背景：目前，對於 EGFR 外顯子 20 插入突變的 NSCLC 尚無批準的靶向藥物。DZD9008是一種設計合理的具有選擇性、不可逆的 EGFR exon20ins抑製劑，目前正在進行兩項Ⅰ、II 期研究（NCT03974022 和 CTR20192097）。

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).

方法：本研究旨在評估 DZD9008 對 EGFR 或 HER2 突變的 NSCLC 的安全性、耐受性、藥代動力學和初步抗腫瘤療效，這兩項研究均包括不同劑量梯度組，應用彙集分析來確定 II期研究劑量。

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).

結果：2019.7.9 至 2020.2.5.對 97 名具有 EGFR 或 HER2 突變的 NSCLC 患者給予 DZD9008（劑量範圍：50 mg 至 400 mg，每日一次）。其中 44 例男性，53 例女性；59 例患者 EGFR外顯子 20 突變。DZD9008 每日最大耐受劑量為 400 mg，劑量限製性毒性為腹瀉和心律不齊，最常見的 TEAE 是腹瀉（3 級，5.2％）和皮疹（3 級，1％）。DZD9008 藥物代謝動力學顯示半衰期與初始劑量成正比，約為 50 小時。有 16 個不同 EGFR exon20ins 突變的 56 名患者進行了 1 次以上的治療後療效評估。既往治療：92.9％（52 /56）接受過化療；44.6％（25/56）接受過 TKI 治療，其中 1 例患者接受了波齊替尼治療，腦轉移患者占 42.9％（24/56）。在藥物劑量大於 100 mg 水平下觀察到部分反應，II 期研究藥物劑量為 300 mg 每日一次，客觀緩解率為 48.4％（15/31），疾病控製率為 90.3％（28/31）。在 2 名接受過 JNJ-61186372 的患者中初次觀察到了療效。在不同的 EGFR exon20ins 突變亞型中觀察到了抗腫瘤活性。截止數據統計，中位治療時間為 100 天（範圍 1–422 天）。最長的緩解時間超過了 6 個月，且 22位緩解者中有 18 位患者仍在緩解中。

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.

結論：DZD9008 在既往接受過治療的 EGFR exon20ins 突變 NSCLC 中具有良好的安全性和抗腫瘤療效。

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).