Abstract 44P
Background
Sitra is a spectrum-selective tyrosine kinase inhibitor targeting multiple receptors, including VEGFR2. Here, we present an exploratory analysis of PD biomarkers in SAFFRON-103, a phase 1b study investigating Sitra with TIS, an anti-PD-1 antibody, in patients (pts) with solid tumors including advanced non-squamous-non-small cell lung cancer (NSCLC), squamous-NSCLC, melanoma, or ovarian cancer.
Methods
Peripheral blood samples were collected at Cycle (C) 1 Day (D) 1, C2D1, and C3D1 prior to Sitra dosing, to investigate changes in cytokines (Meso Scale Discovery [MSD] multiplexing), plasma proteins (ELISA), and immune cell populations (fluorescence-activated cell sorting [FACS]). Generalized linear mixed models were used to estimate fold change and analyze biomarker changes; Wald tests were used to generate P-values.
Results
Baseline characteristics were balanced across pts with evaluable biomarker results (n=186 cytokines/plasma proteins, n=113 immune cell populations) and in the overall population (N=216). For all pts, changes in individual biomarker levels were consistent from C1D1 to both C2D1 and C3D1, with significant increases in VEGFA (P<0.0001; both) and CXCL10 (P<0.0001; both) and significant decreases across soluble (s) VEGFR2 (P<0.0001; both), peripheral G-MDSCs (P=0.0005; P=0.0002), and monocytes (P<0.0001; both). Estimated fold changes of PD biomarkers across tumor types are shown (Table). Changes in VEGFA (increased) and monocytes (decreased) after treatment (C2D1/C1D1) were associated with improved objective response rates (odds ratio [OR] 4.67, P=0.0005; OR 5.82, P<0.0001). Table: 44P
Estimated fold change from C1D1 | Non-squamous-NSCLC | Squamous-NSCLC | Melanoma | Ovarian cancer | ||||
C2D1 | C3D1 | C2D1 | C3D1 | C2D1 | C3D1 | C2D1 | C3D1 | |
ELISA/MSD eligible | n=60 | n=48 | n=22 | n=54 | ||||
VEFGA | 2.77 | 2.65 | 2.53 | 2.53 | 2.89 | 2.38 | 2.16 | 2.14 |
sVEFGR2 | 0.67 | 0.63 | 0.61 | 0.59 | 0.65 | 0.66 | 0.70 | 0.69 |
CXCL10 | 1.70 | 1.97 | 1.65 | 1.43 | 1.75 | 1.44 | 2.21 | 1.90 |
FACS eligible | n=44 | n=21 | n=10 | n=28 | ||||
G-MDSCs | 0.74 | 0.71 | 0.59 | 0.60 | 0.83 | 0.74 | 0.81 | 0.84 |
Monocytes | 0.70 | 0.72 | 0.72 | 0.64 | 0.73 | 0.72 | 0.81 | 0.85 |
Abbreviations: G-MDSC, granulocyte-like myeloid derived suppressor cells; NSCLC, non-small cell lung cancer; VEFGA, vascular endothelial growth factor A; sVERGR2, soluble vascular endothelial growth factor receptor 2
Conclusions
VEGFA increased and sVEGFR2 decreased consistently and significantly after Sitra plus TIS therapy, demonstrating the on-target anti-angiogenesis effect of Sitra. Decrease of G-MDSCs and monocytes in peripheral blood indicates a potential immune-modulating role for Sitra with TIS.
Clinical trial identification
NCT03666143.
Editorial acknowledgement
This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Gemma Walker, BSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.
Legal entity responsible for the study
BeiGene.
Funding
BeiGene.
