Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma

Abstract

Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 µg/dose, or 20 µg/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 µg/dose expansion. Adverse events grade ≥3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 µg (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.

Keywords:

• TLR4
• glucopyranosyl lipid A
• follicular lymphoma
• immunotherapy
• pembrolizumab

Acknowledgments

Colleen Brown (Mark Consulting, Inc.), a medical writer supported by funding from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, provided drafts, editorial, and formatting assistance to the authors during the preparation of this manuscript.

Disclosure statement

A.S.H.: Research and travel support from Immune Design (paid to institution) and research support from Genentech (paid to institution). C.P.: Support from Immune Design for the clinical trial reported in this manuscript; consulting fees from Bristol-Myers Squibb and Kyowa Kirin; payments or honoraria from Roche Pharma and Janssen; payment for expert testimony from Celgene; and support for attending meetings and/or travel from Roche Pharma. I.I.: No disclosures related to this study. A.F.H.: Grants/research support from Bristol-Myers Squibb, Merck & Co., Inc., Genentech, Inc./F. Hoffman-La Roche Ltd., Gilead Sciences, Inc., Seattle Genetics, AstraZeneca, and ADC Therapeutics; consultant for Bristol-Myers Squibb, Merck & Co., Inc., Genentech, Inc./F. Hoffman-La Roche, Ltd., Seattle Genetics, Karyopharm Therapeutics, AstraZeneca, Tubulis, Takeda Pharmaceutical Company, and ADC Therapeutics; and support for attending meetings and/or travel from Bristol-Myers Squibb. C.O.: No disclosures related to this study. E.H.C.: Speaker for Bristol-Myers Squibb. B.K.: No disclosures related to this study. J.M.C.: No disclosures related to this study. N.L.B.: Support from Immune Design for the clinical trial reported in this manuscript; advisory board participation for ADC Therapeutics, Roche/Genentech, Seattle Genetics, BTG, and Acerta; and research funding from ADC Therapeutics, Affimed, Autolus, Bristol-Myers Squibb, Celgene Corporation, Forty Seven, Gilead, Immune Design, Janssen, Kite Pharma, Merck & Co., Inc., Millennium Pharmaceuticals, Inc., Pfizer Inc., Pharmacyclics LLC, Roche/Genentech, and Seattle Genetics. W.A.: No disclosures related to this study. L.C-M.: No disclosures related to this study. L.J.B.: No disclosures related to this study. R.H.: No disclosures related to this study. K.L.: Research funding from Genmab, Roche, Celgene Corporation, and Beigene; grants or contracts from Blood Cancer UK and Roy Castle Lung Cancer Foundation; consulting fees from Genmab and Roche; honoraria from Aptitude Health, Hartley Taylor, and Roche; support for attending meetings and/or travel from Janssen and Celgene Corporation; and participation on a Data Safety Monitoring Board or advisory board at Kite, Karyopharm, and Celgene Corporation. J.B.: No disclosures related to this study. I.C.: Advisory board for Eli Lilly and Company, Bristol Meyers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, Astra-Zeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astella, GSK, Sotio, and Eisai; research funding from Eli Lilly and Company and Janssen-Cilag Pty Ltd.; honoraria from Eli Lilly and Company and Eisai. G.R.v.K.: Consulting fees from Merck & Co., Inc., Incyte, and Pharmacylics LLC. H.L. Full-time employee of Immune Design with stock options during conduct of the study. A.Y. Full-time employee of Immune Design with stock options during conduct of the study; consulting fees from Merck & Co., Inc. (former employer) paid to assist with manuscript preparation following the end of full-time employment. M.C. Former employee of Immune Design with stock ownership and stock options. J.t.M. Full-time employee of Immune Design with stock options during conduct of the study; patent US20140328904: GLA Monotherapy for Use in Cancer Treatment; stockholder of Merck & Co. F.J.H.: Full-time employee of Immune Design during conduct of the study; stock or stock options and support for attending meetings and/or travel as employee of Immune Design and Oncternal Therapeutics. S.Y.: Former employee of Immune Design with stock options. C.R.F.: Research funding from 4 D, AbbVie Inc., Acerta Pharma, LLC, Adaptimmune, Allogene Therapeutics, Amgen Inc., Bayer, Celgene Corporation, Cellectis, EMD, Gilead Sciences, Inc., Genentech/Roche Pharma, Guardant, Iovance Biotherapeutics, Janssen Pharmaceuticals, Inc., Kite Pharma, MorphoSys AG, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda Pharmaceutical Company, TG Therapeutics, Inc., Xencor, Ziopharm, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, V Foundation for Cancer Research, and Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research; consultant for AbbVie Inc., Bayer, BeiGene, Celgene Corporation, Denovo Biopharma LLC, Genentech/Roche Pharma, Genmab, Gilead Sciences, Inc., Karyopharm Therapeutics, Pharmacyclics/Janssen Pharmaceuticals, Inc., Seagen, and Spectrum Pharmaceuticals, Inc.

Data availability statement

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.

Prior presentation

Presented as a poster at the 2017 American Society for Clinical Oncology Meeting, Chicago, IL, June 1–5, 2017; the 2017 American Society of Hematology Annual Meeting, Atlanta, GA, December 9–12, 2017; the Inaugural AACR International Meeting: Advances in Malignant Lymphoma, Boston, MA, June 22–26, 2018; the 2018 American Society of Hematology Annual Meeting, San Diego, CA, November 30–December 4, 2018; and the 2018 Society for Immunotherapy of Cancer Annual Meeting, Washington, DC, November 7–11, 2018.

Additional information

Funding

This study was supported by research funding from Immune Design Corp., a wholly-owned subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.