation study. We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of ONO-4578 monotherapy (Part A) and combination with Nivolumab (Part B) in pts with advanced or metastatic solid tumours. Patients received ONO-4578 (30-100 mg, QD, orally), or a combination of ONO-4578 (2-60 mg, QD, orally) and Nivolumab (240 mg, i.v., Q2W). We evaluated pharmacological effect on ex vivo TNF-α release and urinary tetranor-PGEM.

Results

As of 6 Feb 2020, 10 pts received ONO-4578 monotherapy (1 pt at 30 mg, 3 pts at 60 mg, 6 pts at 100 mg), and 21 pts received a combination of ONO-4578 and Nivolumab (3 pts each at 2, 5, 10, 20, 40 mg and 6 pts at 60 mg of ONO-4578). DLTs occurred in 3 pts: grade (G) 3 duodenal ulcer at 100 mg in Part A; G3 erythema multiforme at 60 mg, G3 amylase increased and G4 lipase increased at 60 mg in Part B. MTD was not reached in either parts. Treatment was discontinued due to AEs for 2 pts in Part A (2 duodenal ulcers, duodenitis and gastritis) and 2 pts in Part B (erythema multiforme, amylase increased and lipase increased). ONO-4578 exposure was dose-proportional up to 100 mg and not interactive with nivolumab. Of 10 tumour-evaluable pts in Part A, no pts had complete or partial responses, and 3 pts had stable disease (SD). Of 21 tumour-evaluable pts in Part B, 1 pt (SCLC, ONO-4578 dose, 40 mg) had partial response (PR), and 5 pts had SD including 1 pt (PDAC, 2 mg) unconfirmed PR.

Conclusions

ONO-4578, both monotherapy and in combination with Nivolumab, was well tolerated. The MTD was not reached in patients with solid tumours.

Legal entity responsible for the study

ONO PHARMACEUTICAL CO., LTD.

Funding

ONO PHARMACEUTICAL CO., LTD. Bristol-Myers Squibb.

Disclosure

N. Yamamoto: Advisory/Consultancy, Research grant/Funding (institution): Eisai; Advisory/Consultancy, Research grant/Funding (institution): Takeda; Advisory/Consultancy: Otsuka; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Advisory/Consultancy: Cimic; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Chugai; Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eli Lilly; Speaker Bureau/Expert testimony, Research grant/Funding (institution): ONO; Speaker Bureau/Expert testimony: Sysmex; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Taiho; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Kyowa-Hakko Kirin; Research grant/Funding (institution): Janssen Pharma; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Merck; Research grant/Funding (institution): GSK. T. Koyama: Honoraria (self): Sysmex; Honoraria (self): Chugai. M. Nishino: Honoraria (self): AstraZeneca; Honoraria (self): BMS; Honoraria (self): Boehringer Ingelheim Japan; Honoraria (self), Honoraria (institution): Chugai; Honoraria (self), Honoraria (institution): Eli Lilly; Honoraria (self): MSD; Honoraria (self): ONO; Honoraria (self): Taiho. S. Iwasa: Honoraria (self), Research grant/Funding (institution): ONO; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self): Eli Lilly; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Merck Biopharma. S. Kondo: Research grant/Funding (institution): MSD; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): AZD; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Boehringer Ingelheim. K. Yonemori: Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self): Pfizer; Honoraria (self): Taiho; Advisory/Consultancy: Novartis; Advisory/Consultancy: Chugai; Advisory/Consultancy: Ono; Advisory/Consultancy: Takeda. T. Yoshida: Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: Chugai; Speaker Bureau/Expert testimony: Novartis; Research grant/Funding (institution): Ono; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): MSD; Research grant/Funding (institution): AbbVie. K. Tamura: Speaker Bureau/Expert testimony, Research grant/Funding (self): Eli Lilly; Speaker Bureau/Expert testimony, Research grant/Funding (self): Chugai; Speaker Bureau/Expert testimony, Research grant/Funding (self): Pfizer; Research grant/Funding (self): Daiichi Sankyo; Research grant/Funding (self): Sanofi; Research grant/Funding (self): MSD; Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Novartis; Research grant/Funding (self): Clovis Oncology. T. Ozaki: Full/Part-time employment: Ono pharmaceutical. M. Kondo: Full/Part-time employment: Ono pharmaceutical. T. Shimizu: Advisory/Consultancy, Research grant/Funding (institution): Millenium-Takeda; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): BMS; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Symbio Pharmaceuticals; Research grant/Funding (institution): 3D-Medicine; Research grant/Funding (institution): Chordia Therapeutics; Research grant/Funding (institution): Five Prime; Research grant/Funding (institution): PharmaMar. All other authors have declared no conflicts of interest.

