On-Demand E-Poster Display - ESMO Virtual Congress 2020

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Found 2 Presentations For Request "Abs: 582P"

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Poster Display session

582P - Preclinical development of AT1412, a patient derived CD9 antibody that does not induce thrombosis for treatment of precursor B ALL

Presentation Number

582P

Speakers

Julien Villaudy (Amsterdam, Netherlands)

Date

17.09.2020

Abstract

Abstract

Background

Despite recent advances in treatment of precursor B-acute lymphoblastic leukemia (B-ALL) there is still a need for novel targeted therapies. The tetraspanin CD9 is expressed in 60-80% of B-ALL and correlates with adverse prognosis. Recently, the mouse CD9 antibody ALB6 was shown to induce leukemia rejection in NOD/SCID mice. However, clinical development of ALB6 and other CD9-targeting antibodies was hampered by their CD9 mediated induction of platelet aggregation.

Methods

AT1412 is a fully human antibody isolated from B cells of a patient that was cured from stage IV metastatic melanoma.

Results

AT1412 targets CD9, without inducing platelet aggregation in vitro or thrombosis in cynomolgus monkeys after intravenous administration at therapeutic dose levels. By crystallography AT1412 was shown to bind a unique epitope distinct from those recognized by mouse CD9 antibodies. AT1412 binds a majority of patient B-ALL samples, but not T-ALL and induces ADCC of CD9 positive B-ALL primary cells and the level of cytotoxicity significantly correlated with that of AT1412 binding. In immunodeficient mice harboring a human immune system AT1412 demonstrated a strong, dose-dependent tumor rejection of B ALL, most pronounced in the extramedullary sites. In addition, AT1412 showed accumulation of T cells and CD14+ myeloid cells at the tumor sites. To support clinical development, pre-clinical safety of AT1412 was evaluated in cynomolgus monkeys. AT1412 demonstrated a half-life of 8.5 days, supporting 2-3 weekly administration. Besides transient thrombocytopenia no other pathological deviations were observed. The thrombocytopenia is reversible and its recovery accelerated in those animals developing anti-AT1412 antibodies. No effect on coagulation parameters, bruising or bleeding were observed macro- or microscopically.

Conclusions

Taken together, we demonstrate that CD9 on B-ALL cells can be successfully targeted by AT1412. AT1412 targets a unique epitope and does not induce thrombosis. Pre-clinical safety assessment is supporting that AT1412 can be safely administered. A First in Human clinical study is scheduled to start early 2021 and will evaluate AT1412 in B-ALL as well as CD9+ solid tumors.

Legal entity responsible for the study

The authors.

Funding

AIMM Therapeutics.

Disclosure

J. Villaudy: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. R. Schotte: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. G. de Jong: Full/Part-time employment: AIMM Therapeutics. V. Neviani: Full/Part-time employment: Utrecht University. W. Pos: Full/Part-time employment: AIMM Therapeutics. S. Levie: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. E. Yasuda: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. M. Cercel: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. A. Szabó: Full/Part-time employment: Erasmus University Medical Center. C. Fatmawati: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. M. Kedde: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. S. Horbach: Honoraria (self): Sjeng Horbach Consultancy. E.M.E. Verdegaal: Full/Part-time employment: Leiden University. P. van Helden: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. S.H. van der Burg: Full/Part-time employment: Leiden University. A. Rijneveld: Full/Part-time employment: Erasmus University. P. Gros: Full/Part-time employment: Utrecht University. H. Spits: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. M. Hazenberg: Spouse/Financial dependant: AIMM Therapeutics. H. van Eenennaam: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics.

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Poster Display session

1165P - Subgroup analysis by Ki-67 and primary tumour origins of the randomized, placebo-controlled phase III study of surufatinib in advanced well-differentiated extrapancreatic neuroendocrine tumours (SANET-ep)

Presentation Number

1165P

Speakers

Zhiwei Zhou (Guangzhou, China)

Date

17.09.2020

Abstract

Abstract

Background

Surufatinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (1,2,3), fibroblast growth factor receptor 1 and colony stimulating factor 1 receptor, has demonstrated superior efficacy in extrapancreatic neuroendocrine tumors (NETs) in a phase III study (SANET-ep, ESMO 2019 Abs. LBA76). The proliferation marker Ki-67 and primary tumor origins are the major prognostic factors in NETs.

Methods

The post-hoc efficacy analysis of surufatinib versus placebo was conducted by Ki-67 subcategory (<3%, 3-10%, >10%) and primary tumor origins (foregut, midgut, hindgut, others or unknown) in patients (pts) with advanced well-differentiated (grade 1 or 2) extrapancreatic NETs. The primary endpoint (progression-free survival [PFS]) and secondary endpoint (objective response rate [ORR]) both by investigator assessment (RECIST1.1) were analyzed.

Results

Median PFS was significantly prolonged with surufatinib compared to placebo in subgroups of Ki-67 3-10% (7.6 vs 4.6 months [mo], hazard ratio [HR] 0.47, P=0.0012), Ki-67 >10% (8.3 vs 2.1 mo, HR 0.14, P<0.0001), foregut (8.4 vs 4.6 mo, HR 0.29, P=0.0001) and hindgut (8.3 vs 2.1 mo, HR 0.35, P=0.0014). There was numerical PFS improvement with surufatinib compared to placebo in the rest subgroups: Ki 67 <3% (13.9 vs 7.4 mo, HR 0.43, P=0.0557), midgut (19.2 vs 8.9 mo, HR not analyzed due to small sample size) and unknown origin (9.2 vs 5.5 mo, HR 0.56, P=0.2943). ORR in the subgroups of Ki-67 <3%, 3-10%, >10% with surufatinib were 4.8%, 7.7%% and 20.0% respectively. There was no objective response in the placebo arm. ORR in the subgroups of foregut, midgut and unknown origin with surufatinib was 18.4%, 16.7% and 10.0% respectively while no response was observed in subgroups of hindgut or other origins.

Conclusions

Surufatinib demonstrated clinically significant benefits for pts with advanced well-differentiated extrapancreatic NETs compared to placebo. Results of this exploratory analysis were consistent with those reported for the SANET-ep primary analysis, and improved outcomes were observed across major subgroups.

Clinical trial identification

NCT02588170.

Legal entity responsible for the study

Hutchison MediPharma Limited.

Funding

Hutchison MediPharma Limited.

Disclosure

J. Li, J. He: Full/Part-time employment: Hutchison MediPharma Limited. W. Su: Shareholder/Stockholder/Stock options, Full/Part-time employment: Hutchison MediPharma Limited. All other authors have declared no conflicts of interest.

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