Abstract 2339
Background
Linrodostat mesylate is a potent, selective, oral, once-daily IDO1i being evaluated in combination with NIVO. The kynurenine (KYN) pathway, mediated through the enzymatic activity of IDO1 and TDO2, reflects an immunosuppressive mechanism that may limit clinical response to immune checkpoint blockade. In the phase I/IIa CA017-003 study (NCT02658890), linrodostat + NIVO decreased serum and tumoral KYN levels and increased tumoral CD8+ T-cell proliferation in pts with advanced cancers (Luke et al. SITC 2017). Here we describe an RNA-based composite biomarker that may enrich for clinical benefit with linrodostat + NIVO.
Methods
Tumor and serum samples were obtained from pts with solid tumors (bladder, cervical, melanoma, lung, pancreatic, renal cell, head and neck) and lymphoma treated with linrodostat + NIVO during the expansion phase in CA017-003. KYN and tryptophan (TRP) levels were measured in frozen serum (n = 400) and tumors (n = 45) obtained before and during treatment (cycle 1, day 15) using liquid chromatography–mass spectrometry. RNA sequencing was done on baseline formalin-fixed, paraffin-embedded solid tumor samples (n = 108).
Results
In serum and tumors, decreases in KYN and KYN/TRP were consistently observed; however, baseline and change from baseline in KYN or KYN/TRP did not correlate with response. Overall, in the tumor-based gene expression cohort, high IFN-γ gene signature (Ayers et al. J Clin Invest. 2017) was associated with response and improved progression-free and overall survival; nonresponders had higher expression of TDO2. In the non-melanoma subset (n = 56), a composite biomarker of IFN-γ signature and TDO2 gene expression was more significantly associated with response (P = 0.021) than the IFN-γ signature alone (P = 0.063).
Conclusions
IFN-ɣ signature and TDO2 gene expression may be a potential composite biomarker to identify pts with certain tumor types more likely to respond to linrodostat mesylate + NIVO. Future studies are needed to clarify the underlying mechanisms and validate the potential of this composite biomarker.
Clinical trial identification
NCT02658890. Release date January 20, 2016.
Editorial acknowledgement
Writing and editorial assistance was provided by Jillian Brechbiel, PhD, of Chrysalis Medical Communications, Inc, funded by Bristol-Myers Squibb.
Legal entity responsible for the study
Bristol-Myers Squibb.
Funding
Bristol-Myers Squibb.
Disclosure
J. Luke: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Actym Therapeutics; Advisory / Consultancy: 7 Hills Pharma; Advisory / Consultancy: Aduro Biotech; Advisory / Consultancy: Alphamab Oncology; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Array BioPharma; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca/MedImmune; Research grant / Funding (institution): Abbvie; Advisory / Consultancy, Travel / Accommodation / Expenses: Benevir; Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Travel / Accommodation / Expenses: Castle Biosciences; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Checkmate Pharmaceuticals; Research grant / Funding (institution): Celldex; Advisory / Consultancy, Research grant / Funding (institution): Compugen; Research grant / Funding (institution): Corvus Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution): Delcath Systems; Advisory / Consultancy, Travel / Accommodation / Expenses: Gilead Sciences; Research grant / Funding (institution): Evelo Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Ideaya Biosciences; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: Jounce Therapeutics; Advisory / Consultancy: Mavu Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Reflexion Medical; Advisory / Consultancy: Spring Bank; Advisory / Consultancy: Syndax; Advisory / Consultancy: Tempest Therapeutics; Advisory / Consultancy: TTC Oncology; Advisory / Consultancy: Vividion; Advisory / Consultancy: WntRx; Research grant / Funding (institution): Five Prime Therapeutics ; Research grant / Funding (institution): FLX Bio ; Research grant / Funding (institution): Genentech/Roche ; Research grant / Funding (institution): Immunocore ; Research grant / Funding (institution): Incyte ; Research grant / Funding (institution): Macrogenics ; Research grant / Funding (institution): MedImmune ; Research grant / Funding (institution): Palleon Pharmaceuticals ; Research grant / Funding (institution): Pharmacyclis; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Xencor ; Licensing / Royalties: Serial #15/612,657 (Cancer Immunotherapy); Licensing / Royalties: Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof. L.L. Siu: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy: Morphosys; Advisory / Consultancy: Roche; Advisory / Consultancy: GeneSeeq; Advisory / Consultancy: Loxo; Advisory / Consultancy: Oncorus; Advisory / Consultancy, Research grant / Funding (institution): Symphogen; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boerhinger-Ingelheim; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Intensity Therapeutics; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Shattucks. J. Santucci-Pereira: Full / Part-time employment: Bristol-Myers Squibb. D. Nelson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. E.H. Kandoussi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. B. Fischer: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. M. Wind-Rotolo: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. D. Greenawalt: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. Y. Ishii: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb.
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