AC0010, an Irreversible EGFR Inhibitor Selectively Targeting Mutated EGFR and Overcoming T790M-Induced Resistance in Animal Models and Lung Cancer Patients

Xu, Xiao; Mao, Long; Xu, Wanhong; Tang, Wei; Zhang, Xiaoying; Xi, Biao; Xu, Rongda; Fang, Xin; Liu, Jia; Fang, Ce; Zhao, Li; Wang, Xiaobo; Jiang, Ji; Hu, Pei; Zhao, Hongyun; Zhang, Li

doi:10.1158/1535-7163.mct-16-0281

Cited by 75 publications

(76 citation statements)

References 32 publications

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“…Avitinib is a pyrrolopyrimidine-based irreversible EGFR inhibitor and is structurally distinct from other pyrimidine-based irreversible EGFR inhibitors such as osimertinib and has activity against EGFR mutations including T790 M whilst spares EGFR WT [29]. …”

Section: Introductionmentioning

confidence: 99%

Third generation EGFR TKIs: current data and future directions

et al. 2018

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Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development. Unfortunately, despite good initial response, patients who was treated with third generation EGFR TKI would develop acquired resistance and several mechanisms had been identified and the commonest being C797S mutation at exon 20. Several novel treatment options were being developed for patients who had progressed on third generation EGFR TKI but they are still in the early phase of development. Osimertinib under FLAURA study had been shown to have better progression-free survival over first generation EGFR TKI in the first line setting and likely will become the new standard of care.

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Section: Introductionmentioning

confidence: 99%

Third generation EGFR TKIs: current data and future directions

et al. 2018

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“…To our knowledge, there is no evidence that the sequential use of different first generation TKIs (gefitinib, erlotinib, icotinib) could bring more benefits to patients, because all first‐generation TKIs target the same EGFR ‐sensitive mutation. With regard to the effectiveness of osimertinib as a subsequent therapy after abivertinib, despite both being third‐generation EGFR TKIs, we supposed that it may be due to the unique structure of abivertinib, which differs from osimertinib …”

Section: Discussionmentioning

confidence: 99%

“…Abivertinib is a novel oral, potent, irreversible EGFR TKI that selectively targets EGFR mutations and overcomes T790M‐induced resistance in NSCLC patients . Ma et al .…”

Section: Introductionmentioning

confidence: 99%

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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“…In the reported dose escalation study (55), 25 patients were treated. The most common AEs were diarrhea, rash, and pruritus.…”

Section: Third-generation Tkismentioning

confidence: 99%

“…Outcomes for two patients with T790M-positive lung cancer showed partial responses. The clinical characteristics and efficacy outcomes of the remaining patients are not reported (55). …”

Section: Third-generation Tkismentioning

confidence: 99%

Third-Generation Tyrosine Kinase Inhibitors Targeting Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer

Barnes

O’Kane

Vincent³

2017

Front. Oncol.

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Sensitizing mutations in the epidermal growth factor receptor (EGFR) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced EGFR-mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy. Resistance mechanisms are being identified to these novel agents, and the treatment landscape of EGFR-mutant lung cancer continues to evolve. The sequence of EGFR TKIs may change in the future and combination therapies targeting resistance appear highly promising.

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AC0010, an Irreversible EGFR Inhibitor Selectively Targeting Mutated EGFR and Overcoming T790M-Induced Resistance in Animal Models and Lung Cancer Patients

Cited by 75 publications

References 32 publications

Third generation EGFR TKIs: current data and future directions

Third generation EGFR TKIs: current data and future directions

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

Third-Generation Tyrosine Kinase Inhibitors Targeting Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer

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