Browsing Over 131 Presentations
ADCs and new targets in solid tumours (ID 37)
- Giuseppe Curigliano (Milan, Italy)
- Giuseppe Curigliano (Milan, Italy)
29P - Non-diploidy related prognostic molecular signature (NPMS) predict an “immunologically hot” phenotype in squamous cell lung cancer (ID 192)
- Zixin HU (Beijing, China)
- Zixin HU (Beijing, China)
- Huijuan Cui (Peking, China)
- Kexin Tan (Beijing, China)
- Jia Lee (Beijing, China)
Abstract
Background
Lung squamous cell carcinoma (LUSC) patients suffer from less targetable onco-drivers and potentially acquire clinical benefit from immune checkpoint inhibitors (ICIs). DNA content aberrations contribute to genomic instability and are initial events of tumorigenesis. We established a non-diploidy related prognostic molecular signature (NPMS) based on differentially expressed genes (DEGs) and investigated the immune features of it.
Methods
We conducted a retrospective analysis based on data downloaded from TCGA database. By integrating CNA and SNV via ABSOLUTE algorithm, we obtained the DNA ploidy status and divided patients into near-diploid and non-diploid group. DEGs were selected and gene functional enrichments were carried out. NPMS was established by all subset multivariate Cox regression to further stratify patients and validated by integrative analysis of GSE73403, GSE41271, GSE4212. Gene sets enrichment analysis was applied to further figure out the mechanism behind NPMS.
Results
Non-diploidy coincided with higher TMB and intratumor heterogeneity. Functional enrichment indicated that DEGs mainly participated in genomic instability. NPMS containing HOXB5, TINAGL1, POLR3GL, APOB, FABP6, SCARF1 was established. Patients with low score had better OS than those with high score (HR 0.60, 95%CI 0.45-0.79, p-value=0.000321). This was validated in the GEO cohorts (HR 0.57, 95%CI 0.37-0.88, p-value=0.0121). Dysregulation of DNA repair and cell cycle checkpoints were higher enriched in high score group. The immune phenotype of high score tended to be "immunologically hot", which was characterized as high density but low activity immune cells infiltrated, accompanied by expression of higher immunosuppressive factors, such as PD-1, CTLA4, IDO1. Meanwhile, the upregulation of IFN-γ signaling pathway, lipid alternation and the high correlation between them were observed.
Conclusions
High NPMS score corresponded with an "immunologically hot" feature thereby led to shorter OS. The crosstalk of upregulated IFN-γ signaling and aberrations of tumor metabolism mignt participate. It's rational to deduced that patients with high score might be the potential ICIs benefited subpopulation.
Legal entity responsible for the study
Z. Hu.
Funding
This work was supported by Horizontal Scientific Research Project of China-Japan Friendship Hospital (Grants No. 2018-HX-26).
Disclosure
All authors have declared no conflicts of interest.
36MO - Safety, tolerability and preliminary efficacy of poziotinib with twice daily strategy in EGFR/HER2 Exon 20 mutant non-small cell lung cancer (ID 274)
- Adrian Sacher (Toronto, ON, Canada)
- Adrian Sacher (Toronto, ON, Canada)
- Xiuning Le (Houston, TX, United States of America)
- Robin Cornelissen (Rotterdam, Netherlands)
- Elaine Shum (New York, AL, United States of America)
- Marie Suga (Vallejo, CA, United States of America)
- Mark Socinski (Orlando, PA, United States of America)
- Julian R. Molina (Rochester, MN, United States of America)
- Eric Haura (Tampa, FL, United States of America)
- Jeffrey Clarke (Durham, NC, United States of America)
- Gajanan Bhat (Irvine, CA, United States of America)
- Francois Lebel (Irvine, CA, United States of America)
- Marina C. Garassino (Milan, Italy)
Abstract
Background
Effective treatment of patients with metastatic non-small cell lung cancer (mNSCLC) harboring EGFR or HER2 exon 20 insertion mutations represents a critical unmet need. Poziotinib is a potent, irreversible, tyrosine kinase inhibitor (TKI) being studied in a multi-cohort phase II study (ZENITH20). Poziotinib half-life of 7.2 hours and pharmacokinetic modeling suggests an opportunity to improve tolerability with a twice daily (BID) dosing schedule. Here we present efficacy data from once daily (QD) in treatment naïve patients as well as an exploratory study of BID dosing.
