Abstract CT183: First-in-human study of MEDI1191 (mRNA encoding IL-12) plus durvalumab in patients (pts) with advanced solid tumors
Autor: | Benedito A. Carneiro, Dmitriy Zamarin, Thomas Marron, Inderjit Mehmi, Sandip P. Patel, Vivek Subbiah, Anthony El-Khoueiry, David Grand, Kirema Garcia-Reyes, Sanjay Goel, Phillip Martin, Jixin Wang, Yuling Wu, Steven Eck, Benjamin Ridgway, Nairouz Elgeioushi, Jim Eyles, Nicholas Durham, Analia Azaro, Omid Hamid |
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Rok vydání: | 2022 |
Předmět: | |
Zdroj: | Cancer Research. 82:CT183-CT183 |
ISSN: | 1538-7445 0394-6800 |
Popis: | Background: IL-12 is a key mediator of antitumor immune response. In preclinical models, IT IL-12 mRNA led to IFNγ release and CD8+ T cell-dependent tumor regression and potentiated PD-L1 blockade. MEDI1191, a lipid nanoparticle-formulated mRNA encoding IL-12 delivered by IT injection, drives IL-12 production and enhances antitumor immune response with improved tolerability. We hypothesized that combining MEDI1191 with PD-L1 blockade would augment antitumor immunity in vivo. Here we report updated results from the dose-escalation phase of the first-in-human study of IT MEDI1191 and IV durvalumab (D; anti-PD-L1) for advanced/metastatic solid tumors (NCT03946800). Methods: In this multicenter, open-label study, MEDI1191 was dosed sequentially (seq, Part 1A) or concurrently (conc, Part 1B) with D. In Part 1A, MEDI1191 was given IT on Days 1 and 22 followed by D 1500 mg on day 43 and then Q4W IV. In Part 1B, MEDI1191 was given IT on Days 1, 29, 57 and then Q8W, along with D on Day 1 and then Q4W. Treatment continued until progression or unacceptable toxicity for up to 2 years. Eligible adult pts had any solid tumor with cutaneous or subcutaneous lesions suitable for IT injection and progression on standard therapy for recurrent/metastatic disease. Primary objectives were safety and tolerability and determination of maximum tolerated dose (MTD); secondary objectives included preliminary antitumor activity by RECIST v1.1. Results: Starting in May 2019, 31 pts received seq MEDI1191 with D (Part 1A cohorts 0.1-12 μg; n=20) or conc MEDI1191 with D (Part 1B cohorts 1.0-3.0 μg; n=11); 23 pts had received prior anti-PD-1/PD-L1 therapy. Most common tumor types were melanoma, n=8; head and neck cancer, n=4; and breast cancer, n=4. At the data cutoff of Dec 7, 2021, there were no dose-limiting toxicities and no MTD was identified. One pt (3.2%) had a Gr ≥3 MEDI1191-related AE (Gr 3 pyrexia, resolved within 24 hr) and 1 (3.2%) had a MEDI1191-related serious AE (SAE; Gr 2 confusion). Two pts had Gr 3 D-related AEs (6.5%, pyrexia also related to MEDI1191 and pruritus; each n=1); none had a D-related SAE. There were no Gr 4 related AEs. 3 pts had partial responses (PR): 1 with head and neck cancer (unconfirmed, off study) and 2 with anti-PD-1 resistant melanoma (1 confirmed, >12 months on treatment; 1 unconfirmed, off study); 10 pts had stable disease (including the 2 unconfirmed PRs). Among pts with available biomarker data (up to 3 μg in Part 1A and 1 μg in Part 1B), MEDI1191 increased serum IL-12 in 15/17 pts, increased CD8+ T cell tumor infiltration by >2-fold in 8/14 pts and increased tumor PD-L1 expression in 6/14 pts. Conclusions: IT MEDI1191 plus systemic anti-PD-L1 was safe and feasible. Preliminary antitumor efficacy and pharmacodynamics, including tumor CD8+ T cell recruitment, were consistent with expected mechanism of action. Pts with injectable deep visceral and superficial lesions are being recruited. Citation Format: Benedito A. Carneiro, Dmitriy Zamarin, Thomas Marron, Inderjit Mehmi, Sandip P. Patel, Vivek Subbiah, Anthony El-Khoueiry, David Grand, Kirema Garcia-Reyes, Sanjay Goel, Phillip Martin, Jixin Wang, Yuling Wu, Steven Eck, Benjamin Ridgway, Nairouz Elgeioushi, Jim Eyles, Nicholas Durham, Analia Azaro, Omid Hamid. First-in-human study of MEDI1191 (mRNA encoding IL-12) plus durvalumab in patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT183. |
Databáze: | OpenAIRE |
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