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Mini Oral - Developmental therapeutics Mini Oral session

535MO - BGB-A333, an anti-PD-L1 monoclonal antibody, in combination with tislelizumab in patients with urothelial carcinoma

Presentation Number
535MO
Speakers
  • Juan Martin Liberal (Barcelona, Spain)

Abstract

Background

Preclinical studies have shown potential synergism from blocking both programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1). BGB-A333 is an investigational humanized monoclonal antibody against PD-L1 that has antitumor activity in xenograft models. Tislelizumab, a clinical-stage anti-PD-1 antibody, showed clinical activity in patients (pts) with advanced solid tumors. We report results from the expansion cohort (phase IIB) of an open-label phase I/II study (NCT03379259) of BGB-A333 plus tislelizumab in pts with previously treated advanced urothelial carcinoma (UC).

Methods

Patients received BGB-A333 1350 mg IV Q3W + tislelizumab 200 mg IV Q3W. Eligible pts had locally advanced or metastatic UC without prior PD-(L)1 therapy, could not tolerate or progressed during/after treatment with platinum-based chemotherapy, and had an ECOG performance status of ≤1. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Key secondary endpoints included duration of response (DoR) per RECIST v1.1, progression-free survival (PFS) estimated with Kaplan-Meier analysis, and the safety/tolerability profile evaluated by monitoring adverse events (AEs).

Results

As of 10 March 2020, 12 pts (median age, 69.5 yr; 92% male) with UC were enrolled; median study follow-up, 8.3 mo. Most pts (n=10, 83%) had 1 prior systemic therapy. Median duration of treatment for both BGB-A333 and tislelizumab was 5.5 mo (range: 1.2, 9.9). Confirmed ORR was 42% (95% CI: 15.2, 72.3); 3 pts had complete responses, 2 had partial responses, 4 had stable disease (SD; 2 had SD >6 mo), 2 had progressive disease, and 1 was not evaluable (due to missing postbaseline assessment). Median DoR was not reached; median PFS was 6.1 mo (95% CI: 1.9, not estimable). Across the entire study (n=39), treatment-related AEs (TRAEs) occurred in 19 pts. Of the 24 pts receiving combination treatment, four pts (including one with UC) had grade ≥3 TRAEs. One pt with UC had an immune-related AE (myositis); no pts with UC had a fatal TRAE.

Conclusions

BGB-A333 in combination with tislelizumab was well tolerated and demonstrated antitumor activity in pts with advanced UC.

Clinical trial identification

NCT03379259.

Editorial acknowledgement

Writing and editorial assistance was provided by Stephan Lindsey, PhD, and Elizabeth Hermans, PhD (OPEN Health Medical Communications, Chicago. IL), and funded by the study sponsor.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