Methods
ZENITH20-3 enrolled treatment-naïve mNSCLC patients with EGFR exon 20 mutations at 16mg QD. Patients were treated until death, progression or significant toxicity. ZENITH20-5 treated patients with EGFR or HER2 exon 20 mutations in randomized arms of 10, 12, 16 mg QD or 6 and 8 mg BID. The endpoints were objective response rate (ORR per RECIST 1.1), duration of response (DOR), progression-free-survival (PFS) and safety.
Results
In ZENITH20-3 (N=79), the median time of follow up was 9.2 months with 12 patients still receiving treatment. The intent-to-treat analysis showed an ORR of 27.8% (22/79; 95% CI: 18.4 – 39.1%) and disease control rate of 86.1%. 91% of all study patients had tumor reduction. The median DOR was 6.5 months and the median PFS was 7.2 months. Adverse event profile was similar to 2nd generation EGFR TKIs with ≥ grade 3 rash of 33% and diarrhea of 23%. Preliminary data from ZENITH20-5 (N=40) randomized cohorts of QD vs BID dosing (16mg QD vs 8mg BID; 12mg QD vs and 6mg BID) indicate that the expected AE rate was lower with BID dosing (31% vs. 21% and 27% vs. 16% respectively) in cycle 1. BID dosing schedules resulted in the relative reduction in dose interruptions by 38% and 52% respectively. Updated safety, tolerability and preliminary efficacy data will be presented.
Conclusions
Poziotinib demonstrated clinically meaningful activity in treatment-naïve mNSCLC patients with EGFR exon 20 mutations at 16 mg QD dosing. Preliminary data demonstrates improved tolerability and safety with BID dosing strategy and warrants further evaluation.
Clinical trial identification
NCT03318939.
Legal entity responsible for the study
Spectrum Pharmaceuticals, Inc.
Funding
Spectrum Pharmaceuticals, Inc.
Disclosure
A. Sacher: Honoraria (institution), Advisory/Consultancy: AstraZeneca; Honoraria (institution), Advisory/Consultancy: Amgen; Honoraria (institution), Advisory/Consultancy: Merck; Honoraria (institution): Pfizer; Honoraria (institution), Advisory/Consultancy: Bayer; Honoraria (institution), Advisory/Consultancy: Genentech-Roche; Honoraria (institution), Advisory/Consultancy: Kisoji; Honoraria (institution), Advisory/Consultancy: BMS; Honoraria (institution): Tesaro. X. Le, M. Socinski, M.C. Garassino: Research grant/Funding (institution): Spectrum Pharmaceuticals. J. Clarke: Advisory/Consultancy: Spectrum Pharmaceuticals. G. Bhat, F. Lebel: Full/Part-time employment: Spectrum Pharmaceuticals. All other authors have declared no conflicts of interest.
