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
© 2022. Springer-Verlag GmbH Germany, part of Springer Nature..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:71 |
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| Enthalten in: |
Cancer immunology, immunotherapy : CII - 71(2022), 12 vom: 06. Dez., Seite 2985-2998 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Moreno, V [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.10.2022 Date Revised 26.04.2024 published: Print-Electronic ClinicalTrials.gov: NCT03739138, NCT03065023 Citation Status MEDLINE |
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| doi: |
10.1007/s00262-022-03191-8 |
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| 245 | 1 | 0 | |a Treatment with a retinoic acid-inducible gene I (RIG-I) agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors |b results from two phase 1 studies |
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| 500 | |a ClinicalTrials.gov: NCT03739138, NCT03065023 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. Springer-Verlag GmbH Germany, part of Springer Nature. | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
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