Abstract 3211: OQL025, a topical cream for the prevention of epidermal growth factor receptor inhibitor-induced skin rash
Authors: Liu Shilan , Zeng Wenqin , Li Wenxi , You Qing , Tyler Robert Claude , Luo Jie , Tang Hong , Zhang Shiyi 
Published: June 2023

Abstract
Background: Epidermal growth factor (EGF) and its receptor (EGFR) are expressed by several cell types including epidermal keratinocytes. EGF facilitates skin healing by promoting DNA synthesis and cell proliferation. However, driver mutations in EGFR can cause uncontrolled cell growth and cancers. Thus, EGFR has become a therapeutic target for tumors, especially those with EGFR mutations. EGFR inhibitors (EGFRIs) are widely used to treat various tumor types (e.g., non-small cell lung & colorectal cancers). EGFRIs cause inflammatory skin reactions (e.g., acneiform rash) generally within the first 3 weeks of therapy. We propose a novel topically applied cream (OQL025) containing a prodrug, OQRC184 that releases tofacitinib, a Janus Kinase (JAK) inhibitor, as a prophylaxis for EGFRi-induced skin rash.
Methods: OQRC184 is designed to enhance lipophilicity/solubility and when topically applied releases tofacitinib into cutaneous tissue. OQRC184 & tofacitinib potencies were characterized for JAK (JAK1, JAK2, JAK3, TyK2) in a cell-free isolated kinase assay. Pharmacokinetics (PK) were studied in Bama minipigs (n=15) with shaved dorsal skin (~10 mg/cm2) that were randomly assigned to 3 groups of OQRC184 @ 0.15, 0.3, 0.5 mg/cm2. Blood was collected (1 mL in EDTA-K2) at pre-dose & 0.5, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 h post-dose. Plasma concentrations of OQRC184 and tofacitinib (LLOQ of 0.01 ng/mL range 0.01 to 10 ng/mL) were determined with LC-MS/MS. Prevention of EGFRI-induced rash was studied with topically applied 3% or 6% OQRC184 or vehicle cream (CRM) in an SD rat EGFRI-induced rash model (oral afatinib 30 mg/kg (AF)), QD vs. vehicle (water (VW)). The four groups were VW+CRM; AF+CRM; AF+3%OQRC184; AF+6% OQRC184.
Results: OQRC184 had low inhibitory activity compared to tofacitinib against JAK1, JAK2, JAK3, and TyK2 with IC50 ratios of OQRC184 to tofacitinib for JAK1 (3610:1), JAK2 (4435:1), JAK3 (3814:1) and TyK2 (&gt;385:1). After a single topical administration, OQRC184 plasma concentrations were below the LLOQ in 42~52% of samples, and &lt;10-fold of LLOQ in 83%~88% of samples. Tofacitinib plasma concentrations were below the LLOQ in 67~87% of samples and &lt;10-fold of LLOQ in 90%~97% of samples. All rats treated with AF developed a rash by day 5. The incidence of rash grade ≥ 2 was lower in 3% and 6% OQRC184 groups vs. controls. Prophylactic treatment with 6% OQRC184 had almost no rash ≥ grade 2. The mean ±SE rash grade in the 3% and 6% OQRC184 prophylactic treatment groups was significantly lower than in the AF+CRM group (3% (0.53±0.23), 6% (0.30±0.16) vs. AF+CRM (1.03±0.44 (p&lt;0.05)).
Conclusion: OQRC184, a prodrug designed for releasing tofacitinib into dermal layers, lacks inhibitory potential for a family of JAK kinases. OQL025 topical cream containing OQRC184 showed minimal systemic exposure for either OQRC184 or tofacitinib and effectively prevented/reduced EGFRI-induced rash in preclinical models.
Citation Format: Shilan Liu, Wenqin Zeng, Wenxi Li, Qing You, Robert Claude Tyler, Jie Luo, Hong Tang, Shiyi Zhang. OQL025, a topical cream for the prevention of epidermal growth factor receptor inhibitor-induced skin rash [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3211.