Abstract 5457: QLH11811, a selective 4th-generation EGFR inhibitor for osimertinib-resistant EGFR-mutant NSCLC
Authors: Zheng Shansong , Deng Wei , Zheng Qingmei , Yang Yingying , Li Na , Pang Tan , Feng Xueying , Taylor Simon , Ma Lina , Wu Yaqiong , Zhao Ziwei 
Published: June 2022

Background: The 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), like osimertinib, provide marked clinical benefit for EGFR-mutant non-small cell lung cancer (NSCLC) patients with extended overall survival vs former EGFR TKIs (e.g., gefitinib). Approximate 10%-24% of NSCLC patients acquired C797S mutation when treated with osimertinib. Unfortunately, limited treatments are available for patients after osimertinib resistance. QLH11811 is a new generation EGFR TKI designed to target the EGFR with ex19del/L858R/T790M/C797S mutations. Here, we disclosed its preclinical data to support its clinical development in EGFR-mutant NSCLC.

Methods: The inhibitory activity of QLH11811 on mutated and wild-type EGFR was tested in engineered cell lines and patient-derived organoid (PDO). The in vivo antitumor activity of QLH11811 was evaluated in the patient-derived xenograft (PDX) model with cis EGFR ex19del/T790M/C797S triple mutations, and the H1975 (cis EGFR L858R/T790M/C797S and cis EGFR ex19del/T790M/C797S), PC-9 (EGFR ex19del), and Ba/F3 (EGFR ex19del/C797S) cell line-derived xenograft (CDX) models. The pharmacokinetic (PK) profile was investigated in animals, and the human PK profile was projected using allometric scaling method.

Results: QLH11811 displayed potent anti-proliferation activity against Ba/F3 (EGFR ex19del/T790M/C797S, L858R/T790M/C797S, ex19del/C797S, or L858R/C797S), PC-9 (EGFR ex19del/T790M/C797S), H1975 (EGFR L858R/T790M/C797S, L858R/T790M), H3255 (L858R) and HCC827 (ex19del) with IC50 of 2.6, 3.1, 2.4, 4.1, 51, 50, 27, 21, and 11 nM, respectively. QLH11811 also showed excellent selectivity when compared the above values with its IC50 against Ba/F3 (EGFR wild-type, 61 nM) and A431 (EGFR wild-type, 440nM). QLH11811 demonstrated excellent inhibitory activities against seven osimertinib-resistant PDO models. Daily oral QLH11811 significantly inhibited tumor growth at all doses tested (P &lt;0.001) in the PDX model, the H1975, PC-9, and Ba/F3 CDX models. QLH11811 had good PK profile in mice, rats, dogs, and monkeys, with the absolute bioavailability at 71%, 29%, 80% and 42%. The human PK parameters were obtained by allometric scaling method, and the efficacious dose in human was projected to 103 mg, daily.

Conclusion: The in vitro and in vivo preclinical data demonstrated QLH11811 is a highly potent and selective 4th-generation EGFR TKI with activity against the osimertinib-resistant NSCLC with EGFR C797S mutation. The preclinical PK data supported the efficacious dose of QLH11811 in human would be 103 mg.

Citation Format: Shansong Zheng, Wei Deng, Qingmei Zheng, Yingying Yang, Na Li, Tan Pang, Xueying Feng, Simon Taylor, Lina Ma, Yaqiong Wu, Ziwei Zhao. QLH11811, a selective 4th-generation EGFR inhibitor for osimertinib-resistant EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5457.