J. Martin Liberal: Speaker Bureau/Expert testimony, lecture fees: Astellas; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Lecture fees, advisory fees, travel grant: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Lecture fees, advisory fees, travel grant: Merck Sharp & Dohme (MSD); Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Lecture fees, advisory fees, travel grant: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Lecture fees, advisory fees, travel grant: Pierre Fabre; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Lecture fees, travel grant: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Lecture fees, advisory fees, travel grant: Roche; Travel/Accommodation/Expenses, travel grant: Ipsen. P.C. Fong: Honoraria (self): AstraZeneca, Merck Sharp & Dohme; Advisory/Consultancy: Merck Sharp & Dohme; Speaker Bureau/Expert testimony: Janssen; Travel/Accommodation/Expenses: Pfizer. V. Moreno: Travel/Accommodation/Expenses, Personal Fees: BMS; Travel/Accommodation/Expenses, Personal Fees: Bayer; Travel/Accommodation/Expenses, Personal Fees: Pieris. J. Desai: Advisory/Consultancy: Amgen; Advisory/Consultancy: BeiGene; Advisory/Consultancy, Research grant/Funding (institution): Bionomics; Advisory/Consultancy: Eisai; Advisory/Consultancy: Lilly; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Roche; Research grant/Funding (institution): GlaxoSmitKline. B. Markman: Advisory/Consultancy: Novartis; Advisory/Consultancy: Amgen. M. Voskoboynik: Travel/Accommodation/Expenses, personal fees: MSD; Travel/Accommodation/Expenses, personal fees: AstraZenca. N. Budha: Shareholder/Stockholder/Stock options, Full/Part-time employment: BeiGene, Ltd. J. Wu: Shareholder/Stockholder/Stock options, Full/Part-time employment: BeiGene, Ltd. W. Shen: Full/Part-time employment: BeiGene, Ltd. M. Singh: Full/Part-time employment: BeiGene, Ltd. E. Calvo: Advisory/Consultancy, Research grant/Funding (institution): Boehringer-Ingelheim; Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): PsiOxus; Advisory/Consultancy, Research grant/Funding (institution): Nanobiotix Janssen; Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): PharmaMar; Research grant/Funding (institution): Puma, Sanofi, Lilly, Pfizer, Merck, Nektar; Advisory/Consultancy: Nanobiotix, AbbVie, AstraZenca, Guidepoint Global, GLG, PFizer, Servier, Amcure; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche/Genentech,; Honoraria (self), Full/Part-time employment: Hm Hospitals Group; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): Amcure; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Principia Bayer; Research grant/Funding (institution): CytomX; Research grant/Funding (institution): H3; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Kura; Research grant/Funding (institution): LOXO, Macrogenics, Menarini, Merck Serono, Merus, Millenium, Rigontec, Tahio, Tesaro; Advisory/Consultancy: Janssen-Cilag; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Cerulean Pharma; Advisory/Consultancy: EUSA; Advisory/Consultancy: Celgene; Full/Part-time employment, Officer/Board of Directors: START. All other authors have declared no conflicts of interest.

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Mini Oral - Developmental therapeutics Mini Oral session

Invited Discussant 532MO, 533MO, 534MOand 535MO

Speakers
  • Ulrik N. Lassen (Copenhagen, Denmark)
Mini Oral - Developmental therapeutics Mini Oral session

536MO - A phase I, first-in-human, safety, pharmacokinetic, and pharmacodynamic study of oral dubermatinib (TP-0903) in patients with advanced solid tumours

Presentation Number
536MO
Speakers
  • John Sarantopoulos (San Antonio, TX, United States of America)

Abstract

Background

AXL is upregulated in many solid tumors and may drive resistance to targeted cancer therapeutics, traditional chemotherapies, and immuno-oncology agents. Dubermatinib is a novel, orally administered small molecule AXL kinase inhibitor affecting mesenchymal-epithelial transition while targeting oncogenesis and chemoresistance.

Methods

Ph I enrolled 45 pts with advanced solid tumors across 9 dose levels (1.5-37mg/m2) and 50mg flat dose. The RPh2D was determined as 50mg dubermatinib QD 21/28 days based on dose-proportionate drug accumulation including metabolites, and thrombocytopenia. Five expansion cohorts enrolled 1) dubermatinib plus IO with progression after response (n=19); 2) dubermatinib plus EGFR inhibitor in EGFR+ NSCLC with progression after response (n=18); 3) KRAS+ CRC (n=47); 4) platinum refractory/resistant ovarian cancer (n=22); 5) BRAFmut/wt melanoma (n=13).

Results

In 125 patients receiving at least one 50mg dose the most frequently observed Gr3/4 AEs were anemia, diarrhea (7/5.6%); hyponatremia, dyspnea (5/4.0%); vomiting, ascites, fatigue, incr alkphos, decr potassium, PE (3/2.4%). PK values for plasma dubermatinib and active metabolites rose incrementally with dose (t½ 12-20hrs). Day 1 Cmax and AUC0-24 (50mg) were 14.8 ng/mL and 160.9 ng*hr/mL, respectively. Increases were observed at Day 21. Clinical activity included 4 PRs: 2 NSCLC (1 pt 37mg/m2 dubermatinib+TKI, 1 pt 50mg dubermatinib+nivolumab), 1 melanoma pt. 9mg/m2 and 1 cholangiocarcinoma pt. 50mg, both single agent dubermatinib. Dose reduction rate at RP2D was <10% with overall CBR observed in 18.4% (23/125) of pts including 4 PRs and SD>4 months in heavily pretreated patients. PD evaluation of pre, post-treatment tumor biopsies and PBMCs correlated with drug activity (dose dependent sAXL reduction and GAS6 increase on treatment Day 8). Changes in immune cell infiltration, activity of antigen presenting cells and polarization of macrophages will be presented.

Conclusions

Dubermatinib at 50mg orally once daily was tolerated, with evidence of AXL engagement in surrogate tissues and preliminary evidence of clinical activity. Combination studies with TKIs and IO agents are being analyzed.

Clinical trial identification

NCT02729298 JAPIC ID: JapicCTI-194793.

Legal entity responsible for the study

Tolero Pharmaceuticals, Inc.

Funding

Tolero Pharmaceuticals, Inc.

