Abstract 4046: Targeting jak/stat adaptive mechanism with jak1 inhibitor azd4205 reduces residual disease and prolongs benefit of osimertinib
Authors: Chen Huawei (Ray) , Bebernitz Geraldine , Bell Kirsten , Anderson Erica , Deng Nanhua , Kettle Jason , Lyne Paul , Woessner Richard 
Published: July 2017

EGFR kinase inhibitors have provided tremendous benefit for non-small cell lung cancer (NSCLC) patients with EGFR driver mutations. However, many patients fail to respond or have responses of limited duration. Accumulating evidence suggests that the JAK1/STAT3 axis plays a role in tumor escape, and that combined inhibition of EGFR and JAK1 may drive more complete and durable responses. Here we report AZD4205, a potent ATP-competitive inhibitor that inhibits JAK1 with a Ki of 2.8 nM and exhibits excellent selectivity vs. other JAK family kinases and across the kinome.

Combination of AZD4205 (dosed at 12.5, 25 or 50 mg/kg BID, PO) with Osimertinib (doses ranging from 1 to 25 mg/kg QD, PO) led to enhanced in vivo anti-tumor activity in several NSCLC xenograft models driven by mutant EGFR: H1975 (L858R/T790M), PC-9 (del19), and HCC827 (del19). In the H1975 model, after 18 days of treatment beginning with 189mm3 established tumors, treatment with osimertinib at 2.5 mg/kg led to tumor growth inhibition of 92% relative to vehicle. Addition of AZD4205 at 12.5 and 50 mg/kg led to 30% and 69% tumor regression, respectively. AZD4205 dosed at 12.5 and 50 mg/kg BID resulted in pSTAT3 (Y705) knockdown of 72% and 91% at peak plasma concentration (2H) respectively, and 42% and 86% at 8H. In the PC-9 model, after 22 days of treatment beginning with 234mm3 established tumors, osimertinib at 1 mg/kg induced an average 41% regression, and increased to 74% with the addition of 50 mg/kg BID AZD4205. The volume of vehicle treated tumors increased by 3.7-fold over this treatment period. In the HCC827 model, beginning with 127mm3 established tumors, osimertinib at 25 mg/kg induced a complete response in 100% of mice after 11 days of treatment, but tumors regrew to the average starting volume ~24 days after stopping treatment. When 50 mg/kg of AZD4205 was added to the osimertinib treatment, regrowth was delayed by an additional ~7 days. Combination activity was also observed in the PDX (patient-derived xenograft) model LG1049 (del19 and T790M EGFR mutations). Beginning with 189mm3 established tumors, osimertinib at 25 mg/kg induced an average 39% regression after 28 days of treatment, which increased to 56% with the addition of 25 mg/kg AZD4205 on a 4 days on / 3 days off / week schedule. AZD4205 treatment led to 67% knockdown of pSTAT3 after 4H of treatment in this model.

Our experiments establish AZD4205 as a potent and selective JAK1 inhibitor with desirable biophysical properties. While additional work is needed to build a patient enrichment strategy, the data generated supports targeting the adaptive JAK1/STAT3 axis with JAK1 inhibitor AZD4205 in clinic as a strategy to reduce residual disease and prolong the benefit of Osimertinib in lung cancer patients with EGFR activating mutations.

Citation Format: Huawei (Ray) Chen, Geraldine Bebernitz, Kirsten Bell, Erica Anderson, Nanhua Deng, Jason Kettle, Paul Lyne, Richard Woessner. Targeting jak/stat adaptive mechanism with jak1 inhibitor azd4205 reduces residual disease and prolongs benefit of osimertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4046. doi:10.1158/1538-7445.AM2017-4046