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AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or MetastaticNon-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations.

ABSTRACT:

Purpose

Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768).

Methods

Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment.

Results

A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively.

Conclusion

Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR-mutant NSCLC in the first-line setting.

SUBMITTER: Lu S

PROVIDER: S-EPMC9509093 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or MetastaticNon-Small-Cell Lung Cancer With <i>EGFR</i> Exon 19 Deletion or L858R Mutations.

Lu Shun S Dong Xiaorong X Jian Hong H Chen Jianhua J Chen Gongyan G Sun Yuping Y Ji Yinghua Y Wang Ziping Z Shi Jianhua J Lu Junguo J Chen Shaoshui S Lv Dongqing D Zhang Guojun G Liu Chunling C Li Juan J Yu Xinmin X Lin Zhong Z Yu Zhuang Z Wang Zhehai Z Cui Jiuwei J Xu Xingxiang X Fang Jian J Feng Jifeng J Xu Zhi Z Ma Rui R Hu Jie J Yang Nong N Zhou Xiangdong X Wu Xiaohong X Hu Chengping C Zhang Zhihong Z Lu You Y Hu Yanping Y Jiang Liyan L Wang Qiming Q Guo Renhua R Zhou Jianying J Li Baolan B Hu Chunhong C Tong Wancheng W Zhang Helong H Ma Lin L Chen Yuan Y Jie Zhijun Z Yao Yu Y Zhang Longzhen L Jie Weng W Li Weidong W Xiong Jianping J Ye Xianwei X Duan Jianchun J Yang Haihua H Sun Meili M Sun Changan C Wei Hongying H Li Chuan C Ali Siraj M SM Miller Vincent A VA Wu Qiong Q

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20220517 27

<h4>Purpose</h4>Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic <i>EGFR</i>-mutated non-small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768).<h4>Methods</h4>Patients at 53 sites in China were randomly ass ...[more]

PMID: 35580297

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Project description:BackgroundThe initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study.MethodsEligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS).ResultsOf the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed.ConclusionsThese results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases.Trial registrationClinicalTrials.gov number, NCT03849768.

Project description:BackgroundAumolertinib (HS-10296), a 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been shown to have efficacy in treating tumors harboring EGFR sensitive mutations: EGFR in-frame deletions or insertions within exon 19 deletion (19Del) and the exon 21 L858R mutation and EGFR T790M resistance mutation. Research has shown that tumor protein p53 (TP53) 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 TP53 mutation is a common concomitant mutation of EGFR amplification in solid tumors. First-line aumolertinib treatment is effective in EGFR concurrent mutated NSCLC, however, the efficacy and survival outcomes in these patients with leptomeningeal metastasis remain unknown.Case descriptionWe retrospectively examined the data of a lung adenocarcinoma patient, 51 years old, male, multi-mutations of EGFR and TP53, 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 EGFR 19del (p.Leu747_Thr751del)/TP53 (p.lys120fs)/EGFR 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 EGFR p. L747_T751 del, TP53 p. K120fs and EGFR amplification mutations.ConclusionsThis is the first reported case in which aumolertinib was used to treat a patient with the multi-mutations of EGFR 19Del, TP53, and EGFR amplification and leptomeningeal metastases. The findings suggested that almonertinib may result in long-period clinical improvement and tolerable safety in concurrent mutated LM NSCLC.