DZD6008, a fourth-generation EGFR TKI, in pretreated NSCLC patients with <i>EGFR</i> C797X mutations: Results from phase 1/2 studies.

Abstract

8520 Background: Patients with EGFR-mutant NSCLC whose disease progresses on or after 3 rd generation EGFR TKI treatment often acquire resistance mutations, among which EGFR C797X is one of the most frequently reported. DZD6008 is a 4 th generation EGFR TKI, designed to target classical EGFR sensitizing mutations (L858R/19del), as well as resistant double (T790M and L858R/19del) and triple mutations (C797X, T790M and L858R/19del), with preclinical data showing high selectivity over wild-type EGFR and other kinases and full blood-brain-barrier (BBB) penetration. Here we report results in pretreated NSCLC patients with EGFR C797X mutations (C797X+) from phase 1/2 studies. Methods: TIAN-SHAN1 (NCT06905197) and TIAN-SHAN2 (NCT06813365; CTR20241790) are ongoing, multicenter phase 1/2 studies evaluating the safety, tolerability, and anti-tumor activity of DZD6008 in EGFR-mutant NSCLC patients, conducted in the US/Australia and China, respectively. The efficacy endpoints include objective response rate (ORR), duration of response (DoR) and progression-free survival (PFS) by investigator per RECIST v1.1, and safety endpoints include treatment-related adverse events (TRAEs) per CTCAE 5.0. Results: As of December 19, 2025, a total of 24 patients with confirmed C797X+ NSCLC were treated with once daily (QD) oral DZD6008 (20 mg, n=1; 40 mg, n=13; 60 mg, n=10), and had at least 1 post-baseline tumor assessment. The median age was 66.5 years, 58.3% were female, 91.7% were Asian, 58.3% had ECOG PS of 1. All patients had metastatic disease upon study entry and received median 2 (range 1 - 6) lines of prior therapies. Across all dose levels, tumor shrinkage was observed in 75% of patients, with an ORR of 41.7%. Intracranial anti-tumor activity was observed in patients with baseline brain metastasis. The doses of 40 mg and 60 mg QD were defined as the recommended phase 2 doses (RP2Ds). The ORRs were 23.1% and 60.0% at these two dose levels, respectively. The median DoR and median PFS were not reached for either dose. The 9-month PFS rates were 54.5% and 64.8%, respectively. DZD6008 was well tolerated at the doses evaluated, with no dose limiting toxicities observed. The majority of TRAEs were grade 1 or 2. The TRAEs with grade ≥3 included lymphocyte count decreased (8.3%), anemia, malaise, fatigue and amylase increased (all 4.2%). There were no Grade 5 TRAEs. Conclusions: DZD6008 demonstrated promising and durable anti-tumor activity in patients with EGFR C797X+ NSCLC with a manageable safety profile, supporting its potential use as a later line treatment option after 3 rd generation EGFR TKI failure. The updated data will be presented at the meeting. Clinical trial information: NCT06905197 , NCT06813365 .