Disclosure

A.A. Adjei: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc. M. Beg: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc. J. Melear: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Speaker Bureau/Expert testimony: Janssen; Speaker Bureau/Expert testimony: AstraZeneca. J. Thompson: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Advisory/Consultancy: Pfizer. F.Y-C. Tsai: Advisory/Consultancy: Tempus Lab; Leadership role: Caremission LLC; Shareholder/Stockholder/Stock options: Salarius Pharmaceuticals; Research grant/Funding (institution): Tolero Pharmaceuticals, Inc. J.C. Baranda: Research grant/Funding (institution): Exelixis; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Tolero Pharmaceuticals; Research grant/Funding (institution): Xencor; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): SQZ; Shareholder/Stockholder/Stock options: Forty-Seven Inc; Shareholder/Stockholder/Stock options: Moderna; Shareholder/Stockholder/Stock options: Zymeworks; Shareholder/Stockholder/Stock options: Morphosys AG. B. Bastos: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Speaker Bureau/Expert testimony: Regeneron; Speaker Bureau/Expert testimony: Sanofi Genzyme. A. Spira: Honoraria (self), Research grant/Funding (self): Cytomx; Honoraria (self), Research grant/Funding (self): Amgen; Honoraria (self), Research grant/Funding (self): Novartis; Honoraria (self), Research grant/Funding (self): Merck; Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self), Research grant/Funding (self): Bristol-Myers-Squibb; Research grant/Funding (self): EMD Serono; Research grant/Funding (self): Turning Point; Research grant/Funding (institution): Tolero Pharmaceuticals, Inc. Y. Lou: Advisory/Consultancy: Novocure; Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Merck Sharp & Dohme; Research grant/Funding (institution): Blueprint Medicines; Research grant/Funding (institution): Vaccinex; Advisory/Consultancy: AstraZeneca; Research grant/Funding (institution): Macrogenics; Advisory/Consultancy: Clarion Healthcare; Research grant/Funding (institution): Kyowa Hakko Kirin Pharma; Research grant/Funding (institution): Harpoon Therapeutics; Research grant/Funding (institution): Sun Pharma Advanced Research Company Limited. M. Seetharam: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Advisory/Consultancy: Daiichi-Sankyo; Honoraria (self): CME Horizon. M. Uemura: Shareholder/Stockholder/Stock options: Abbott Laboratories; Advisory/Consultancy: Seattle Genetics; Shareholder/Stockholder/Stock options, Spouse/Financial dependant: Regeneron Pharmaceuticals. D.R. Camidge: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Advisory/Consultancy: Anchiarno; Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Takeda; Advisory/Consultancy, Research grant/Funding (institution): Roche / Genentech; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Sanofi; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: CBT Pharmaceuticals; Advisory/Consultancy: Daiichi-Sankyo; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Advisory/Consultancy: Achilles; Advisory/Consultancy: BeyondSpring; Advisory/Consultancy: Apollomics; Advisory/Consultancy: 14ner / Elevation; Advisory/Consultancy: Archer; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Glaxo-Smith-Kline; Advisory/Consultancy, Research grant/Funding (institution): Hansoh; Research grant/Funding (institution): InhibRx; Research grant/Funding (institution): Lycera; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Phosplatin; Research grant/Funding (institution): Psioxus; Research grant/Funding (institution): Rain; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Symphogen. N. Yamamoto: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Research grant/Funding (institution): Astellas; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Chugai; Advisory/Consultancy, Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Taiho; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers-Squibb; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Novartis; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Boehringer-Ingelheim; Research grant/Funding (institution): Kyowa-Hakko Kirin; Advisory/Consultancy, Research grant/Funding (institution): Takeda; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Ono; Research grant/Funding (institution): Janssen Pharma; Research grant/Funding (institution): Merck Sharp & Dohme; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Glaxo-Smith-Kline; Research grant/Funding (institution): Sumitomo Dainippon; Advisory/Consultancy: Otsuka; Advisory/Consultancy: Cimic; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Sysmex. C.L. Cowey: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc. T. Doi: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self): Astellas; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Honoraria (self): Ono; Honoraria (self): Oncolys BioPharma; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Taiho; Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Sumitomo Dainippon; Advisory/Consultancy: Rakuten Medical; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy: Takeda; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Merck, Sharp and Dohme; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Kyowa Hakko Kirin; Research grant/Funding (institution): IQVIA; Research grant/Funding (institution): Pfizer. S.P. Anthony: Full/Part-time employment: Tolero Pharmaceuticals, Inc; Advisory/Consultancy: Paradigm. M. Janat-Amsbury: Full/Part-time employment: Tolero Pharmaceuticals, Inc. M. Wade: Full/Part-time employment: Tolero Pharmaceuticals, Inc. D.J. Bearss: Officer/Board of Directors: Tolero Pharmaceuticals, Inc. J. Sarantopoulos: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc.

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Mini Oral - Developmental therapeutics Mini Oral session

537MO - First-in-human study of JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced cancers

Presentation Number
537MO
Speakers
  • Maria Vieito Villar (Barcelona, La Coruña, Spain)

Abstract

Background

PRMT5 regulates proteins important for tumorigenesis via symmetric arginine dimethylation (SDMA). JNJ64619178 is an oral, potent and selective PRMT5 inhibitor that demonstrates efficacy in multiple tumor models. Here, we present a phase I study of JNJ64619178 in adults with advanced solid tumors and non-Hodgkin lymphoma (Part 1).

Methods

Dose escalation was supported by a modified continual reassessment method. Patients (pts) received JNJ64619178 either intermittently (14 days on/7 days off) or once daily (QD) on a 21-day cycle. Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy were evaluated to identify the recommended phase II doses (RP2D).

