Abstract CT004: Intratumoral (IT) MEDI1191 + durvalumab (D): Update on the first-in-human study in advanced solid tumors
Authors: Castañón Eduardo , Zamarin Dmitriy , Carneiro Benedito A. , Marron Thomas , Patel Sandip Pravin , Subbiah Vivek , Mehmi Inderjit , Oberoi Honey Kumar , El-Khoueiry Anthony , Ridgway Benjamin , Elgeioushi Nairouz , Durham Nicholas M. , Jennings Emily , Abadier Michael , Fraenkel Paula G. , Azaro Analia , Hamid Omid 
Published: April 2023

Abstract
Background: MEDI1191 is an IT-administered lipid nanoparticle-formulated mRNA encoding IL-12. This phase 1, open-label study (NCT03946800) showed that MEDI1191 in sequential (seq) or concurrent (conc) combination with IV D (anti-PD-L1) was safe and had preliminary antitumor activity in pts with advanced/metastatic solid tumors who had progressed on SoC. Here we present updated analyses, including the first report of pts with deep-seated lesions.
Methods: In Part 1A (subcutaneous/cutaneous [SC/C] lesions), pts received MEDI1191 on Days 1 and 22, followed by D 1500 mg on Day 43 then Q4W. In Parts 1B (SC/C) and 1D (deep-seated lesions), pts received MEDI1191 on Days 1, 29 and 57 then Q8W, with D on Day 1 then Q4W. Treatment continued for up to 2 years, until progression or unacceptable toxicity. Primary objectives were safety, tolerability and maximum tolerated dose (MTD); secondary objectives included preliminary antitumor activity per RECIST v1.1 in injected/non-injected lesions.
Results: As of October 5, 2022, 61 pts (40 had prior anti-PD-[L]1) received seq (Part 1A 0.1-12.0 μg, n=25 [4/25 had MEDI1191 only]) or conc (Part 1B 1.0-12.0 μg, n=27; Part 1D 1.0-3.0 μg, n=9) MEDI1191 + D. The most commonly represented cancer was melanoma (n=14). Pts in Part 1D had pancreatic (n=2), colorectal (n=2), gastric, anal, melanoma, neuroendocrine or unknown primary cancer (each n=1); all had hepatic metastases. There were no dose-limiting toxicities for MEDI1191 and no MTD was identified. Gr ≥3 MEDI1191-related AEs occurred in 3 pts (4.9%; Gr 3 asthenia and pyrexia, each n=1; Gr 4 lymphocyte count decreased, n=1); 2 pts (3.3%) had a MEDI1191-related serious AE (SAE; Gr 2 pyrexia and confusion, each n=1). Gr ≥3 D-related AEs occurred in 3 pts (4.9%; Gr 3 asthenia, pyrexia [both also MEDI1191-related] and pruritus; each n=1); 1 pt (1.6%) had a D- and MEDI1191-related SAE (Gr 2 pyrexia). In Parts 1A and 1B, 7 pts had partial responses (PRs): 5 confirmed (cPRs) in melanoma (n=2), sarcoma, breast and neuroendocrine cancer (each n=1), and 2 unconfirmed (uPRs) in melanoma and head and neck cancer (each n=1); no pts had PRs in Part 1D. 3/5 pts with cPR had prior anti-PD-(L)1; 2/3 also had prior anti-CTLA-4. For the 5 cPRs, DoR was 1.9-22.3 months (median not reached); 3 had ongoing PRs and 2 had stable disease (SD) at data cutoff. Non-target injected lesions shrank in 4 pts with cPRs. Overall, 15 pts had SD (including the 2 uPRs). MEDI1191 induced pharmacodynamic changes in the periphery and tumor microenvironment. A ≥2-fold increase in serum IL-12 levels was seen in 42/46 pts, with increases in serum IFNγ in 37/46; 9/22 pts had ≥2-fold increases in CD8+ T cell tumor infiltration and tumoral PD-L1 expression.
Conclusions: MEDI1191 + D was safe and tolerable in pts with SC/C or deep-seated lesions. Antitumor activity was seen in injected and distant lesions, and pharmacodynamic activity was consistent with expectations based on mechanistic biology.
Citation Format: Eduardo Castañón, Dmitriy Zamarin, Benedito A. Carneiro, Thomas Marron, Sandip Pravin Patel, Vivek Subbiah, Inderjit Mehmi, Honey Kumar Oberoi, Anthony El-Khoueiry, Benjamin Ridgway, Nairouz Elgeioushi, Nicholas M. Durham, Emily Jennings, Michael Abadier, Paula G. Fraenkel, Analia Azaro, Omid Hamid. Intratumoral (IT) MEDI1191 + durvalumab (D): Update on the first-in-human study in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT004.