BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M+ NSCLC: Efficacy and safety at the RP2D.

Park, Keunchil; Lee, Jong-Seok; Lee, Ki Hyeong; Kim, Joo-Hang; Cho, Byoung Chul; Min, Young Joo; Cho, Jae Yong; Han, Ji‐Youn; Kim, Bong-Seog; Lee, Dong Hoon; Kang, Jin Hyoung; Cho, Eun Kyung; Kim, Hoon-Gu; Lee, Kyung Hee; Kim, Hoon Kyo; Jang, In‐Jin; Kim, Hyo-Yeon; Son, Jacques A.M. van; Kim, Dong-Wan

doi:10.1200/jco.2016.34.15_suppl.9055

Cited by 35 publications

(26 citation statements)

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“…In contrast, the development of rociletinib was abandoned because the initially reported ORR of 59% was reduced to 45%: initial data were not unconfirmed partial responses although partial responses must be maintained on a second scan obtained at least 4 weeks later . Recently, olmutinib (BI1482694/HM61713) was approved for T790M‐positive tumors in South Korea and received FDA breakthrough therapy designation . Other 3G‐TKI, nazartinib (EGF816) and ASP8273, are undergoing clinical evaluation …”

Section: First Second and Third Generation Egfr ‐Tyrosine Kinase Inhmentioning

confidence: 99%

Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy

2016

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Somatic mutations in the epidermal growth factor receptor (EGFR) gene are present in approximately 20% (in Caucasians) to 40% (in East Asians) of adenocarcinomas of the lung. Targeted therapy for these lung cancers has been established based on evidence regarding mainly common mutations; that is, exon 19 deletions (Del19) and L858R. EGFR‐tyrosine kinase inhibitors (TKI), gefitinib, erlotinib or afatinib showed high objective response rates (ORR) of approximately 60%. Several studies suggested that Del19 might be more sensitive to EGFR‐TKI than L858R. On the other hand, it has been difficult to establish evidence for other less common mutations, accounting for 12% of all EGFR mutations, because there are many variants and many studies have excluded patients with these uncommon mutations. However, recent studies revealed that these rare genotypes could be targetable if appropriate TKI are selected. For example, G719X (X denotes A, S, C and so on), Del18, E709K, insertions in exon 19 (Ins19), S768I or L861Q showed moderate sensitivities to gefitinib or erlotinb with ORR of 30%–50%. However, afatinib appeared to be especially effective for these tumors. Although Ins20s (except for insFQEA) have been regarded as resistant mutations, osimertinib may be effective for rare subtypes of them and nazartinib (EGF816) is promising for the majority of them. For the further development of targeted therapy in all EGFR mutations, it is important to precisely detect targetable mutations, to select the most appropriate TKI for each mutation, and to continue investigating in vitro studies and collecting clinical data on even rare mutations.

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Section: First Second and Third Generation Egfr ‐Tyrosine Kinase Inhmentioning

confidence: 99%

Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy

2016

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“…The ORR was 61% and median PFS ( n = 76) was 6.9 months [95% CI, 5.36–9.49]. The most common drug-related AEs (all grades) were diarrhea (59%), pruritus (42%), rash (41%), and nausea (39%) (44). These data validate previous preliminary trial results presented at the European Society for Medical Oncology Asia Congress in December 2015 (45).…”

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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“…In that study, 76 EGFR T790M -positive patients received olmutinib therapy at a dose of 800 mg/day, and the median PFS was 6.9 months. The confirmed ORR was 54% among 70 evaluable patients, and activity against central nervous system metastases was also observed [59]. The treatment-related AEs from this study are listed in Table 1.…”

Section: Main Text Of the Reviewmentioning

confidence: 58%

“…The treatment-related AEs from this study are listed in Table 1. One patient experienced ILD and discontinued therapy, but there was no AE of hyperglycemia [59]. …”

Section: Main Text Of the Reviewmentioning

confidence: 99%

Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors

et al. 2016

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The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (1/2G EGFR-TKIs) gefitinib, erlotinib, and afatinib have all been approved as standard first-line treatments for advanced EGFR mutation-positive non-small cell lung cancer. The third-generation (3G) EGFR-TKIs have been developed to overcome the EGFR T790M mutation, which is the most common mechanism of acquired resistance to 1/2G EGFR-TKI treatment. This resistance mutation develops in half of the patients who respond to 1/2G EGFR-TKI therapy. The structures of the novel 3G EGFR-TKIs are different from those of 1/2G EGFR-TKIs. Particularly, 3G EGFR-TKIs have lower affinity to wild-type EGFR, and are therefore associated with lower rates of skin and gastrointestinal toxicities. However, many of the adverse events (AEs) that are observed in patients receiving 3G EGFR-TKIs have not been observed in patients receiving 1/2G EGFR-TKIs. Although preclinical studies have revealed many possible mechanisms for these AEs, the causes of some AEs remain unknown. Many mechanisms of resistance to 3G EGFR-TKI therapy have also been reported. Here, we have reviewed the recent clinical and preclinical developments related to novel 3G EGFR-TKIs, including osimertinib, rociletinib, olmutinib, EGF816, and ASP8273.

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BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M+ NSCLC: Efficacy and safety at the RP2D.

Cited by 35 publications

References 0 publications

Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy

Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy

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

Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors

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