背景：目前，对于 EGFR 外显子 20 插入突变的 NSCLC 尚无批准的靶向药物。DZD9008是一种设计合理的具有选择性、不可逆的 EGFR exon20ins抑制剂，目前正在进行两项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：本研究旨在评估 DZD9008 对 EGFR 或 HER2 突变的 NSCLC 的安全性、耐受性、药代动力学和初步抗肿瘤疗效，这两项研究均包括不同剂量梯度组，应用汇集分析来确定 II期研究剂量。

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).

结果：2019.7.9 至 2020.2.5.对 97 名具有 EGFR 或 HER2 突变的 NSCLC 患者给予 DZD9008（剂量范围：50 mg 至 400 mg，每日一次）。其中 44 例男性，53 例女性；59 例患者 EGFR外显子 20 突变。DZD9008 每日最大耐受剂量为 400 mg，剂量限制性毒性为腹泻和心律不齐，最常见的 TEAE 是腹泻（3 级，5.2％）和皮疹（3 级，1％）。DZD9008 药物代谢动力学显示半衰期与初始剂量成正比，约为 50 小时。有 16 个不同 EGFR exon20ins 突变的 56 名患者进行了 1 次以上的治疗后疗效评估。既往治疗：92.9％（52 /56）接受过化疗；44.6％（25/56）接受过 TKI 治疗，其中 1 例患者接受了波齐替尼治疗，脑转移患者占 42.9％（24/56）。在药物剂量大于 100 mg 水平下观察到部分反应，II 期研究药物剂量为 300 mg 每日一次，客观缓解率为 48.4％（15/31），疾病控制率为 90.3％（28/31）。在 2 名接受过 JNJ-61186372 的患者中初次观察到了疗效。在不同的 EGFR exon20ins 突变亚型中观察到了抗肿瘤活性。截止数据统计，中位治疗时间为 100 天（范围 1–422 天）。最长的缓解时间超过了 6 个月，且 22位缓解者中有 18 位患者仍在缓解中。

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.

结论：DZD9008 在既往接受过治疗的 EGFR exon20ins 突变 NSCLC 中具有良好的安全性和抗肿瘤疗效。

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).