Background The oligonucleotide MK-4621 selectively binds RIG-I to activate the RIG-I pathway, inducing a type 1 interferon response. In a first-in-human study (MK-4621-001, NCT03065023), intratumoral MK-4621 resulted in no dose-limiting toxicities (DLTs) and increased circulating chemokine levels and tumor expression of interferon signaling genes in patients with advanced/recurrent solid tumors. We report outcomes from an open-label, dose-escalation phase 1/1b study of intratumoral MK-4621 and intravenous pembrolizumab in patients with advanced solid tumors (MK-4621-002, NCT03739138).

Methods Participants were aged =18 years with histologically/cytologically confirmed advanced/metastatic solid tumors, ECOG PS 0/1, cutaneous, subcutaneous, and/or nodal lesions amenable to intratumoral injection and had received, or were intolerant to, all treatments known to confer clinical benefit. In 3-week cycles, patients received intratumoral MK-4621 0.4, 0.6, or 0.8 mg on days 1, 8, and 15 for 6 cycles (delivered via jetPEI®, Polyplus Transfection, Illkirch, France) plus intravenous pembrolizumab 200 mg on day 1 for 35 cycles. Treatment continued until disease progression or unacceptable toxicity. The primary objective was to establish a preliminary recommended phase 2 dose based on DLTs (cycle-1), AEs, and treatment discontinuations due to AEs; AEs were graded per NCI CTCAE v4.0. Tumor imaging was performed Q9W; response was assessed by the investigator.

Results As of May 14, 2020, 30 participants received therapy with MK-4621 0.4 (n=7), 0.6 (n=5), or 0.8 mg (n=18). Median time on therapy was 57 (range, 1-365) days. The most frequent tumor types were breast (20%) and melanoma (17%); 90% of patients received =2 prior lines of therapy. One patient in the 0.8-mg group experienced a DLT (grade 3 treatment-related pleural effusion), which resulted in treatment discontinuation; no other patient discontinued owing to AEs. Grade 3 treatment-related AEs occurred in 1 patient (14%) at the 0.4-mg dose (pyrexia), 1 patient (20%) at the 0.6-mg dose (hypertension), and 5 patients (28%) at the 0.8-mg dose (anemia [n=2], dyspnea/pleural effusion [n=1], lymphopenia [n=1], pyrexia [n=1]). No treatment-related grade 4/5 AEs occurred. Across dose levels, the most frequently occurring treatment-related AEs were pyrexia (63%), chills (37%), cytokine-release syndrome (20%), and nausea (20%). Efficacy outcomes are below (table 1). Significant changes in blood interferon-gamma inducible protein-10 and monocyte chemotactic protein-2 were observed at each dose level, consistent with the mechanism of action of MK-4621.

Conclusions The combination of intratumoral MK-4621 plus intravenous pembrolizumab had a manageable safety profile. At the highest dose level, modest antitumor activity was observed in patients treated with combination therapy.

Trial Registration ClinicalTrials. gov identifier, NCT03739138

Ethics Approval An independent institutional review board or ethics committee approved the protocol at each study site, and the trial is being conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki.