Safety and preliminary antitumor activity were evaluated in the first-in-human phase 1/2 study (NCT03065023) of intratumoral injections of the RIG-I agonist MK-4621 in patients (pts) with advanced or recurrent tumors.
Pts ≥18 years old with advanced/refractory tumors were included. MK-4621 was administered twice a week over a 4-week period. Dose escalation followed a 3+3 design to determine maximum tolerated dose or maximum feasible dose. Dose levels studied were 0.2, 0.4, 0.6, and 0.8 mg. In the absence of disease progression, additional cycles were allowed (extended treatment). Primary end points were incidence and severity of adverse events (AEs) and dose-limiting toxicities. Secondary end point was ORR per irRECIST.
A total of 15 pts were included in the interim analysis: 3 cohorts of 3 pts each and 1 cohort of 6 pts (0.8 mg). Intended treatment was administered to all 15 pts. Six pts (40.0%) entered the extended treatment period. No dose-limited toxicities were observed, and the safety profile was favorable at all dose levels. All pts experienced at least 1 AE. Most common (≥25%): pyrexia (73.3%), fatigue (73.3%), headache (33.3%), and nausea (26.7%). Fourteen pts (93.3%) had at least 1 drug-related AE; most common were pyrexia (11 pts, 73.3%) and fatigue (6 pts, 40%). All drug-related AEs were grade 1-2 except for 1 grade 3 pyrexia and 1 grade 3 pain and anxiety. Seven pts (47.7%) experienced grade 3-5 AEs, and 8 pts (53.3%) experienced immune-mediated AEs. No drug-related AEs led to study drug withdrawal or death. At data cutoff, 4 pts (26.7%) experienced best overall response of stable disease. Pharmacokinetic findings demonstrate minimal systemic exposure following intratumoral administration of MK-4621 up to the 0.8-mg dose. In addition, MK-4621 treatment increased circulating chemokine levels in serum and expression levels of genes involved in interferon signaling in tumors.
In this interim analysis, MK-4621 appeared to be safe and tolerable for pts with advanced or recurrent tumors with no dose-limiting toxicities.
Clinical trial identification
ClinicalTrials.gov, NCT03065023. Trial initiated: February 27, 2017.
Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA.