Background: There are no approved targeted therapies for EGFR exon20 insertion (exon20ins) mutant NSCLC. DZD9008 is a rationally designed selective, irreversible EGFR exon20ins inhibitor being studied in two ongoing phase 1/2 studies (NCT03974022 and CTR20192097). Methods: The objectives of the studies are to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor efficacy of DZD9008 in NSCLC with EGFR or HER2 mutations. Both studies include dose escalation and expansion cohorts. Pooled analysis is applied to define recommended phase 2 dose (RP2D). Results: Between July 9, 2019 and February 5, 2021, 97 NSCLC patients with EGFR or HER2 mutations were dosed with DZD9008 (dose range: 50 mg to 400 mg, once daily). M/F: 44/53; 59 with EGFR exon 20. DZD9008 was well tolerated up to 400 mg (MTD) once daily. The DLTs were diarrhea and cardiac arrhythmia. The most common TEAEs were diarrhea (grade 3, 5.2%) and skin rash (grade 3, 1%). DZD9008 showed approximately dose-proportional PK, with a half-life of around 50 hours. Fifty-six patients with > 16 different EGFR exon20ins mutations had > 1 post-treatment efficacy assessment. Prior therapies: median 2 (range 1 - 10), prior chemotherapy 92.9% (52/); prior TKI 44.6% (25/56) including 1 patient had poziotinib treatment; 42.9% (24/56) with brain metastasis. Partial response was observed at ≥ 100 mg dose levels. At the RP2D dose of 300 mg once daily, the objective response rate was 48.4% (15/31), and disease control rate (DCR) was 90.3% (28/31). Responses were observed in 2 patients with prior JNJ-61186372 treatment. Anti-tumor activity was observed across different EGFR exon20ins mutation subtypes. By data cut-off, the median treatment duration was 100 days (range 1 – 422). The longest duration of response was over 6 months, and 18 out of 22 responders are still responding. Conclusions: DZD9008 showed a favorable safety profile and promising anti-tumor efficacy in pre-treated NSCLC with EGFR exon20ins mutations. The updated data will be presented at the meeting. DZD9008 is currently in phase II clinical development (NCT03974022). Clinical trial information: NCT03974022