Safety, tolerability, and anti-tumor activity of olmutinib in non-small cell lung cancer with T790M mutation: A single arm, open label, phase 1/2 trial

Kim, Dong Wan; Lee, Dong Hoon; Han, Ji Youn; Lee, Jong-Seok; Cho, Byoung Chul; Kang, Jin Hyoung; Lee, Ki Hyeong; Cho, Eun Kyung; Min, Young Joo; Cho, Jae Yong; An, Ho Jung; Kim, Hoon Gu; Lee, Kyung Hee; Kim, Bong Seog; Jang, In Jin; Yoon, Seo Young; Han, Oak Pil; Noh, Young Su; Hong, Ka Young; Park, Keunchil

doi:10.1016/j.lungcan.2019.07.007

Cited by 24 publications

(21 citation statements)

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“…To confirm the enhancing effect of olmutinib on the anti-tumor efficacy of Dox in vivo , we generated an ETS1-overexpressing K562/ADR cell xenograft model and concluded that olmutinib enhanced the efficacy of Dox on an ETS1-overexpressing Dox-resistant leukemia cell transplantation model in vivo . However, because of olmutinib’s potential to result in skin and gastrointestinal toxicities despite its excellent anticancer activity in various lung cancer cell lines with EGFR mutations, including the T790 M [ 22 , 23 ], and the cardiotoxicity of Dox as a long term schedule [ 24 ], we recommend further in vivo or clinical experiments of the clinically combined application of olmutinib and Dox. In addition, we know that the action of ETS1 is to promote production of blood vessels around the cancer tissues [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Olmutinib Reverses Doxorubicin Resistance in ETS1-Overexpressing Leukemia Cells

Zhong

Zhang

et al. 2020

Med Sci Monit

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Background Drug resistance is a major problem in the treatment of leukemia with doxorubicin (Dox), and the erythroblastosis virus E26 oncogene homolog 1 (ETS1) gene is associated with drug resistance. Olmutinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) reported to play a role in reversing multidrug resistance (MDR) in cancer cells. The objective of this study was to investigate whether olmutinib could reverse Dox resistance in leukemia cells overexpressing ETS1. Material/Methods Human chronic myelogenous leukemia cell line K562 and its Dox-resistant cell line K562/ADR were used. Western blot and qPCR detected the expression of ETS1 and ABCB1. Cell proliferation was measured by cell counting kit-8 and methyl thiazolyl tetrazolium. Cell apoptosis was observed by western blot and flow cytometry. A nude mice K562/ADR xenograft model was used to investigate the inhibitory effects of olmutinib on tumor growth in vivo . Results The mRNA and protein expressions of ETS1 and ABCB1 were up-regulated in Dox-resistant leukemia cell line K562/ADR. We overexpressed ETS1 in both cell lines, finding that olmutinib inhibited the cell viability of K562 and K562/ADR in a concentration-dependent manner. The cytotoxicity of Dox to EST1-overexpressing K562/ADR cells was enhanced by olmutinib. Olmutinib also promoted apoptosis of K562 and K562/ADR cells compared with Dox treatment alone. In vivo , olmutinib enhanced the inhibitory effects of Dox on ETS1-overexpressing K562/ADR cell xenograft growth. Conclusions Our results suggest that the novel EGFR TKI olmutinib enhances the sensitivity of ETS1-overexpressing leukemia cells to Dox.

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Section: Discussionmentioning

confidence: 99%

Olmutinib Reverses Doxorubicin Resistance in ETS1-Overexpressing Leukemia Cells

Zhong

Zhang

et al. 2020

Med Sci Monit

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“…OLMUTINIB (HM61713) is another third-generation drug [103] that selectively inhibits EGFR T790M, L858R and exon 19 deletions but works poorly against WT EGFR [104,105]. In addition, olmutinib also inhibits the function of several ABC (ATP-binding cassette) transporters [106], which are usually overexpressed in cancer cells showing multidrug resistance [107].…”

