Receptor Tyrosine Kinase Fusion-Mediated Resistance to EGFR TKI in EGFR-Mutant NSCLC: A Multi-Center Analysis and Literature Review.

Fusion of receptor tyrosine kinases (RTKs), such as RET, ALK, and FGFR3, has been reported to mediate EGFR TKI resistance.

已报道受体酪氨酸激酶（RTKs）如RET、ALK和FGFR3的融合可以介导EGFR酪氨酸激酶抑制剂（TKI）的耐药性。

Given the rarity of these fusions and the heterogeneous nature of the condition, no prospective clinical trials evaluated the incidence, safety, and therapeutic benefit of dual EGFR-RTK inhibition.

鉴于这些融合的罕见性以及该疾病性质的异质性，尚无前瞻性临床试验评估双重EGFR-RTK抑制的发病率、安全性和治疗益处。

Methods

We queried clinical databases from multiple institutions to identify patients who had RTK fusions detected on next-generation sequencing testing results from tissue or blood at five institutions: the Second Affiliated Hospital Zhejiang University School of Medicine, Hunan Cancer Hospital, Prince of Wales Hospital Chinese University of Hong Kong, Chao Family Cancer Center, and the University of Texas MD Anderson Cancer Center from March 1, 2016, to September 30, 2023.

我们查询了来自多个机构的临床数据库，以识别在2016年3月1日至2023年9月30日期间，于浙江大学医学院附属第二医院、湖南省肿瘤医院、香港中文大学威尔士亲王医院、Chao家族癌症中心和德克萨斯大学MD安德森癌症中心的五个机构中，通过组织或血液的下一代测序检测结果发现RTK融合的患者。

The data analyzed included objective response rate(ORR) to treatment post RTK fusion detection, duration of treatment, and safety.

分析的数据包括治疗后RTK融合检测的客观缓解率（ORR）、治疗持续时间以及安全性。

A comprehensive literature search was conducted to identify patients with RTK fusion as the primary resistance mechanism in EGFR-mutated NSCLC patients.

为识别EGFR突变型NSCLC患者中RTK融合作为主要耐药机制的患者，进行了全面的文献搜索。

Results

Twenty-seven patients were identified to be eligible in the analysis.

分析中确定了27名患者符合资格。

ALK fusions were most reported (42.9%), followed by RET fusions (35.7%).

报告中ALK融合最为常见（占42.9%），其次是RET融合（占35.7%）。

Fifteen patients received dual TKI after fusion detection and nine received fusion targeting single TKIs.

15名患者在接受融合检测后接受了双靶向酪氨酸激酶抑制剂治疗，而9名患者接受了针对融合的单靶向酪氨酸激酶抑制剂治疗。

The median time on treatment was 169 days or 5.8 months (35-1050 d).

治疗的中位时间为169天或5.8个月（范围35-1050天）。

ORR by the Response Evaluation Criteria in Solid Tumors in the evaluable 25 patients was 24% and the disease control rate was 80%.

在可评估的25名患者中，实体瘤疗效评价标准的客观缓解率为24%，疾病控制率为80%。

In 14 evaluable patients who received dual TKI therapy, ORR by the Response Evaluation Criteria in Solid Tumors was 21.4%, and the disease control rate was 78.6%.

在14名接受双靶向酪氨酸激酶抑制剂治疗的可评估患者中，实体瘤疗效评价标准的客观缓解率为21.4%，疾病控制率为78.6%。

No new toxicities were observed with dual EGFR-RTK inhibition.

在双重EGFR-RTK抑制治疗中未观察到新的毒性反应。

In the literature review, after pooling 291 patients from 59 studies, RET fusions were the most common (50.0%), followed by BRAF (13.3%), ALK (13.3%), FGFR (10%), NTRK (5.3%), EGFR (1.7%), ROS1 (1.3%), MET (1%), and ERBB (0.7%).

在文献综述中，通过汇总来自59项研究的291名患者，RET融合是最常见的（50.0%），其次是BRAF（13.3%）、ALK（13.3%）、FGFR（10%）、NTRK（5.3%）、EGFR（1.7%）、ROS1（1.3%）、MET（1%）和ERBB（0.7%）。

Conclusions

The emergence of RTK fusions is one of the mechanisms of bypass resistance of EGFR TKI.

RTK融合的出现是EGFR TKI旁路耐药机制之一。

Dual inhibition of EGFR-RTK was safe and efficacious in patients with targetable RTK fusion after progression to EGFR TKIs.

在EGFR TKIs耐药后，针对可靶向RTK融合的患者中，双靶点抑制EGFR-RTK是安全且有效的。