Abstract LB-100: Discovery of HM61713 as an orally available and mutant EGFR selective inhibitor

Lee, Kwang-Ok; Young, Mi; Kim, Mi-Ra; Song, Ji Yeon; Lee, Jae-Ho; Kim, Young Hoon; Lee, Young-Mi; Suh, Kwee Hyun; Son, Jacques A.M. van

doi:10.1158/1538-7445.am2014-lb-100

Cited by 35 publications

(32 citation statements)

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“…Olmutinib is an oral EGFR mutant-specific TKI active against mutant EGFR isoforms, including T790M, while sparing wild-type EGFR (42). A phase I/II trial HM-EMSI-101 (NCT01588145) was conducted to evaluate the safety, tolerability, pharmacokinetics, and preliminary activity of olmutinib in Korean patients with EGFR TKI-pretreated NSCLC (43).…”

Section: Targeting Egfr T790m+ Nsclcmentioning

confidence: 99%

Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line

Sullivan

Planchard

2017

Front. Med.

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Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the known mechanisms of resistance.

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Section: Targeting Egfr T790m+ Nsclcmentioning

confidence: 99%

Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line

Sullivan

Planchard

2017

Front. Med.

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“…The most common mechanism of resistance, accounting for 60% of cases, is the occurrence of the secondary mutation T790M (replacing a gatekeeper amino acid) in the EGFR allele harboring the TKI-sensitive mutation [5]. To overcome resistance to conventional EGFR-TKIs, a new generation of drugs (including AZD9291, CO-1686, and HM61713) that suppress the kinase activity of EGFR proteins harboring secondary T790M substitutions is currently being developed [6][7][8][9]. Phase I clinical trials demonstrate that progressed NSCLC patients who are diagnosed with T790M-positive tumors by genetic testing of rebiopsied tumor tissues respond to these new drugs [10].…”

Section: Introductionmentioning

confidence: 99%

Picoliter-Droplet Digital Polymerase Chain Reaction-Based Analysis of Cell-Free Plasma DNA to AssessEGFRMutations in Lung Adenocarcinoma That Confer Resistance to Tyrosine-Kinase Inhibitors

Seki

Fujiwara²,

Kohno³

et al. 2016

The Oncologist

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Next-generation sequencing ABSTRACTPurpose. The objective of this study was to evaluate the utility of analyzing cell-free plasma DNA (cfDNA) by picoliter-droplet digital polymerase chain reaction (ddPCR) to detect EGFR mutations that confer resistance to tyrosine-kinase inhibitors (TKIs) used for treatment of lung adenocarcinoma (LADC). Experimental design. Thirty-five LADC patients who received epidermal growth factor receptor (EGFR)-TKI therapy, including ten who received tumor rebiopsy after development of resistance, were subjected to picoliter-ddPCR-cfDNA analysis to determine the fraction of cfDNA with TKI-sensitive (L858R and inflame exon 19 deletions) and -resistant (i.e., T790M) mutations, as well as their concordance with mutation status in rebiopsied tumor tissues. Results. cfDNA samples from 15 (94%) of 16 patients who acquired resistance were positive for TKI-sensitive mutations. Also, 7 (44%) were positive for the T790M mutation, with fractions of T790M (1) cfDNA ranging from 7.4% to 97%. T790M positivity in cfDNA was consistent in eight of ten patients for whom rebiopsied tumor tissues were analyzed, whereas the remaining cases were negative in cfDNA and positive in rebiopsied tumors. Prior to EGFR-TKI therapy, cfDNAs from 9 (38%) and 0 of 24 patients were positive for TKIsensitive and T790M mutations, respectively. Next-generation sequencing of cfDNA from one patient who exhibited innate resistance to TKI despite a high fraction of TKI-sensitive mutations and the absence of the T790M mutation in his cfDNA revealed the presence of the L747P mutation, a known driver of TKI resistance. Conclusion. Picoliter-ddPCR examination of cfDNA, supported by next-generation sequencing analysis, enables noninvasive assessment of EGFR mutations that confer resistance to TKIs. The Oncologist 2016;21:156-164 Implications for Practice: Noninvasive monitoring of the predominance of tumors harboring the secondary T790M mutation in the activating mutation in EGFR gene is necessary for precise and effective treatment of lung adenocarcinoma. Because cells harboring the T790M mutation are resistant to epidermal growth factor receptor-tyrosine-kinase inhibitors (TKIs), the predominance of tumor cells harboring the T790M mutations influences the choice of whether to use conventional or next-generation TKIs. Digital polymerase chain reaction-based examination of cfDNA is a promising method; however, its feasibility, including its consistency with examination of rebiopsied tumor tissue, has not been fully proven. Here, picoliter-droplet digital polymerase chain reaction technology is presented as a candidate method for testing cfDNA and assessing the predominance of T790M-mutant tumors.

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“…Disease control rate was 91 % by independent assessment. The most common treatment-related adverse events included diarrhoea (55 %), nausea (37 %), rash (38 %) and pruritus (36 %), the majority were mild-to-moderate [23]. It seems a promising agent; however further studies to confirm therapeutic activity are needed.…”

Section: Hm61713 (Bi 1482694)mentioning

confidence: 99%

Tyrosine kinase inhibitors: new molecules in non-small cell lung cancer (EGFR AND ALK)

et al. 2017

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Abstract LB-100: Discovery of HM61713 as an orally available and mutant EGFR selective inhibitor

Cited by 35 publications

References 0 publications

Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line

Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line

Picoliter-Droplet Digital Polymerase Chain Reaction-Based Analysis of Cell-Free Plasma DNA to AssessEGFRMutations in Lung Adenocarcinoma That Confer Resistance to Tyrosine-Kinase Inhibitors

Tyrosine kinase inhibitors: new molecules in non-small cell lung cancer (EGFR AND ALK)

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