Live Q&A and discussion (ID 343)
- David M. Hyman (Stamford, CT, United States of America)
- David M. Hyman (Stamford, CT, United States of America)
- Christina Yap (Sutton, TX, United Kingdom)
- Ruth Plummer (Newcastle-upon-Tyne, Tyne and Wear, United Kingdom)
- Anthony W. Tolcher (San Antonio, TX, United States of America)
- Xiao Li Wei (Guangzhou, China)
- Omid Hamid (Los Angeles, CA, United States of America)
What is the model for efficient drug development in the pharmaceutical industry? (ID 105)
- David M. Hyman (Stamford, CT, United States of America)
- David M. Hyman (Stamford, CT, United States of America)
2P - Molecular imaging evaluation of a novel Claudin18.2 specific monoclonal antibody labeled with radionuclide (ID 261)
- Hua Zhu (Beijing, China)
- Hua Zhu (Beijing, China)
- Jin Ding (Beijing, China)
- Xiaoyi Chong (Beijing, China)
- Congcong Ji (Beijing, China)
- Cheng Zhang (Beijing, China)
- Fei Teng (Suzhou, China)
- Yi Gu (Suzhou, China)
- Xueming Qian (Suzhou, China)
- Zhi Yang (Beijing, China)
- Lin Shen (Beijing, China)
- Jing Gao (Shenzhen, China)
Abstract
Background
Claudin18.2 (CLDN18.2), a member of tight junction protein family, is strictly limited to differentiated epithelial cells of gastric mucosa and multiple tumor types, such as gastric, esophageal and pancreatic cancers. We have generated a novel species cross-reactive CLDN18.2 specific antibody, and labeled it with “Next Generation” radionuclide I-124 (124I-18B10).
Methods
I-124 was produced by the medical cyclotron using 124Te (p, n) 124I reaction. In the cell-based assay, the uptake of 124I-18B10 in MKN45-CLDN18.2 (CLDN18.2+ cell line) and MKN45 (CLDN18.2- cell line) were detected at 10, 30, 60 and 120 min, and the blocking group using cold 18B10 antibody to block uptake was also evaluated. PDX-bearing mice, which were selected by immunohistochemical (IHC) method and assessed as CLDN18.2+ or CLDN18.2-, were injected with either 18.5 MBq 18F- fluorodeoxyglucose (18F-FDG), or 124I-18B10, or 124I-hIgG via the tail vein, and Micro-PET/CT images were taken at 2, 60 and 120h post injection.
Results
The specific activity of 124I-18B10 was 0.62 mCi/mg antibody and the labeling rate was higher than 95%. The cell-based assay showed that specific uptake of it by the MKN45-CLDN18.2 cells was significantly higher than that of by the MKN45 cells (23.51±0.47 % vs 8.69±0.35 % at 2 h, P<0.05). Both uptake assay and competitive binding assay in the MKN45-CLDN18.2 cells showed that cold 18B10 antibody could significantly reduce the uptake and binding of 124I-18B10 (15.33±0.82 % at 2 h, P<0.05). As expected, the uptake of 124I-hIgG was low (5.21±0.29 % at 2 h). In PDX bearing mice, the uptake of 18F-FDG in tumor sites was low. The distribution of 124I-18B10 in CLDN18.2+ PDX bearing mice was increasingly enriched in the tumor sites over time. The uptake signals of 124I-18B10 in CLDN18.2- PDX bearing mice in all tissues and tumors remained similar at different time points.
Conclusions
The 124I-18B10 antibody has good radio-chemical characteristics and stability. The cell uptake assay and competitive binding assay demonstrated that the probe is highly specific to CLDN18.2. Micro-PET images of PDX bearing mice demonstrated that 124I-18B10 was enriched in the lesion of CLDN18.2 positive tumors rather than negative tumors or normal tissues.
Legal entity responsible for the study
Peking University Cancer Hospital & Institute.
Funding
Has not received any funding.
Disclosure
F. Teng, Y. Gu, X. Qian: Full/Part-time employment: Research, Mabspace Biosciences (Suzhou) Co. Ltd., Suzhou, China. All other authors have declared no conflicts of interest.