Disclosure
Y. Wu: Non-Financial Interests, Personal, Advisory Role: AstraZeneca; Non-Financial Interests, Personal and Institutional, Coordinating PI: AstraZeneca, Roche, Merck; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hengrui, MSD, Pfizer, Roche; Non-Financial Interests, Personal, Leadership Role: Chinese Thoracic Oncology Group (CTONG); Non-Financial Interests, Personal, Local PI: BeiGene, Innoven; Non-Financial Interests, Personal, Member: ASCO, ESMO, IASLC, CSCO; Financial Interests, Institutional, Research Grant: BMS, Pfizer. J.C. Goh: Non-Financial Interests, Institutional, Invited Speaker: Brisbane Cancer Conference; Financial Interests, Personal, Invited Speaker: GSK, MSD; Financial Interests, Personal, Speaker’s Bureau: MSD, GSK, Ipsen, Janssen, Eisai, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen, GSK, BMS, MSD, AstraZeneca; Financial Interests, Personal and Institutional, Full or part-time Employment, Part-time employment: Royal Brisbane & Women’s Hospital; Financial Interests, Personal and Institutional, Full or part-time Employment: ICON Chermside & Greenslopes; Financial Interests, Personal, Stocks/Shares: ICON Cancer Centres, Immutep; Non-Financial Interests, Personal and Institutional, Project Lead, Ceased; Collaborative Group: ITTACc trial; Non-Financial Interests, Institutional, Principal Investigator: MSD, BMS, Janssen, AstraZeneca, BeiGene, Sutro Biopharma, Exelixis, Pfizer, Alloplex, Alkermes, Mersana; Non-Financial Interests, Personal and Institutional, Member, Corporative trials group in ANZ, USA & Europe: ASCO, ANZGOG, ANZUP, ESMO; Non-Financial Interests, Institutional, Leadership Role: Member of ICON Cancer Centre MAC (Medical Advisory Committee). J. Zhao: Non-Financial Interests, Institutional, Coordinating PI: AstraZeneca; Non-Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Merck, BeiGene, Pfizer; Non-Financial Interests, Personal, Local PI: Merck, Roche; Non-Financial Interests, Personal, Steering Committee Member: Pfizer, Pierre Fabre, BeiGene. Q. Zhou: Financial Interests, Personal, Speaker, Consultant, Advisor: Lecture and presentations fees to myself from AstraZeneca; Non-Financial Interests, Personal, Speaker, Consultant, Advisor: Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, Sanofi outside the submitted work. M. Millward: Financial Interests, Personal, Advisory Board: BeiGene Australia Pty Ltd, Bristol Myers Squibb Australia Pty Ltd, AstraZeneca Australia Pty Ltd, The Limbic, Eli Lilly Australia Pty Ltd, IQVIA Australia Pty Ltd, Amgen Australia Pty Ltd, Merck Pte Ltd, Pfizer Australia Pty Ltd, Guardant Health, Roche Products Pty Ltd; Financial Interests, Personal, Full or part-time Employment, Employee: University of Western Australia; Financial Interests, Personal, Other, Consultant: Linear Clinical Research; Financial Interests, Institutional, Local PI, Trial payments to Institution: Bristol Myers Squibb, Genentech/Roche, BeiGene, Eli Lilly, Albion Laboratories, Akeso Biopharma, AbbVie, Five Prime Therapeutics, Dizal Pharma, Maxinovel, Amgen, Atridia, INXMED, Alpine Immune Sciences, Turning Point Therapeutics, IMPACT Therapeutics, Kinnate Biopharma, Rely Therapeutics, GenFleet Therapeutics, Vivace Therapeutics, Eucure Biopahrma, InventisBio, Cullinan Oncology, Tyra Biosciences, Axelia Oncology; Non-Financial Interests, Personal, Other, Scientific Advisory Committee member: Thoracic Oncology Group Australasia. T. Tian: Other, Institutional, Full or part-time Employment: GSDS, BeiGene USA, Inc. 1840 Gateway Drive, 3rd Floor, San Mateo, CA 94404; Financial Interests, Institutional, Stocks/Shares: GSDS, BeiGene USA, Inc. 1840 Gateway Drive, 3rd Floor, San Mateo, CA 94404. J. Guo: Financial Interests, Institutional, Speaker, Consultant, Advisor: Merck Sharp & Dohme, Roche, Bayer, Novartis, Simcere Pharmaceutical Group, Shanghai Junshi Biosciences, Oriengene. All other authors have declared no conflicts of interest.
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