Intratumoral Injection of mRNA-2752 and Pembrolizumab for High-Risk Ductal Carcinoma In Situ: A Phase 1 Nonrandomized Clinical Trial.

Importance: Intratumoral immunotherapy that leverages the biological characteristics of high-risk ductal carcinoma in situ (DCIS) may be able to reduce the extent of surgical treatment and provide an alternative approach to improve patient outcomes. Objective: To determine if combination intratumoral immunotherapy can activate immune cells to shrink or eliminate high-risk DCIS. Design, Setting, and Participants: This phase 1 open-label nonrandomized clinical trial at a single academic center tested the safety and efficacy of intratumoral immunotherapy in patients with high-risk DCIS, defined as at least 2 of the following present: younger than 45 years, tumor size greater than 5 cm, high-grade, palpable mass, hormone receptor (HR)-negative, or ERBB2-positive. Patients were enrolled between June 8, 2021, and December 13, 2022. Intervention: Pembrolizumab (anti-programmed cell death protein 1), dose ranging from 2 mg to 8 mg, and mRNA-2752 (a combination of interleukin [IL]-23, IL-36γ, and OX40L mRNAs), dose ranging from 1 mg to 4 mg, delivered intratumorally, with 2 to 4 doses given 2 to 3 weeks apart. Main Outcomes and Measures: The primary objective was to evaluate the safety and tolerability of intratumoral injections of pembrolizumab and mRNA-2752. The secondary objectives were to assess radiologic and pathological responses and immunological and histological differences in the posttreatment tumor microenvironment. Results: Ten female patients with high-risk DCIS (median [range] age, 46 [35-80] years) were enrolled. The median (range) tumor size was 5.3 (1.0-10.0) cm. Five tumors were HR-negative ERBB2-positive; 2 HR-negative ERBB2-negative; 2 HR-positive ERBB2-negative; and 1 HR-positive ERBB2-positive. Of all treated patients, 8 of 10 responded to treatment, and all 8 patients had ERBB2-positive or HR-negative DCIS. Three patients had complete responses. Three patients with negative posttreatment core biopsy results declined surgery and remained disease-free after 1 to 2 years. Multiplex immunofluorescence staining demonstrated that high baseline levels of tumor-infiltrating lymphocytes and programmed cell death ligand 1-positive cells (immune or tumor) were associated with a better treatment response. All patients experienced up to 1 week of fever, malaise, flulike symptoms, axillary adenopathy, erythema, injection site swelling, and swelling in the breast. One patient had intermittent urticaria for 3 months. The dose was serially reduced from 8 mg to 2 mg for pembrolizumab and 4 mg to 1 mg for mRNA-2752 to improve tolerability. The final recommended combination dose is pembrolizumab, 4 mg, with mRNA-2752, 1 mg. Conclusions and Relevance: In this phase 1 nonrandomized clinical trial, the results suggest that intratumoral injections of pembrolizumab and mRNA-2752 are safe and may induce rapid regression of high-risk DCIS with high immune infiltrates. These findings warrant additional investigation, and studies are ongoing. Trial Registration: ClinicalTrials.gov Identifier: NCT02872025.