Results

Fifty-four pts were enrolled as of 17 Mar 2020. The most common tumor types were adenoid cystic carcinoma (ACC; 20%), prostate cancer (15%), and uveal melanoma (13%). Median age was 59 (range 28-82), and median number of prior systemic therapies was 3 (range 0-11). Dosing ranged from 0.5 mg to 4 mg intermittently, and from 1 mg to 2 mg QD. Median treatment duration was 1.5 mo (range 0.4-22.4). The only dose-limiting toxicity observed was thrombocytopenia, at 3 and 4 mg intermittently and 2 mg QD. Fifty-one pts (91%) experienced treatment-related adverse events (TRAE), the most common being thrombocytopenia (52%), anemia (41%), nausea (39%), fatigue (32%), dysgeusia (30%), asthenia (24%), and diarrhea (20%). Grade 3/4 TRAEs in >1 pt were thrombocytopenia (20%), anemia (17%), and neutropenia (6%). Thirty pts (56%) had dose interruptions or reductions due to AE. JNJ64619178 plasma Cmax and AUC were linearly dose-proportional. Robust target engagement, as measured by plasma SDMA, was achieved even with intermittent dosing. A confirmed partial response (RECIST) was observed in ACC, and 7 pts (13%) with ACC, prostate cancer, salivary gland carcinomas, and other tumor types had stable disease >6 mo. Two provisional RP2Ds were selected: 1.5 mg intermittently and 1 mg QD.

Conclusions

JNJ64619178 demonstrated manageable toxicity and preliminary evidence of antitumor activity at selected dose levels. Intermittent dosing maintains target inhibition. Assessment of two provisional RP2Ds is ongoing.

Clinical trial identification

NCT03573310.

Editorial acknowledgement

Editorial assistance was provided by Ramji Narayanan of SIRO Clinpharm Pvt Ltd, funded by Janssen Global Services, LLC.

Legal entity responsible for the study

Janssen Research & Development, LLC.

Funding

Janssen Research & Development, LLC.

Disclosure

M. Vieito Villar: Advisory/Consultancy, Unpaid consultant: Debiopharma; Advisory/Consultancy, Unpaid consultant: Roche. A. Spreafico: Advisory/Consultancy: Merck; Advisory/Consultancy, Research grant/Funding (self): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (self): Novartis ; Advisory/Consultancy: Oncorus; Research grant/Funding (self): Symphogen AstraZeneca/Medimmune; Research grant/Funding (self): Bayer; Research grant/Funding (self): Surface Oncology; Research grant/Funding (self): Northern Biologics; Research grant/Funding (self): Janssen; Research grant/Funding (self): Roche; Research grant/Funding (self): Array Biopharma. I. Braña: Advisory/Consultancy: MSD; Speaker Bureau/Expert testimony, Research grant/Funding (self): AstraZeneca; Speaker Bureau/Expert testimony, Research grant/Funding (self): Bristol-Myers Squibb; Research grant/Funding (self): Gliknik; Research grant/Funding (self): GlaxoSmithKline; Research grant/Funding (self): MSD; Research grant/Funding (self): Novartis; Research grant/Funding (self): Pfizer; Research grant/Funding (self): Shattuck Labs; Research grant/Funding (self): Roche; Speaker Bureau/Expert testimony: Merck Serono. J.S. Wang: Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca. N. Haddish-Berhane: Full/Part-time employment: Janssen. J. Mehta: Full/Part-time employment: Janssen. A. Johnson: Full/Part-time employment: Janssen. A. Maes: Full/Part-time employment: Janssen. J. Haslam: Full/Part-time employment: Janssen. P. Mistry: Full/Part-time employment: Janssen. A. Kalota: Full/Part-time employment: Janssen. L. Lenox: Full/Part-time employment: Janssen. J.R. Infante: Full/Part-time employment: Janssen. M.V. Lorenzi: Full/Part-time employment: Janssen. H. Xie: Full/Part-time employment: Janssen. J. Lauring: Full/Part-time employment: Janssen. M.R. Patel: Honoraria (self): Gilead; Honoraria (self): Exelixis; Honoraria (self): BMS; Honoraria (self): Genentech; Honoraria (self): Medivation. All other authors have declared no conflicts of interest.

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Mini Oral - Developmental therapeutics Mini Oral session

Invited Discussant 536MOand 537MO

Speakers
  • Anastasios Stathis (Bellinzona, Switzerland)