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. DZD9008is a rationally designed selective, irreversible EGFR/HER2 inhibitor being studied in two ongoing phase 1/2 studies (NCT03974022 and CTR20192097).

摘要：

大約2%的 非小細胞肺癌(NSCLC)攜帶EGFR Exon20插入(Exon20ins)突變。目前還沒有針對這一患者群體的被批準的靶向治療方法，而且目前可用的治療方法隻能提供有限的臨床益處。DZD9008是一種合理設計的選擇性、不可逆EGFR/HER2抑製劑，目前正在進行兩項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期研究的目的是評估DZD9008在EGFR或HER2突變NSCLC中的安全性、耐受性、藥代動力學和初步抗腫瘤療效。兩項研究都包括劑量增加和擴大隊列。

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.

研究結果：

在2019年7月9日和2021年2月5日之間，97例患有EGFR或HER2突變的NSCLC患者服用DZD9008(劑量範圍:50mg - 400mg，每日一次)。男/女：44/53；平均年齡59歲(32-85歲)。患者攜帶EGFR致敏突變、T790M雙突變、不常見突變、Exon20ins或HER2 Exon20ins。

DZD9008表現出近似劑量成比例的PK，半衰期約為50小時。DZD9008的耐受性良好，最高可達每日一次400mg (MTD)。劑量限製毒性(DLTs)為腹瀉和心律失常。最常見的TEAEs為腹瀉(3級，5.2%)和皮疹(3級，1%)。56例患者攜帶超過16種不同的EGFR外顯子20ins，進行> 1治療後療效評估。這些患者接受了中位2(範圍1 - 10)種既往治療，包括既往化療92.9%(52/56)，既往EGFR TKI 44.6%(25/56)(1例患者接受poziotinib治療)，腫瘤免疫治療30.4% (17/56)，VEGFR抗體41.1% (23/56)，JNJ-61186372 7.1%(4/56)和其他17.9%(10/56)。24例(42.9%，24/56)患者有基線性腦轉移。≥100 mg劑量水平時觀察到部分反應。所有劑量水平的客觀緩解率(ORR)為39.3%(22/56)。在300mg /日劑量水平下，ORR為48.4% (15/31)，DCR為90.3%(28/31)。2例既往使用JNJ-61186372治療的患者出現緩解。在不同的EGFR外顯子20ins突變亞型中觀察到抗腫瘤活性。通過數據截斷，中位治療時間為100天(範圍1 - 422)。最長的應答時間超過6個月，22名應答者中有18人仍在應答。此外，在EGFR致敏突變、雙突變或HER2 Exon20ins患者中也觀察到PR。最新的數據將在會議上提出。

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.

結論：

DZD9008在EGFR exon20ins和其他EGFR或HER2突變的預處理的NSCLC中，顯示了良好的安全性和有前景的抗腫瘤療效。DZD9008目前正處於EGFR Exon20ins NSCLC的2期臨床開發階段。