Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial

Yang, James Chih Hsin; Camidge, D. Ross; Yang, Cheng‐Ta; Zhou, Jianying; Guo, Renhua; Chiu, Chao Hua; Chang, Gee Chen; Shiah, Her Shyong; Chen, Yuan; Wang, Chin Chou; Berz, David; Su, Wu Chou; Yang, Nong; Wang, Ziping; Fang, Jian; Chen, Jianhua; Nikolinakos, Petros; Lü, You; Pan, Hongming; Maniam, Ajit; Bazhenova, Lyudmila; Shirai, Keisuke; Jahanzeb, Mohammad; Willis, Maurice; Masood, Nehal; Chowhan, N. M.; Hsia, Te Chun; Hong, Jian; Lü, Shun

doi:10.1016/j.jtho.2020.09.001

Cited by 96 publications

(82 citation statements)

References 20 publications

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“…Preclinically, biochemical kinase inhibition studies revealed that the values of the concentration that inhibits 50% (IC 50 ) of almonertinib are the following: T790M (0.37 ± 0.04 nM), del19/T790M (0.21 ± 0.10 nM), L858R/T790M (0.29 ± 0.10 nM), and EGFR WT (3.39 ± 0.53 nM). 12 In cell-based assays, almonertinib inhibits EGFR phosphorylation at IC 50 of 3.3 nM in HCC827 (EGFR del19) cell line, IC 50 of 4.1 nM in PC9 (EGFR del19) cell line, IC 50 of 3.3 nM in NCI-H1975 (EGFR L858R/T790M) cell line, but only IC 50 of 596.6 nM in A431 (EGFR WT) cell line. 13 HAS-719, a metabolite of almonertinib, also has activity against various EGFR mutations albeit with less potency than almonertinib.…”

Section: Almonertinib (Hs-10296)mentioning

confidence: 99%

“…13 HAS-719, a metabolite of almonertinib, also has activity against various EGFR mutations albeit with less potency than almonertinib. 13 The phase 1/2 dose escalation and dose-expansion trial of almonertinib enrolled 120 patients 12,14 (Fig. 1 and Table 1).…”

Section: Almonertinib (Hs-10296)mentioning

confidence: 99%

“…The mean half-life of almonertinib at 110 mg daily was 30.7 hours. 12,14 The maximum tolerated dose (MTD) was not reached. The mean area under the curve at 110 mg daily was similar to 220 mg daily but with much lower incidence of creatinine phosphokinase (CPK) elevation (13.3% versus 51.6%) and diarrhea (6.7% versus 19.7%).…”

Section: Almonertinib (Hs-10296)mentioning

confidence: 99%

“…The substitutions are highlighted in red. Sources of the structures: almonertinib, 12 larzertinib, 18 alflutinib, 26 rezivertinib (https://www.medkoo.com/products/36827), ASK120067. 37 TKI, tyrosine kinase inhibitor.…”

Section: Almonertinib (Hs-10296)mentioning

confidence: 99%

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Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

Nagasaka

Zhu

Lim

et al. 2021

Journal of Thoracic Oncology

136

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Single-agent osimertinib is the standard of care for the firstline treatment of advancedEGFRþ NSCLC and remained the only marketed third-generation EGFR tyrosine kinase inhibitor (TKI) until March 2020 when almonertinib (HS-10296) was approved in the People's Republic of China for the treatment of advanced EGFR T790Mþ NSCLC based on a phase 2 expansion study of a phase 1/2 trial. In this review, we profiled many of the third-generation EGFR TKIs in latestage clinical development (e.g., almonertinib, lazertinib, alflutinib 1 , rezivertinib, ASK120069, SH-1028, D-0316, and abivertinib) based on their interim results from phase 1 and phase 2 trials, and included the designs of the phase 3 trials and their chemical structures when publicly available. We also listed other third-generation EGFR TKIs in pipeline development based on the search of clinical trial registration websites. In addition, we summarized the results of clinical trials that previously reported third-generation EGFR TKIs (rociletinib, olmutinib, nazartinib, mavelertinib), including phase 3 results of rociletinib and naquotinib. We further profiled combination clinical trial design of the thirdgeneration EGFR TKIs including FLAURA2 (NCT04035486), MARIPOSA (NCT04487080), ACROSS1 (NCT04500704), and ACROSS2 (NCT04500717) that if positive can potentially usher in the next standard of care for advanced EGFRþ NSCLC.

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Section: Almonertinib (Hs-10296)mentioning

confidence: 99%

Section: Almonertinib (Hs-10296)mentioning

confidence: 99%

Section: Almonertinib (Hs-10296)mentioning

confidence: 99%

Section: Almonertinib (Hs-10296)mentioning

confidence: 99%

See 2 more Smart Citations

Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

Nagasaka

Zhu

Lim

et al. 2021

Journal of Thoracic Oncology

136

View full text Add to dashboard Cite

show abstract

“…Different other third-generation EGFR inhibitors have been developed to target both standard EGFR-sensitizing and T790M resistance mutations, including rociletinib [ 110 ], abivertinib [ 111 ], lazertinib [ 112 ], nazartinib [ 113 ] and almonertinib [ 114 ]. Efficacy for these EGFR-TKIs was assessed in early phase trials, mostly in heavily pre-treated patients, and the response rates vary considerably.…”

Section: Egfr Mutationsmentioning

confidence: 99%

Targeted Therapy in Advanced and Metastatic Non-Small Cell Lung Cancer. An Update on Treatment of the Most Important Actionable Oncogenic Driver Alterations

König

Prince

Rothschild

2021

Cancers

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Due to groundbreaking developments and continuous progress, the treatment of advanced and metastatic non-small cell lung cancer (NSCLC) has become an exciting, but increasingly challenging task. This applies, in particular, to the subgroup of NSCLC with oncogenic driver alterations. While the treatment of epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged NSCLC with various tyrosine kinase inhibitors (TKIs) is well-established, new targets have been identified in the last few years and new TKIs introduced in clinical practice. Even for KRAS mutations, considered for a long time as an “un-targetable” alteration, promising new drugs are emerging. The detection and in-depth molecular analysis of resistance mechanisms has further fueled the development of new therapeutic strategies. The objective of this review is to give a comprehensive overview on the current landscape of targetable oncogenic alterations in NSCLC.

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Mutated circulating tumor DNA as a liquid biopsy in lung cancer detection and treatment

Filipska

2021

Molecular Oncology

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Over the past decade, substantial developments have been made in the detection of circulating tumor DNA (ctDNA)—cell‐free DNA (cfDNA) fragments released into the circulation from tumor cells and displaying the genetic alterations of those cells. As such, ctDNA detected in liquid biopsies serves as a powerful tool for cancer patient stratification, therapy guidance, detection of resistance, and relapse monitoring. In this Review, we describe lung cancer diagnosis and monitoring strategies using ctDNA detection technologies and compile recent evidence regarding lung cancer‐related mutation detection in liquid biopsy. We focus not only on epidermal growth factor receptor (EGFR) alterations, but also on significant co‐mutations that shed more light on novel ctDNA‐based liquid biopsy applications. Finally, we discuss future perspectives of early‐cancer detection and clonal hematopoiesis filtering strategies, with possible inclusion of microbiome‐driven liquid biopsy.

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Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial

Cited by 96 publications

References 20 publications

Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

Targeted Therapy in Advanced and Metastatic Non-Small Cell Lung Cancer. An Update on Treatment of the Most Important Actionable Oncogenic Driver Alterations

Mutated circulating tumor DNA as a liquid biopsy in lung cancer detection and treatment

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