DZD6008 Demonstrates Salvage Potential in EGFR C797X–Mutant NSCLC

June 2, 2026 | Caroline Seymour

DZD6008 demonstrated encouraging antitumor activity and no evidence of grade 3 or greater rash, diarrhea, or paronychia in patients with previously treated, EGFR C797X–mutant non–small cell lung cancer (NSCLC), according to data from the phase 1/2 TIAN-SHAN1 (NCT06905197) and TIAN-SHAN2 (NCT06813365; CTR20241790) trials that were presented at the 2026 ASCO Annual Meeting.¹

Within the 40-mg cohort (n = 17), the objective response rate (ORR) was 41.2% (n = 7; 95% CI, 18.4%-67.1%), and the disease control rate (DCR) was 94.1% (n = 16; 95% CI, 71.3%-99.9%). Best responses included partial response (PR; n =7; 41.2%), stable disease (SD; n = 9; 52.9%), and progressive disease (PD; n = 1; 5.9%). The 6-month progression-free survival (PFS) rate was 70.6% (95% CI, 38.9%-88.0%).

In the 60-mg cohort (n = 21), the ORR was 42.9% (n = 9; 95% CI, 21.8%-66.0%), and the DCR was 90.5% (n = 19; 95% CI, 69.6%-98.8%). Best responses included PR (n = 9; 42.9%), SD (n = 10; 47.6%), and PD (n = 2; 9.5%). The 6-month PFS rate was 61.8% (95% CI, 35.8%-78.9%).

Median follow-up in the respective cohorts was 6.1 months and 5.7 months.

Wang noted that 82.1% of patients had tumor shrinkage after treatment with DZD6008 and that responses also occurred in patients with baseline brain metastases.

“DZD6008 showed promising and durable antitumor activity in patients [whose disease] relapsed after third-generation EGFR TKI treatment, with potency against single, double, and triple EGFR mutations,” , chief physician, professor, and doctoral supervisor in the Department of Respiratory and Critical Care Medicine at Peking Union Medical College Hospital in Beijing, China, said in a presentation of the data.

What do I need to know about DZD6008 and how it was evaluated in TIAN-SHAN1/2?

DZD6008 is a potent inhibitor of major EGFR single-, double-, and triple-mutant variants. The agent, which is not active in wild-type EGFR driven cells, has been shown to be well tolerated at highly effective doses in animal models that express EGFR activating mutations and anti–central nervous system (CNS) metastatic models, as well as in T790M- and C797S-mutant disease.

TIAN-SHAN1 and TIAN-SHAN2 are ongoing, multicenter, phase 1/2 trials evaluating the safety, tolerability, and efficacy of DZD6008 in EGFR-mutant NSCLC in the US/Australia and China, respectively.

To be eligible, patients must be at least 18 years old and have received a diagnosis of locally advanced or metastatic NSCLC with an EGFR sensitizing mutation (exon 19 deletion or L858R mutation) and have experienced disease progression or intolerance after a third-generation EGFR TKI. An ECOG performance status of 0 or 1 and stable brain metastases were also required.

In dose escalation patients received DZD6008 either at 20 mg once daily (n = 3 to 10), 40 mg once daily (n = 3 to 10), 60 mg once daily (n = 3 to 10), or 90 mg once daily (n = 3 to 10). As part of dose expansion patients were randomly assigned 1:1 to cohort 1 (n = 20 to 30) or 2 (n = 20 to 30), where they received DZD6008 at 40 mg once daily or 60 mg once daily, respectively.

The primary end points in dose escalation were safety and tolerability, and in dose expansion was ORR by investigator per RECIST 1.1 criteria. Secondary end points included PFS, duration of response, DCR, and overall survival.

The safety analysis set comprised 51 patients with C797X mutations, and the efficacy analysis set comprised 40 evaluable patients with C797X mutations.

What were the baseline characteristics of the total population?

The median age in the efficacy set was 68 years (range, 37-78) and most patients were female (n = 21; 52.5%). The predominant race was Asian (n = 37; 92.5%), followed by White (n = 2; 5.0%), and other (n = 1; 2.5%). ECOG performance status was largely 1 (n = 27; 67.5%) and almost all patients had stage IV disease (n = 39; 97.5%). Brain metastases at baseline were present in 37.5% (n = 15) of patients, and the median number of prior lines of therapy was 2 (range, 1-9). Most patients had EGFR exon 19 deletions (n = 31; 77.5%) as opposed to L858R mutations (n = 9; 22.5%).

How was the brain penetrance of the agent characterized?

Wang reported that 5 patients with measurable brain lesions were included. None of these patients had undergone prior irradiation of brain lesions prior to study entry. After treatment with DZD6008 4 patients had disease control in the brain and 3 showed evidence of brain tumor shrinkage. One patient experienced an intracranial PR. Moreover, 1 case of CNS-PFS extended beyond 8 months

What was the safety profile of the agent and how does it compare with osimertinib?

Treatment-emergent adverse effects (TEAEs) that occurred in at least 20% of patients (n = 48; 94.1%) included anemia (all grade, 76.5%; grade ≥ 3, 9.8%), increased blood bilirubin (37.3%; 2.0%), increased aspartate aminotransferase levels (35.3%; 2.0%), increased alanine aminotransferase levels (29.4%; 2.0%), increased blood creatinine phosphokinase (23.5%; 0.0%), increased blood creatinine (23.5%; 0.0%), and decreased appetite (23.5%; 2.0%).

Common TEAEs were largely laboratory abnormalities, and the majority were grade 1 or 2. No interstitial lung disease or pneumonitis occurred, nor was there an absolute QTcF interval above 480 ms or change from baseline greater than 60 ms.

Diarrhea, rash, and paronychia were also evaluated as adverse effects (AEs) of special interest for EGFR TKIs.

The rates were as follows in the 20-mg (n = 2), 40-mg (n = 24), 60-mg (n = 24), and 90-mg (n = 1) cohorts:

20-mg cohort:

• Diarrhea (all grade, 0.0%; grade ≥3, 0.0%)
• Rash (50.0%; 0.0%)
• Paronychia (0.0%; 0.0%)

40-mg cohort:

• Diarrhea (all grade, 12.5%; grade ≥3, 0.0%)
• Rash (20.8%; 0.0%)
• Paronychia (0.0%; 0.0%)

60-mg cohort:

• Diarrhea (all grade, 20.8%; grade ≥3, 0.0%)
• Rash (8.3%; 0.0%)
• Paronychia (0.0%; 0.0%)

90-mg cohort:

• Diarrhea (all grade, 0.0%; grade ≥3, 0.0%)
• Rash (0.0%; 0.0%)
• Paronychia (0.0%; 0.0%)

For comparison, Wang included the rates of these events from the pivotal, phase 3 FLAURA trial (NCT02296125), which were significantly higher with the 80-mg dose of osimertinib (n = 279):²

• Diarrhea (all grade, 58%; grade ≥3, 2.2%)
• Rash (58%; 1.1%)
• Paronychia (35%; 0.4%)

“DZD6008 is a highly selective, mutant only EGFR inhibitor, with minimal AEs due to wild-type EGFR pharmacology,” Wang concluded.¹

Disclosures: Wang had no relationships to disclose.

References

Wang M, Shum E, Hu Y, et al. DZD6008, a fourth-generation EGFR TKI, in pretreated NSCLC patients with EGFR C797X mutations: results from phase 1/2 studies. J Clin Oncol. 2026;44(suppl 16):8520. doi:10.1200/JCO.2026.44.16_suppl.8520

Prescribing information. AstraZeneca; 2015. Accessed June 2, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf