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Intratumoral administration of the first‑in‑class mRNA therapeutic mRNA‑2416, given alone or in combination with durvalumab (Imfinzi), was well tolerated and demonstrated preliminary biologic activity in patients with ovarian cancer and other advanced solid tumors, according to results from a first‑in‑human, phase 1/2 study (NCT03323398).
Findings published in The Oncologist demonstrated that the overall response rate (ORR) was 0.0% (95%, 0.0%-11.9%) with mRNA‑2416 monotherapy in arm A (n = 29) and 5.3% (95% CI, 0.1%-26.0%) for mRNA‑2416 plus durvalumab in arm B (n = 19). In arm A, the stable disease (SD) rate was 31%; progressive disease (PD) occurred in 52% of patients, and 17% were not evaluable. In arm B, 1 patient (5%) with ovarian cancer experienced a partial response (PR) at the 4.0‑mg mRNA‑2416 dose; however, this response was unconfirmed due to a lack of a confirmatory scan. Additionally, 11% achieved SD, and 84% experienced PD.
Median progression‑free survival (PFS) was 60 days (95% CI, 50-108; range, 29-179) in arm A and 50 days (95% CI, 38-55; range, 11-117) in arm B. By immune‑related response criteria (irRC), SD was observed in 7 patients (24%) in arm A, with PD in 16 patients (55%) and 6 patients (21%) not evaluable. In arm B, 1 patient (5%) achieved PR, 2 patients (11%) achieved SD, 15 patients (79%) had PD, and 1 patient (5%) was not evaluable.
The maximum tolerated dose (MTD) was not reached. Treatment‑related adverse effects (TRAEs) were primarily grade 1/2 in severity; 8 grade 3 TRAEs occurred, and no grade 4/5 TRAEs were reported.
“Although predefined primary efficacy end points were not met, pharmacodynamic analyses provide evidence of the mechanism of action and support continued research into mRNA-based therapeutics to address the unmet challenge of difficult-to-treat malignancies,” lead study author Ryan J. Sullivan, MD, of Massachusetts General Hospital, and colleagues noted in the publication. “Additional research is needed to further elucidate biomarkers of response and identification of the subset of patients most likely to benefit.”
Phase 1/2 Study Design and Enrollment Criteria
The first‑in‑human, open‑label, multicenter study evaluated intratumoral administration of the mRNA therapeutic mRNA‑2416 alone or in combination with intravenous durvalumab in patients with advanced solid tumors or lymphoma. The trial included dose‑escalation, dose‑confirmation, and dose‑expansion phases.
Patients were required to have at least one measurable lesion per RECIST 1.1 criteria and a tumor of sufficient size to support intratumoral injection. Other eligibility criteria included an ECOG performance status of 0 or 1, adequate organ function, and a life expectancy of greater than 12 weeks. Patients in the ovarian cancer expansion cohort were required to have received more than 2 prior lines of therapy, and those with BRCA‑mutated disease must have progressed on prior PARP inhibitor therapy. There were no restrictions on prior immune checkpoint inhibitor exposure.
In the dose‑escalation phase, patients in arm A received mRNA‑2416 at 1.0 mg, 2.0 mg, 4.0 mg, or 8.0 mg. Following assessment of the MTD and recommended dose for expansion (RDE), arm B evaluated mRNA‑2416 starting at 4.0 mg in combination with durvalumab at 1500 mg every 4 weeks, with escalation to 8.0 mg. Dose expansion was not pursued in arm A due to modest single‑agent activity. In arm B, expansion was conducted in patients with recurrent ovarian cancer based on preclinical evidence supporting synergy between OX40L agonism and PD‑L1 inhibition.
In the combination arm, mRNA‑2416 was injected intratumorally first, followed by durvalumab infusion more than 30 minutes later. Durvalumab was administered at a fixed dose of 1500 mg intravenously every 4 weeks for patients weighing over 30 kg, or 20 mg/kg for patients below 30 kg.
The primary end points for phase 1 were safety, tolerability, and identification of the MTD/RDE. The primary end point for phase 2 was investigator‑assessed ORR. Secondary end points included disease control rate (DCR), PFS, duration of response (DOR), pharmacokinetics, and anti‑OX40L antibody development. Exploratory end points included assessment of systemic and intratumoral immune responses.
Safety Profile
Across both phases of the trial, no dose‑limiting toxicities (DLTs) were observed. In arm A the most common TRAEs occurring in at least 10% of patients included injection‑site pain (28%), flushing (26%), pyrexia (23%), fatigue (21%), injection‑site erythema (21%), nausea (18%), chills (15%), myalgia (13%), dyspnea (13%), back pain (10%), and influenza‑like illness (10%).
In arm B, the most common mRNA‑2416‑related TRAEs were pyrexia (46%), injection‑site pain (41%), nausea (32%), fatigue (27%), flushing (23%), chills (14%), influenza‑like illness (14%), tachycardia (14%), hypotension (14%), dyspnea (14%), and hyperhidrosis (14%). Durvalumab‑related AEs occurring in more than 10% of patients included fatigue (27%), pyrexia (23%), and nausea (23%).
Serious treatment-emergent AEs considered related to mRNA‑2416 occurred in 5 patients. In arm A, these effects included grade 3 skin ulceration, grade 3 dyspnea, grade 2 injection‑related reaction with hypoxia, and grade 2 systemic inflammatory response syndrome. In arm B, 1 patient experienced a grade 3 cerebrovascular accident with a positive lupus anticoagulant, assessed by the investigator as possibly related to both mRNA‑2416 and durvalumab.
Biomarker Assessments
Intratumoral administration of mRNA‑2416 induced pharmacodynamic changes consistent with immune activation. In monotherapy‑treated patients, OX40L protein expression increased within the tumor microenvironment after injection. In combination‑treated patients, OX40L expression increased in 4 of 4 biopsies obtained 24 to 48 hours post‑treatment.
Immunohistochemical and multiplex quantitative immunofluorescence analyses demonstrated increased T‑cell infiltration in tumor nests and surrounding stroma. Gene expression profiling revealed activation of proinflammatory immune pathways, including upregulation of T‑cell–inflamed signature genes in 6 of 9 monotherapy patients assessed. PD‑L1 expression, an interferon‑inducible marker, was also elevated following treatment, with effects most pronounced in injected lesions.
Reference
Sullivan RJ, Yeku OO, Teoh D, et al. First-in-human phase I/II, open-label study of mRNA-2416 alone or combined with durvalumab in patients with advanced solid tumors and ovarian cancer. Oncologist. 2025;30(6). doi:10.1093/oncolo/oyaf115