V Moreno1, E Calvo2, M R Middleton3, F Barlesi4,5, C Gaudy-Marqueste4, A Italiano6,7, E Romano8, A Marabelle5, E Chartash9, K Dobrenkov9, H Zhou9, E C Connors9, Y Zhang9, M Wermke10. 1. START Madrid-FJD, Hospital Fundación Jimenez Diaz, Av. de los Reyes Católicos, 28040, Madrid, Spain. victor.moreno@startmadrid.com. 2. START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain. 3. Department of Oncology, University of Oxford, Oxford, UK. 4. CEPCM CLIP2, Assistance Publique Hôpitaux de Marseille, Aix Marseille University, Marseille, France. 5. Medical Oncology Department, Gustave Roussy, Villejuif, France. 6. Department of Medical Oncology, University of Bordeaux, Bordeaux, France. 7. Early Phase Trials Unit, Institut Bergonié, Bordeaux, France. 8. Center for Cancer Immunotherapy, Dept of Oncology, INSERM U932, PSL Research University, Institut Curie, Paris, France. 9. Merck & Co., Inc., Rahway, NJ, USA. 10. Technische Universität Dresden, Medizinische Fakultät, NCT/UCC Early Clinical Trial Unit, Dresden, Germany.
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.
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.
Authors: Lesley Seymour; Jan Bogaerts; Andrea Perrone; Robert Ford; Lawrence H Schwartz; Sumithra Mandrekar; Nancy U Lin; Saskia Litière; Janet Dancey; Alice Chen; F Stephen Hodi; Patrick Therasse; Otto S Hoekstra; Lalitha K Shankar; Jedd D Wolchok; Marcus Ballinger; Caroline Caramella; Elisabeth G E de Vries Journal: Lancet Oncol Date: 2017-03-02 Impact factor: 41.316
Authors: David L Elion; Max E Jacobson; Donna J Hicks; Bushra Rahman; Violeta Sanchez; Paula I Gonzales-Ericsson; Olga Fedorova; Anna M Pyle; John T Wilson; Rebecca S Cook Journal: Cancer Res Date: 2018-09-17 Impact factor: 12.701