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Clinical Trial
. 2022 Dec;71(12):2985-2998.
doi: 10.1007/s00262-022-03191-8. Epub 2022 May 21.

Treatment with a retinoic acid-inducible gene I (RIG-I) agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: results from two phase 1 studies

V Moreno  1 , E Calvo  2 , M R Middleton  3 , F Barlesi  4   5 , C Gaudy-Marqueste  4 , A Italiano  6   7 , E Romano  8 , A Marabelle  5 , E Chartash  9 , K Dobrenkov  9 , H Zhou  9 , E C Connors  9 , Y Zhang  9 , M Wermke  10
Affiliations
Clinical Trial

Treatment with a retinoic acid-inducible gene I (RIG-I) agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: results from two phase 1 studies

V Moreno et al. Cancer Immunol Immunother. 2022 Dec.

Abstract

Background: We evaluated MK-4621, an oligonucleotide that binds and activates retinoic acid-inducible gene I (RIG-I), as monotherapy (NCT03065023) and in combination with the anti-programmed death 1 antibody pembrolizumab (NCT03739138).

Patients and methods: Patients were ≥ 18 years with histologically/cytologically confirmed advanced/metastatic solid tumors with injectable lesions. MK-4621 (0.2‒0.8 mg) was administered intratumorally as a stable formulation with jetPEI™ twice weekly over a 4-week cycle as monotherapy and weekly in 3-week cycles for up to 6 cycles in combination with 200 mg pembrolizumab every 3 weeks for up to 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), treatment-related adverse events (AEs), and treatment discontinuation due to AEs.

Results: Fifteen patients received MK-4621 monotherapy and 30 received MK-4621 plus pembrolizumab. The only DLT, grade 3 pleural effusion that subsequently resolved, occurred in a patient who received MK-4621/jetPEI™ 0.8 mg plus pembrolizumab. 93% of patients experienced ≥ 1 treatment-related AE with both monotherapy and combination therapy. No patients experienced an objective response per RECIST v1.1 with MK-4621 monotherapy; 4 (27%) had stable disease. Three (10%) patients who received combination therapy had a partial response. Serum and tumor biomarker analyses provided evidence that MK-4621 treatment induced an increase in gene expression of interferon signaling pathway members and associated chemokines and cytokines.

Conclusions: Patients treated with MK-4621 monotherapy or in combination with pembrolizumab experienced tolerable safety and modest antitumor activity, and there was evidence that MK-4621 activated the RIG-I pathway. At the doses tested, MK-4621 did not confer meaningful clinical benefit.

Trial registration: ClinicalTrials.gov, NCT03065023 and NCT03739138.

Keywords: Innate immunity; Interferon type I; Intratumoral injection; Pembrolizumab; RIG-I.

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Conflict of interest statement

V. Moreno: consulting fees from: Bayer, Pieris, BMS, Janssen. Traveling support from: Regeneron/Sanofi, BMS, Bayer. Speaker´s Bureau: Nanobiotix, BMS, Bayer. Educational Grant: Medscape/Bayer. E. Calvo: Advisory: Adcendo, Alkermes, Amunix, Anaveon, Amcure, AstraZeneca, BMS, Janssen, MonTa, MSD, Nanobiotix, Nouscom, Novartis, OncoDNA, PharmaMar, Roche/Genentech, Sanofi, Servier, SyneosHealth, TargImmune, T-knife; Research grants: Achilles, BeiGene (IDMC steering committee), EORTC IDMC (non-financial interest), MedSIR (steering committee); Scientific Board: Adcendo, Chugai Pharmaceuticals, PsiOxus Therapeutics; Employee: HM Hospitals Group and START Program of Early Phase Clinical Drug Development in Oncology; Medical Oncologist, Clinical Investigator; Director, Clinical Research Ownership: START corporation; Oncoart Associated; International Cancer Consultants; Non-profit Foundation INTHEOS (Investigational Therapeutics in Oncological Sciences): founder and president. M. R. Middleton: Dr. Middleton reports grants from Roche and AstraZeneca; grants and personal fees from GSK, personal fees and other from Novartis, Immunocore, Bristol-Myers Squibb, other from Millenium, Pfizer, Regeneron, personal fees, non-financial support, and other from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; personal fees and other from BiolineRx, personal fees and non-financial support from Replimune, personal fees from Kineta and Silicon Therapeutics, and personal fees from Silicon Therapeutics outside the submitted work. F. Barlesi: personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda. C. Gaudy-Marqueste: Honoraria for lectures by Bristol-Myers Squibb; travel support from MSD, BMS, Pierre Fabre. A. Italiano: grants to institution from Bayer, AstraZeneca, Bristol-Myers Squibb, MSD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Roche, Springworks, Epizyme; and consulting fees from AstraZeneca, Bayer, Roche, Daiichi-Sankyo. E. Romano: travel support from MSD for participation in a scientific meeting outside the topic of the submitted work. A. Marabelle: institutional research funding from MSD; grant from Fondation MSD Avenir outside the topic of the manuscript; and honoraria and travel expenses for participation in a scientific advisory board from MSD outside the topic of the submitted work. E. Chartash: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholder in Merck & Co., Inc., Rahway, NJ, USA. K. Dobrenkov: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholder in Merck & Co., Inc., Rahway, NJ, USA. H. Zhou: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. E.C. Connors: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholder in Merck & Co., Inc., Rahway, NJ, USA. Y. Zhang: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholder in Merck & Co., Inc., Rahway, NJ, USA. M. Wermke: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA for funding of study and professional medical writing; research funding to institution from Roche; consulting fees from Novartis, Pfizer, Boehringer-Ingelheim, Gemoab, Roche, Takeda, Lilly, MSD, AstraZeneca, Amgen, Bristol-Myers Squibb, Immatics; honoraria from Novartis and Roche; travel support from Roche, Bristol-Myers Squibb, Amgen, Pfizer; and participation on data safety monitoring board or advisory board for ISA Therapeutics.

Figures

Fig. 1
Fig. 1
Time on study treatment and response based on investigator assessment per RECIST v1.1 for patients treated with (a) MK-4621 monotherapy and (b) MK-4621 + pembrolizumab combination therapy. c Maximum change in dimensions for injected and noninjected lesions for patients treated with MK-4621 + pembrolizumab. d Percentage change from baseline of target lesion (injected and noninjected) dimensions based on investigator assessment per RECIST v1.1 for patients enrolled in the combination study. *Indicates no change from baseline. CRC, colorectal cancer; EC, esophageal cancer; Adeno, adenoid-cystic carcinoma
Fig. 1
Fig. 1
Time on study treatment and response based on investigator assessment per RECIST v1.1 for patients treated with (a) MK-4621 monotherapy and (b) MK-4621 + pembrolizumab combination therapy. c Maximum change in dimensions for injected and noninjected lesions for patients treated with MK-4621 + pembrolizumab. d Percentage change from baseline of target lesion (injected and noninjected) dimensions based on investigator assessment per RECIST v1.1 for patients enrolled in the combination study. *Indicates no change from baseline. CRC, colorectal cancer; EC, esophageal cancer; Adeno, adenoid-cystic carcinoma
Fig. 2
Fig. 2
Plasma concentration of MK-4621 following intratumoral administration. a Patients treated with MK-4621 monotherapy. b Patients treated with MK-4621 + pembrolizumab combination therapy. Each line represents an individual patient. LOQ, limit of quantification
Fig. 3
Fig. 3
Type I IFN pathway biomarker expression. Serum fold-change of CXCL10 and CCL8 following treatment with MK-4621 in patients treated with (a) MK-4621 monotherapy and (b) MK-4621 + pembrolizumab combination therapy. IFIT1 fold change in tumor tissue from baseline (c) to week 5, day 29 among patients with paired baseline and on-treatment samples treated with MK-4621 monotherapy (n = 10) or MK-4621 + pembrolizumab combination therapy (n = 7) (paired samples are from the same patient but not necessarily from the same injected lesion) and (d) to cycle 3, day 1 for patients treated with MK-4621 + pembrolizumab combination therapy. (e) Change in TcellinfGEP from baseline to cycle 3, day 1 for patients treated with MK-4621 + pembrolizumab combination therapy (n = 7) (paired samples are from the same patient but not necessarily from the same injected lesion)
Fig. 3
Fig. 3
Type I IFN pathway biomarker expression. Serum fold-change of CXCL10 and CCL8 following treatment with MK-4621 in patients treated with (a) MK-4621 monotherapy and (b) MK-4621 + pembrolizumab combination therapy. IFIT1 fold change in tumor tissue from baseline (c) to week 5, day 29 among patients with paired baseline and on-treatment samples treated with MK-4621 monotherapy (n = 10) or MK-4621 + pembrolizumab combination therapy (n = 7) (paired samples are from the same patient but not necessarily from the same injected lesion) and (d) to cycle 3, day 1 for patients treated with MK-4621 + pembrolizumab combination therapy. (e) Change in TcellinfGEP from baseline to cycle 3, day 1 for patients treated with MK-4621 + pembrolizumab combination therapy (n = 7) (paired samples are from the same patient but not necessarily from the same injected lesion)
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