Section: Epidermal Growth Factor Receptor (Egfr)mentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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“…Preclinical studies reported that olmutinib had excellent antitumor activity in various lung cancer cell lines with EGFR mutations (including T790M mutation) while producing minimal activity against wild‐type EGFR 22 . Clinical information about olmutinib is available from a phase 1 study in healthy volunteers 23 and from a phase 1/2 Korean study in patients with NSCLC who were pretreated with an EGFR‐TKI 24 . Olmutinib 800 mg once daily was the maximum tolerated dose and was recommended for phase 2 evaluation.…”

Section: Introductionmentioning

confidence: 99%

“…Olmutinib 800 mg once daily was the maximum tolerated dose and was recommended for phase 2 evaluation. In a phase 2 trial, the objective response rate (ORR) was 55.1% (95% CI, 42.6%‐67.1%), most patients had tumor shrinkage relative to baseline (maximum shrinkage ranged from 27.7% to 100%), and the estimated median progression‐free survival (PFS) was 6.9 months (95% CI, 5.6‐9.7 months) 24 . Therefore, preclinical and clinical data indicate that olmutinib is effective in patients who have EGFR ‐mutant NSCLC with the T790M mutation.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, preclinical and clinical data indicate that olmutinib is effective in patients who have EGFR ‐mutant NSCLC with the T790M mutation. Olmutinib had a safety profile expected of an EGFR‐TKI, and most adverse events (AEs) were mild to moderate 20,21,24,25 . Furthermore, specific efficacy data from the phase 1/2 study suggested that olmutinib had significant clinical activity in patients with T790M‐positive NSCLC after failing initial EGFR‐TKI therapy and that reduced tumor volume was positively correlated with olmutinib exposure.…”

Section: Introductionmentioning

confidence: 99%

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Olmutinib in T790M‐positive non–small cell lung cancer after failure of first‐line epidermal growth factor receptor‐tyrosine kinase inhibitor therapy: A global, phase 2 study

Park

Kim

Han

et al. 2021

Cancer

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Background In this open‐label, international phase 2 study, the authors assessed the efficacy and safety of olmutinib in patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) who had a confirmed T790M mutation and disease progression on previous epidermal growth factor receptor‐tyrosine kinase inhibitor therapy. Methods Patients aged ≥20 years received once‐daily oral olmutinib 800 mg continuously in 21‐day cycles. The primary endpoint was the objective response rate (patients who had a confirmed best overall response of a complete or partial response), assessed by central review. Secondary endpoints included the disease control rate, the duration of objective response, progression‐free survival, and overall survival. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Results Overall, 162 patients (median age, 63 years; women, >60%) were enrolled from 68 sites in 9 countries. At the time of database cutoff, 23.5% of enrolled patients remained on treatment. The median treatment duration was 6.5 months (range, 0.03‐21.68 months). Overall, 46.3% of patients (95% CI, 38.4%‐54.3%) had a confirmed objective response (all partial responses). The best overall response (the objective response rate regardless of confirmation) was 51.9% (84 patients; 95% CI, 43.9%‐59.8%). The confirmed disease control rate for all patients was 86.4% (95% CI, 80.2%‐91.3%). The median duration of objective response was 12.7 months (95% CI, 8.3‐15.4 months). Estimated median progression‐free survival was 9.4 months (95% CI, 6.9‐12.3 months), and estimated median overall survival was 19.7 months (95% CI, 15.1 months to not reached). All patients experienced treatment‐emergent adverse events, and 71.6% of patients had grade ≥3 treatment‐emergent adverse events. Conclusions Olmutinib has meaningful clinical activity and a manageable safety profile in patients with T790M‐positive non–small cell lung cancer who received previous epidermal growth factor receptor‐tyrosine kinase inhibitor therapy.

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Safety, tolerability, and anti-tumor activity of olmutinib in non-small cell lung cancer with T790M mutation: A single arm, open label, phase 1/2 trial

Cited by 24 publications

References 24 publications

Olmutinib Reverses Doxorubicin Resistance in ETS1-Overexpressing Leukemia Cells

Olmutinib Reverses Doxorubicin Resistance in ETS1-Overexpressing Leukemia Cells

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Olmutinib in T790M‐positive non–small cell lung cancer after failure of first‐line epidermal growth factor receptor‐tyrosine kinase inhibitor therapy: A global, phase 2 study

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