Live Q&A (ID 331)
- Timothy A. Yap (Houston, TX, United States of America)
- Ruth Plummer (Newcastle-upon-Tyne, Tyne and Wear, United Kingdom)
- Christoph Oing (Hamburg, Germany)
- Timothy A. Yap (Houston, TX, United States of America)
- Ruth Plummer (Newcastle-upon-Tyne, Tyne and Wear, United Kingdom)
- Christoph Oing (Hamburg, Germany)
Patient selection for early phase clinical trials: How akkermansia muciniphila can become a diagnostic tool and a therapeutic strategy (ID 29)
- Lisa Derosa (Villejuif, France)
- Lisa Derosa (Villejuif, France)
Live Q&A and discussion (ID 64)
- Johann S. De Bono (London, United Kingdom)
- Johann S. De Bono (London, United Kingdom)
- Ignacio Melero (Pamplona, Spain)
- Marijo Bilusic (Bethesda, United States of America)
- Joan Seoane (Barcelona, Spain)
15P - A pivotal multicenter translational research project on malignant pleural mesothelioma (MPM): Preliminary results (ID 249)
- Raimondo Di Liello (Napoli, Italy)
- Raimondo Di Liello (Napoli, Italy)
- Carminia M. Della Corte (Napoli, Italy)
- Vincenza Ciaramella (Napoli, Italy)
- Amelia Insa (Valencia, Spain)
- Desamparados Compañ-Quilis (Valencia, Spain)
- Guzmán Alonso (Valencia, Spain)
- Ricard Borrás (Valencia, Spain)
- Giuseppe Viscardi (Napoli, Italy)
- Nicoletta Zanaletti (Napoli, Italy)
- Francesca Sparano (Napoli, Italy)
- Immacolata Cozzolino (Napoli, Italy)
- Marco Montella (Napoli, Italy)
- Giovanni Vicidomini (Napoli, Italy)
- Irene Pastor-Escartín (Valencia, Spain)
- Mario Santini (Napoli, Italy)
- Renato Franco (Napoli, Italy)
- Fortunato Ciardiello (Napoli, Italy)
- Paloma Martín-Martorell (Valencia, Spain)
- Floriana Morgillo (Napoli, Italy)
Abstract
Background
Platinum-based therapy (PL) remains the standard of care in MPM, despite encouraging emerging data from immunotherapy (IO) trials. Recently, prognostic MPM clusters with potential implications for targeted-treatments were identified by multiplatform profiling but we are still far from translating these data in therapeutic opportunities for pts. In this scenario, we are leading an international multicenter projecton new biomarkers in MPM.
Methods
We used preclinical models to compare PL-naïve and PL-resistant MPM. Protein expression of biomarkers of interest from cells were analyzed by FACS and Western blot at Università degli Studi della Campania Luigi Vanvitelli (Naples, IT). Further, specimens of MPM pts treated with PL and IO will be used for an IHC-based pivotal analysis on known and emerging biomarkers as BAP1, AURKA and CDKN2A. VISTA and PD-L1 will be also analyzed and correlated to other results.
Results
In PL-resistant MPM H2452 cells, generated treating parental cell line with PL dose-escalation, FACS analysis revealed an increased PD-L1 expression (1% in PL-naïve vs 39.1% in PL-resistant). Western blot protein expression analysis confirmed this result, suggesting a PL-driven increased IO-sensitivity, independent from response, as shown in other cancer types. Sixty-two MPM pts treated at Hospital Clínico Universitario de Valencia (Valencia, ES) from 2001 to 2020 were selected for the translational part of the project so far. Mean age was 67.5 years (36-89), 90% (n=56) of pts were male, 80% (n=50) exposed to asbestos and 61% (n=38) ECOG PS<2. The majority (69%, n=43) with epithelioid MPM; 52% (n=33) stage III-IV at diagnosis. Of 58 pts included in the analysis, 4 were exposed to IO and 45 (77%) to PL. 62% (n=28) PL-sensitive and 38% (n=17) PL-resistant. IHC analysis on tissue specimens is ongoing.
Conclusions
Our preliminary results confirmed the activation of PD-L1 by PL, also in resistant setting, showing a biological rationale for IO in these pts. Ongoing analysis will validate on a proteomic level other proposed biomarkers as BAP1, AURKA, CDKN2A and VISTA, to build a cost-effective IHC-based MPM classification, useful for future targeted-treatment strategies.
Legal entity responsible for the study
The authors.
Funding
Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.
