Analysis of resistance mechanisms to abivertinib, a third-generation EGFR tyrosine kinase inhibitor, in patients with EGFR T790M-positive non-small cell lung cancer from a phase I trial

Zhang, Yichen; Chen, Zhihong; Zhang, Xuchao; Xu, Chong-Rui; Yan, Hong‐Hong; Xie, Zhi; Chuai, Shaokun; Ye, Junyi; Han‐Zhang, Han; Zhang, Zhou; Bai, Xiaoyan; Su, Jian; Gan, Bin; Yang, Jin‐Ji; Li, Wenfeng; Tang, Wei; Luo, Feng; Xu, Xiao; Wu, Yi‐Long; Zhou, Qing

doi:10.1016/j.ebiom.2019.04.030

Cited by 32 publications

(41 citation statements)

References 29 publications

(57 reference statements)

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“…Thus, the clinically significant benefit from subsequent treatment with osimertinib among our patients implies that abivertinib progression may be due to incomplete target inhibition, and the efficacy of abivertinib seemed weaker than that of osimertinib. The report by Zhang et al . showed that EGFR T790M loss (15%) with abivertinib resistance was much less frequent than that reported in osimertinib resistance cohorts (42%–68%), which verified the incomplete inhibition of abivertinib compared with osimertinib and also explained our findings regarding the response to osimertinib after abivertinib progression.…”

Section: Discussionsupporting

confidence: 84%

“…also reported the resistance mechanisms to abivertinib according to next‐generation sequencing (NGS)‐based genomic profiling of the plasma samples of 27 patients who developed abivertinib progression from the phase I dose‐escalation/expansion study. Their findings also reveal a heterogenous pattern of resistance mechanisms to abivertinib that is distinct from that previously reported with osimertinib, and EGFR amplification was the most common resistance mechanism in their cohort …”

Section: Discussionmentioning

confidence: 44%

“…Their findings also reveal a heterogenous pattern of resistance mechanisms to abivertinib that is distinct from that previously reported with osimertinib, and EGFR amplification was the most common resistance mechanism in their cohort. 14 We previously reported the low penetration rate of abivertinib through the blood-brain barrier, 24 which could cause poor efficacy in CNS metastasis, resulting in a short PFS, while osimertinib was reported to better control CNS metastasis. 25 Therefore, in cases of isolated CNS metastasis, patients could still benefit from osimertinib.…”

Section: Discussionmentioning

confidence: 99%

“…However, the objective response rate (ORR) was lower than that for osimertinib . The special resistance mechanism spectrum also indicated the difference between abivertinib and osimertinib . Moreover, little is known about sequential treatment with abivertinib and osimertinib.…”

Section: Introductionmentioning

confidence: 99%

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Abivertinib in patients with T790M‐positive advanced NSCLC and its subsequent treatment with osimertinib

et al. 2020

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Background Abivertinib is a novel oral, third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that overcomes T790M‐induced resistance in non‐small cell lung cancer (NSCLC) patients. Here, we report the results of a complete and detailed clinical data of patients treated with abivertinib at our hospital in a phase I dose escalation/expansion study of abivertinib. Methods NSCLC patients with the EGFR T790M mutation were orally administered abivertinib (150–300 mg) twice daily for cycles of 28 continuous days and tumor response was assessed. Further data regarding subsequent treatment protocols and survival were collected. Results A total of 28 NSCLC patients were included. Of the 24 assessable patients, 12 (50%) achieved a partial response (PR), and six (25%) achieved stable disease (SD). Median progression‐free survival (PFS) was 5.9 months (95% confidence interval (CI): 3.259–8.541) and median overall survival (OS) was 17.9 months (95% CI: 11.36–24.5). For salvage therapy in 15 (53.6%) patients after abivertinib, the median PFS following osimertinib treatment was 12 months. The median total treatment duration for the two third‐generation EGFR TKIs was 15.9 months (95% CI: 12.5–19.3). The most frequent abivertinib‐associated adverse effects were elevated hepatic transaminases (10/28, 35.7%) and diarrhea (10/28, 35.7%). Conclusions Abivertinib is a unique novel third‐generation EGFR TKI with good tolerance and efficacy in EGFR T790M(+) NSCLC patients. For patients with progressive disease after treatment with abivertinib, osimertinib could be an option for subsequent therapy but further studies are required. Key points Abivertinib is a novel third‐generation EGFR TKI targeting the EGFR T790M mutation Abivertinib is well tolerated and efficacious in T790M‐positive patients Abivertinib has a unique structure, efficacy, and resistance mechanism compared with osimertinib Osimertinib treatment after AC0010 showed a good response

