Early results from a phase I study showed promising safety, tolerability, and efficacy following sequential intratumoural (IT) administration of MEDI1191, an IL-12 mRNA agent, followed by durvalumab (anti-PD-L1) in patients with advanced solid tumours who progressed on one or more lines of standard systemic treatment. These findings were reported at the ESMO Targeted Anticancer Therapies (TAT) Virtual Congress 2021 held on 1-2 March.
Dr. Omid Hamid, head of Translational Research and ImmunoOncology at The Angeles Clinical and Research Institute, a Cedars-Sinai Affiliate in Los Angeles, USA explained that IL-12 is a strong driver of the TH1 immune response. Systemically delivered recombinant IL-12 is poorly tolerated.
MEDI1191 is a lipid nanoparticle-formulated therapy that was developed to be administered by IT injection in order to drive local IL-12 production and induce anti-tumour activity.
Data from preclinical models showed that IT IL-12 mRNA induced a potent TH1-mediated anti-tumour response, which could be further enhanced by PD-L1 blockade.
Dr. Hamid and co-investigators evaluated the safety and efficacy of MEDI1191 (IL-12 mRNA) in a phase I, multicentre, open-label, dose-escalation and expansion study (NCT03946800).
The dose escalation part 1 of this study aimed to determine the dose of MEDI1191 in combination with durvalumab at 1500 mg intravenously that was delivered every 4 weeks either sequentially or concurrently in patients with advanced solid tumours that included both superficial and deep-seated lesions. The study included patients who were immunotherapy-naïve or pre-treated, including anti-PD-1(L) and CTLA-4 pretreated solid tumours.
The primary endpoints for part 1 included safety and the determination of the maximum tolerated dose (MTD) as well as a pharmacodynamic active dose, and the secondary endpoints were efficacy according to the disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS), pharmacokinetics, and immunogenicity. The study also includes an expansion part 2.
From May 2019 to December 2020, the study enrolled 10 patients with superficial lesions who were relegated to one of three dose escalation cohorts. Of these, 6 patients had received prior immunotherapy.
Preliminary analysis indicates MEDI1191 is safe
Regarding the co-primary endpoint of safety, no dose limiting toxicities, adverse events of special interest, treatment related adverse events ≥ Grade 3, or treatment-related serious adverse events were reported.
In the efficacy analysis, two partial responses (PRs) were demonstrated in patients that had received prior immunotherapy and also had PD-L1 negative tumours. Of these PRs, one occurred in a patient with mucosal melanoma who displayed tumour shrinkage of both injected and non-injected lesions following 2 doses of MEDI1191 that occurred prior to administration of sequential durvalumab. This patient was PD-1 and CTLA-4 pretreated with progression on those regimens. Another patient with PD-1 pretreated HNSCC showed response to therapy.
Preliminary findings from the pharmacodynamic analysis indicated that MEDI1191 induced transient elevation of serum levels of IL-12, as well as concordant changes in IFN-gamma and CXCL10.
Conclusions
Based on these data the authors concluded that the IT MEDI1191 sequentially delivered with durvalumab was well-tolerated and showed encouraging efficacy.
The treatment also demonstrated preliminary anti-tumour and pharmacodynamic activity in immunotherapy pre-treated patients that was consistent with the expected mechanism of action. However, they advised that these preliminary data require further validation.
They noted that this study is active and recruiting. Current regimes will evaluate concurrent administration of MEDI1191 and durvalamab in cutaneous/subcutaneous lesions and in virsceral metastases.
This study was funded by AstraZeneca.
Reference
19O – Hamid O, Hellman M, Carneiro B, et al. Preliminary safety, antitumor activity and pharmacodynamics results of HIT-IT MEDI1191 (mRNA IL-12) in patients with advanced solid tumors and superficial lesions. ESMO Targeted Anticancer Therapies (TAT) Virtual Congress (1-2 March 2021).