Phase I/II study of DZD6008, a 4 th -generation EGFR TKI with full BBB penetration, in EGFR-mutant NSCLC.

8616 Background: NSCLC patients whose disease progressed after 3 rd generation EGFR TKI treatment often have CNS metastasis and acquired EGFR resistance mutations, such as C797S mutation. DZD6008 is a 4 th generation EGFR TKI, designed to target EGFR sensitizing mutations (L858R/del19), resistant double (T790M and L858R/del19) and triple mutations (C797X, T790M and L858R/del19). Preclinical data shows that DZD6008 has high selectivity against wildtype EGFR and other kinases and is fully blood-brain-barrier (BBB) penetrant. Here we report results from the ongoing phase 1/2 studies in advanced EGFR mutation positive (EGFRm) NSCLC. Methods: TIAN-SHAN2 (CTR20241790) is a multi-center, first-in-human phase 1/2 study with expansion designed to evaluate the safety, tolerability, and anti-tumor activity of DZD6008 in EGFRm NSCLC patients who failed prior EGFR TKI treatment. DZD6008’s BBB penetration capability was evaluated by measuring the ratio of free drug concentrations in CSF and blood, as well as tumor response of brain lesions. Results: Preclinically, DZD6008 showed equal potencies against multiple variants of single, double or triple EGFR mutations, with >50-fold selectivity over wild-type EGFR. In osimertinib-resistant CDX and PDX models carrying EGFR triple mutations, DZD6008 induced profound tumor shrinkage in a dose-dependent manner. As of December 24, 2024, 12 patients with EGFRm NSCLC had been enrolled into dose escalation cohorts of TIAN-SHAN2 study, and treated with DZD6008 at 20 mg to 90 mg once daily (QD). The median age was 61 years, 67% were female, and 50% had an ECOG PS of 1. All patients had adenocarcinoma and carried various types of single, double or triple EGFR mutations. The median lines of prior therapies was 5 (range 2 - 8). All patients had been treated with EGFR TKIs and chemotherapy, and 11 had received prior third-generation EGFR TKI treatment. DZD6008 was well tolerated across the doses investigated, and no dose limiting toxicities were reported. The maximum tolerated dose was not reached. DZD6008 exhibited dose-proportional and linear pharmacokinetic characteristics, with excellent blood-brain-barrier penetration (CSF to free plasma ratio >1) in patients with baseline brain metastasis. Ten out of 12 patients (83.3%) showed target lesion tumor shrinkage following DZD6008 treatment. Partial response was observed at ≥ 20 mg in patients with various EGFR mutations. Anti-tumor activity was observed in patients with brain metastasis. The longest duration on treatment was >6 months (treatment ongoing). Conclusions: DZD6008 is a novel, highly selective, full-BBB penetrant EGFR TKI with broad-spectrum of activity against different EGFR mutations. In heavily pre-treated EGFRm NSCLC patients, DZD6008 monotherapy was well-tolerated and showed encouraging anti-tumor activity. TIAN-SHAN2 study is ongoing and updated data will be presented at the meeting. Clinical trial information: CTR20241790 .