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 44%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Abivertinib in patients with T790M‐positive advanced NSCLC and its subsequent treatment with osimertinib

et al. 2020

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“…Acquisition of resistance to erlotinib was associated with the emergence of the EGFR T790M mutation, which has been linked to focal amplification of EGFR . 36 Analysis of the sequential ctDNA samples showed that this subclone was first sensitive to second-line EGFR TKI treatment, as indicated by disappearance of the EGFR T790M mutation. This mutation was detected again in ctDNA samples after SCLC transformation, but not in the second tumor biopsy, possibly due to proliferation of EGFR T790M -positive NSCLC cells at a metastatic site.…”

Section: Discussionmentioning

confidence: 99%

Combination of tissue and liquid biopsy molecular profiling to detect transformation to small cell lung carcinoma during osimertinib treatment

Vendrell

Quantin

Serre³

et al. 2020

Ther Adv Med Oncol

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Background: Histological transformation of advanced non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is one of the mechanisms of resistance to third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib. This acquired TKI resistance is linked to the high degree of tumor heterogeneity and adaptive cellular signaling pathways, including epidermal growth factor receptor ( EGFR)-dependent pathways, observed in NSCLC. Methods: Here, we investigated a series of paired pre- and post-histological transformation biopsies obtained from three patients initially having a NSCLC with an EGFRactivating mutation treated with first-generation TKI, who then received osimertinib as second-line after EGFRT790M resistance and, lastly, developed a histological transformation to SCLC. Both tissue and liquid biopsies were analyzed using large panel sequencing approaches at various time points to reconstruct the clonal evolutionary history of the tumor. Results: Our complementary analysis of tumor tissue and circulating tumor DNA samples allowed us to better characterize the histological and molecular alterations associated with resistance to osimertinib. SCLC transformation was linked to the presence of several concomitant gene alterations, including EGFR, TP53 and RB1, but also to specific signal bypass, such as EGFR and MET amplifications and activation of the PI3K/AKT/mTOR pathway. Conclusion: Our report emphasizes the mutational landscape of SCLC histological transformation and highlights the importance of combining tissue and liquid biopsy profiling before and during osimertinib treatment to predict such histological transformation.

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The clinicopathological and molecular characteristics of resected EGFR‐mutant lung adenocarcinoma

et al. 2022

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Background Epidermal growth factor receptor (EGFR) mutations were frequently found with concomitant genetic alterations in lung adenocarcinoma (LUAD). This study aimed to investigate the profile of concomitant alterations of EGFR‐mutant LUAD ≤3 cm in size and its prognostic effect on recurrence. Methods From January 2018 to December 2018, patients with resected LUAD ≤3 cm in size in Shanghai Chest Hospital were identified. All patients underwent capture‐based targeted next‐generation sequencing (NGS) with a panel of 68 lung cancer‐related genes and were found with EGFR mutation. Clinicopathological and molecular characteristics and recurrence‐free survival (RFS) were analyzed. Results A total of 637 patients were enrolled in this study. The top three frequent co‐mutational genes were TP53 (179 of 637, 28.1%), PIK3CA (27 of 637, 4.2%), and ATM (22 of 637, 3.5%). The most common amplified genes were EGFR (37 of 637, 5.8%), followed by CDK4 (37 of 637, 5.8%) and MYC (12 of 637, 2.0%). Only TP53 mutation and EGFR amplification were adverse prognostic factors for RFS (all p < 0.001) in univariate analysis. Multivariable analysis further demonstrated that TP53 mutation and EGFR amplification were independent risk factors for RFS [(hazard ratio (HR) 2.07, 95% confidence interval (CI) 1.07–4.00, p = 0.030; HR 3.09, 95% CI 1.49–6.40, p = 0.002, respectively]. Conclusions Concomitant TP53 mutation and EGFR amplification were poor prognostic factors for RFS in patients with EGFR‐mutant resected LUAD. Our findings provide valuable understanding of the impact of concurrent alterations and implication for better implementation of precision therapy for patients.

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Analysis of resistance mechanisms to abivertinib, a third-generation EGFR tyrosine kinase inhibitor, in patients with EGFR T790M-positive non-small cell lung cancer from a phase I trial

Cited by 32 publications

References 29 publications

Abivertinib in patients with T790M‐positive advanced NSCLC and its subsequent treatment with osimertinib

Abivertinib in patients with T790M‐positive advanced NSCLC and its subsequent treatment with osimertinib

Combination of tissue and liquid biopsy molecular profiling to detect transformation to small cell lung carcinoma during osimertinib treatment

The clinicopathological and molecular characteristics of resected EGFR‐mutant lung adenocarcinoma

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