Disclosure
F. Ciardiello: Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Sanofi; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Servier; Advisory/Consultancy: BMS; Advisory/Consultancy: Celgene; Advisory/Consultancy: Lilly; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Ipsen. F. Morgillo: Advisory/Consultancy: MSD; Advisory/Consultancy: Lilly; Research grant/Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.
19O - Preliminary safety, antitumor activity and pharmacodynamics results of HIT-IT MEDI1191 (mRNA IL-12) in patients with advanced solid tumours and superficial lesions (ID 323)
- Omid Hamid (Los Angeles, CA, United States of America)
- Omid Hamid (Los Angeles, CA, United States of America)
- Matthew Hellman (New York, NY, United States of America)
- Benedito Carneiro (Providence, RI, United States of America)
- Thomas Marron (New York, NY, United States of America)
- Vivek Subbiah (Houston, TX, United States of America)
- Inderjit Mehmi (Los Angeles, CA, United States of America)
- Jim Eyles (Gaitherburg, MD, United States of America)
- Vincent Dubois (Gaithersburg, MD, United States of America)
- Benjamin Ridgway (Gaithersburg, MD, United States of America)
- Oday Hamid (Gaithersburg, MD, United States of America)
- Amaya Gasco Hernandez (Gaithersburg, MD, United States of America)
Abstract
Background
IL-12 is a strong driver of a TH1 immune response, but systemic recombinant IL-12 is poorly tolerated clinically. MEDI1191 (IL-12 mRNA) is a lipid nanoparticle (LNP)-formulated therapy developed for intratumoral (IT) injection, designed to drive local IL-12 production and induce anenestic anti-tumor activity. In preclinical models, IT IL-12 mRNA induces a potent TH1-mediated antitumor response, that is further enhanced by PD-L1 blockade.
Methods
This phase I, multicenter, open-label, dose-escalation (part 1) and expansion (part 2) study evaluates the safety and efficacy of MEDI1191 IT in sequential or concurrent combination with durvalumab 1500 mg Q4W IV in advanced solid tumors with superficial and deep-seated lesions. Patients (pts) who have progressed on at least 1 line of standard systemic therapy were eligible, including IO naïve or pre-treated pts. Primary endpoints for part 1 are safety and to identify the maximum tolerated dose and a pharmacodynamic active dose. Secondary endpoints for part 1 include efficacy (disease control rate, duration of response, time to response, PFS, and OS), pharmacokinetics and immunogenicity. Here we will be presenting preliminary data that needs further validation.
Results
From May 2019 to December 2020, 10 pts were enrolled across three dose escalation cohorts in part 1 in pts with superficial lesions. 6 out of 10 were IO-pretreated pts. No DLT, AESI, ≥ G3 TRAE or TR-SAE were reported. To date, two partial responses have been observed, both pts had received IO therapies and had PD-L1 negative tumors, including one pt with melanoma with tumor shrinkage of both injected and non-injected lesions following 2 doses of MEDI1191 and prior to durvalumab. Preliminary pharmacodynamic analysis indicate that MEDI1191 induced transient elevation in serum levels of IL-12; and concordant changes in IFN-g and CXCL10.
Conclusions
Sequential combination of IT MEDI119 with IV durvalumab was well tolerated and showed encouraging preliminary antitumor and pharmacodynamic activity including in IO pre-treated pts, consistent with the expected mechanism of action. The study is active and recruiting.
Clinical trial identification
NCT03946800.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
O. Hamid: Research grant/Funding (self): Moderna. M. Hellman: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca. B. Carneiro, V. Subbiah: Research grant/Funding (self): AstraZeneca. T. Marron: Advisory/Consultancy: AstraZeneca. J. Eyles, V. Dubois, B. Ridgway, O. Hamid, A. Gasco Hernandez: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.
CRISPR library and other screens for synthetic lethality (ID 19)
- Rene Bernards (Amsterdam, Netherlands)
- Rene Bernards (Amsterdam, Netherlands)