Qin Zhiquan, Zhang Hang, Yan Peiyuan, Yu Lili, Hong Chaojin, Calvetti Lorenzo, Passaro Antonio, Araujo Antonio, Chen Yun
Oncology Center, Department of Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
Medical Oncology Scientific Group of the Central Medical Department, Hansoh Health Technology Co., Ltd., Shanghai, China.
J Thorac Dis. 2023 Jul 31;15(7):4016-4026. doi: 10.21037/jtd-23-841. Epub 2023 Jul 24.
Aumolertinib (HS-10296), a 3rd-generation epidermal growth factor receptor () tyrosine kinase inhibitor (TKI), has been shown to have efficacy in treating tumors harboring sensitive mutations: in-frame deletions or insertions within exon 19 deletion (19Del) and the exon 21 L858R mutation and T790M resistance mutation. Research has shown that tumor protein p53 () mutations and leptomeningeal metastases (LM) are associated with reduced responsiveness and a poor prognosis in patients with advanced non-small cell lung cancer (NSCLC) who have received targeted therapy with EGFR-TKIs. The mutation is a common concomitant mutation of amplification in solid tumors. First-line aumolertinib treatment is effective in concurrent mutated NSCLC, however, the efficacy and survival outcomes in these patients with leptomeningeal metastasis remain unknown.
We retrospectively examined the data of a lung adenocarcinoma patient, 51 years old, male, multi-mutations of and , who received 1st-line treatment with a 1st-generation TKI followed by 2nd-line treatment with aumolertinib. Before the 1st-line treatment, the patient underwent a lung biopsy to examine the 520 genes of all cancers using illumia high-throughput sequencing. The sequencing results showed that the patient had the 19del (p.Leu747_Thr751del)/ (p.lys120fs)/ amplified multiple mutation with a low tumor mutational burden. The patient was treated with gefitinib and achieved progression-free survival (PFS) for 10 months until secondary malignancy of the lymph nodes. The first-generation TKI combined with chemotherapy was applied and then the patient was diagnosed with leptomeningeal metastases. Subsequently, the patient was treated with aumolertinib for 12 months without disease progression. The efficacy evaluation was partial response (PR) with grade 2 rash. Adenocarcinoma cells were found in the cerebrospinal fluid (CSF). CSF-derived circulating tumor deoxyribonucleic acid was detected using the target area probe capture and 2nd-generation high-throughput sequencing technology. The CSF gene detection showed the p. L747_T751 del, p. K120fs and amplification mutations.
This is the first reported case in which aumolertinib was used to treat a patient with the multi-mutations of 19Del, , and amplification and leptomeningeal metastases. The findings suggested that almonertinib may result in long-period clinical improvement and tolerable safety in concurrent mutated LM NSCLC.
奥莫替尼（HS-10296）是第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），已显示出对携带EGFR敏感突变的肿瘤具有疗效：19号外显子缺失（19Del）内的框内缺失或插入、21号外显子L858R突变以及T790M耐药突变。研究表明，肿瘤蛋白p53（TP53）突变和软脑膜转移（LM）与接受EGFR-TKIs靶向治疗的晚期非小细胞肺癌（NSCLC）患者的反应性降低和预后不良相关。TP53突变是实体瘤中EGFR扩增的常见伴随突变。一线使用奥莫替尼治疗携带EGFR并发突变的NSCLC有效，然而，这些软脑膜转移患者的疗效和生存结果仍不清楚。
我们回顾性分析了一名51岁男性肺腺癌患者的数据，该患者存在EGFR和TP53多重突变，接受了第一代TKI一线治疗，随后接受奥莫替尼二线治疗。在一线治疗前，患者接受了肺活检，使用illumia高通量测序检测所有癌症的520个基因。测序结果显示，患者存在EGFR 19del（p.Leu747_Thr751del）/TP53（p.lys120fs）/EGFR扩增多重突变，肿瘤突变负荷较低。患者接受吉非替尼治疗，实现了10个月的无进展生存期（PFS），直至出现淋巴结继发恶性肿瘤。应用第一代TKI联合化疗，随后患者被诊断为软脑膜转移。随后，患者接受奥莫替尼治疗12个月，病情无进展。疗效评估为部分缓解（PR），伴有2级皮疹。脑脊液（CSF）中发现腺癌细胞。使用靶区域探针捕获和第二代高通量测序技术检测CSF来源的循环肿瘤脱氧核糖核酸。CSF基因检测显示存在EGFR p. L747_T751 del、TP53 p. K120fs和EGFR扩增突变。
这是首例报道使用奥莫替尼治疗携带EGFR 19Del、TP53和EGFR扩增多重突变及软脑膜转移患者的病例。研究结果表明，奥莫替尼可能使携带EGFR并发突变的LM NSCLC患者获得长期临床改善且安全性可耐受。
