Introduction

 

Approximately 2% of Non-Small Cell Lung Cancer (NSCLC) harbors EGFR Exon20 insertion (Exon20ins) mutations. There are no approved targeted therapies for this patient population, and current available therapy only provides limited clinical benefit. DZD9008 is a rationally designed selective, irreversible EGFR/HER2 inhibitor being studied in two ongoing phase 1/2 studies (NCT03974022 and CTR20192097).

 

摘要：

 

大约2%的非小细胞肺癌(NSCLC)携带EGFR Exon20插入(Exon20ins)突变。目前还没有针对这一患者群体的被批准的靶向治疗方法，而且目前可用的治疗方法只能提供有限的临床益处。DZD9008是一种合理设计的选择性、不可逆EGFR/HER2抑制剂，目前正在进行两项1/2期研究(NCT03974022和CTR20192097)。

 

 

Methods

 

The objectives of the phase 1/2 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.

 

研究：

 

 1/2期研究的目的是评估DZD9008在EGFR或HER2突变NSCLC中的安全性、耐受性、药代动力学和初步抗肿瘤疗效。两项研究都包括剂量增加和扩大队列。

 

 

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). Male/Female: 44/53; Median age 59 (32-85). Patients carry EGFR sensitizing mutation, T790M double mutation, uncommon mutation, Exon20ins or HER2 Exon20ins. DZD9008 showed approximately dose-proportional PK, with a half-life of around 50 hours. DZD9008 was well tolerated up to 400 mg (MTD) once daily. The dose limiting toxicities (DLTs) were diarrhea and cardiac arrhythmia. The most common TEAEs were diarrhea (grade 3, 5.2%) and skin rash (grade 3, 1%). Fifty-six patients carrying more than 16 different subtypes of EGFR exon20ins had > 1 post-treatment efficacy assessment. These patients received median 2 (range 1 - 10) lines of prior therapies, including prior chemotherapy 92.9% (52/56), prior EGFR TKI 44.6% (25/56) (1 patient had poziotinib treatment), onco-immunotherapy 30.4% (17/56), VEGFR antibody 41.1% (23/56), JNJ-61186372 7.1% (4/56) and others 17.9% (10/56). Twenty-four patients (42.9%, 24/56) had baseline brain metastasis. Partial response was observed at ≥ 100 mg dose levels. The objective response rate (ORR) was 39.3% (22/56) across all dose levels. At the dose level of 300 mg once daily, the ORR 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. In addition, PR was also observed in patients with EGFR sensitizing mutation, double mutation or HER2 Exon20ins. The updated data will be presented in the meeting.

 

研究结果：

 

在2019年7月9日和2021年2月5日之间，97例患有EGFR或HER2突变的NSCLC患者服用DZD9008(剂量范围:50mg - 400mg，每日一次)。男/女：44/53；平均年龄59岁(32-85岁)。患者携带EGFR致敏突变、T790M双突变、不常见突变、Exon20ins或HER2 Exon20ins。

DZD9008表现出近似剂量成比例的PK，半衰期约为50小时。DZD9008的耐受性良好，最高可达每日一次400mg (MTD)。剂量限制毒性(DLTs)为腹泻和心律失常。最常见的TEAEs为腹泻(3级，5.2%)和皮疹(3级，1%)。56例患者携带超过16种不同的EGFR外显子20ins，进行> 1治疗后疗效评估。这些患者接受了中位2(范围1 - 10)种既往治疗，包括既往化疗92.9%(52/56)，既往EGFR TKI 44.6%(25/56)(1例患者接受poziotinib治疗)，肿瘤免疫治疗30.4% (17/56)，VEGFR抗体41.1% (23/56)，JNJ-61186372 7.1%(4/56)和其他17.9%(10/56)。24例(42.9%，24/56)患者有基线性脑转移。≥100 mg剂量水平时观察到部分反应。所有剂量水平的客观缓解率(ORR)为39.3%(22/56)。在300mg /日剂量水平下，ORR为48.4% (15/31)，DCR为90.3%(28/31)。2例既往使用JNJ-61186372治疗的患者出现缓解。在不同的EGFR外显子20ins突变亚型中观察到抗肿瘤活性。通过数据截断，中位治疗时间为100天(范围1 - 422)。最长的应答时间超过6个月，22名应答者中有18人仍在应答。此外，在EGFR致敏突变、双突变或HER2 Exon20ins患者中也观察到PR。最新的数据将在会议上提出。

 

 

Conclusion

 

DZD9008 showed a favourable safety profile and promising anti-tumor efficacy in pre-treated NSCLC with EGFR exon20ins and other EGFR or HER2 mutations. DZD9008 is currently in phase 2 clinical development in EGFR Exon20ins NSCLC.

 

结论：

 

DZD9008在EGFR exon20ins和其他EGFR或HER2突变的预处理的NSCLC中，显示了良好的安全性和有前景的抗肿瘤疗效。DZD9008目前正处于EGFR Exon20ins NSCLC的2期临床开发阶段。