Abstract 2255: Patient pharmacodynamic biomarker and pk evaluation results from an ongoing phase I dose-escalation study of q702, an axl, mer and csf1r kinase inhibitor in patients with advanced solid tumors
Authors: Choi Bae Jung , Devalingam Devalingam , Alistar Angela , El-Khoueiry Anthony , Mita Alain , Kang Hwankyu , Choi Jinho , Ahn Hyunji , Kim Jeongjun , Lee Seung-Joo , Yang Yeong-In , Ahn Jiye , Jeon Borami , Kim Jaeseung , Nam Kiyean 
Published: April 2023

Background: Axl, Mer and CSF1 receptor tyrosine kinases play vital roles in promoting the immunosuppressive tumor microenvironment (TME) by affecting myeloid functions (e.g., tumor associated macrophage [TAM], myeloid derived suppression cell [MDSC]) and promoting epithelial-to-mesenchymal transition (EMT). Thus, simultaneous inhibition of Axl, Mer and CSF1R may be an effective strategy for TME modification. Q702 is a novel Axl/Mer/CSF1R kinase inhibitor that affects the immune components (modulating TAM and MDSC populations, inducing CD8+ T cell infiltration and increasing IFN-ɣ in CD8+ T cell) as well as changes in malignant cells such as increasing MHC I on the tumor cells of syngeneic mouse models. These nonclinical results suggest that Q702 monotherapy or Q702 combination with conventional therapies may have considerable potential as a novel treatment strategy for patients with advanced solid tumors.

Methods: This is a Phase 1, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic, Pharmacokinetic Study of Q702 with a Cohort Expansion at the recommended phase 2 dose (RP2D) in Patients with Advanced Solid Tumors (NCT04648254). Q702 was administered orally for seven days every other week. Peripheral blood samples were obtained on days 1,8,15, and 21. Axl, Mer and CSF1R target engagement is assessed by the quantifications of soluble Axl, Mer and M-CSF in plasma by Luminex xMAP® technology or ELISA. The pharmacodynamic biomarker changes are measured by flow cytometry for immune cell population shifts and IFN-ɣ levels in specific immune cells.

Results: PK and PD biomarker samples from 22 patients with various tumor types (e.g. colon, pancreas, esophageal) from the dose escalation phase (4 mg to 240 mg) have been analyzed. Pharmacokinetic studies demonstrated dose proportional increase in Cmax and AUClast of Q702 and its two active metabolites which have activity against Axl and/or CSF1R. Axl and CSF1R target engagement by Q702 treatment is observed in a dose dependent manner. From the 60 mg cohort, target engagement for Axl and CSF1R reached a inhibitory level that was observed in nonclinical models. In the pharmacodynamic biomarker analysis, IFN-ɣ in CD8+ T cells and non-T cell populations is increased. Monocytes and M-MDSC population are decreased in peripheral blood.

Conclusion: Up to 240 mg, Q702 has demonstrated the intended pharmacologic activity with acceptable safety profile. In biomarker analysis, immune modulation activity is exerted by Axl/Mer/CSF1R inhibition. Further assessment of pharmacokinetics, pharmacodynamics, safety and antitumor activity will be performed at the expansion phase at the RP2D in patients with selected advanced tumors.

Citation Format: Bae Jung Choi, Devalingam Devalingam, Angela Alistar, Anthony El-Khoueiry, Alain Mita, Hwankyu Kang, Jinho Choi, Hyunji Ahn, Jeongjun Kim, Seung-Joo Lee, Yeong-In Yang, Jiye Ahn, Borami Jeon, Jaeseung Kim, Kiyean Nam. Patient pharmacodynamic biomarker and pk evaluation results from an ongoing phase I dose-escalation study of q702, an axl, mer and csf1r kinase inhibitor in patients with advanced solid tumors [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 2255.