TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations

Hasako, Shinichi; Terasaka, Miki; Abe, Naomi; Uno, Takao; Ohsawa, Hirokazu; Hashimoto, Akihiro; Fujita, Reiko; Tanaka, Kenji F.; Okayama, Takashige; Wadhwa, Renu; Miyadera, Kazutaka; Aoyagi, Yoshimi; Yonekura, Kazuya; Matsuo, Keitaro

doi:10.1158/1535-7163.mct-17-1206

Cited by 72 publications

(61 citation statements)

References 35 publications

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“…Multiple ongoing clinical trials have begun to test the effectiveness of currently available or novel EGFR TKIs on patients with EGFR e20 insertions, including afatinib and cetuximab (NCT03727724), osimertinib (NCT03414814), poziotinib (Robichaux et al, 2018), luminespib (a HSP90 inhibitor) (Piotrowska et al, 2018a), and TAS6417 (a novel EGFR TKI) (Hasako et al, 2018). However, those studies do not discriminate between the different types of insertions and, thus, provide a blanket treatment for all patients.…”

Section: Discussionmentioning

confidence: 99%

Variability of EGFR exon 20 insertions in 24 468 Chinese lung cancer patients and their divergent responses to EGFR inhibitors

Qin

Hong

Tong³

et al. 2020

Molecular Oncology

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EGFR exon 20 insertions (EGFR e20ins) account for up to 10% of EGFR mutations in lung cancer; however, tumors with EGFR e20ins had poor response rates to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, afatinib, and osimertinib, and the heterogeneity of EGFR e20ins further complicates the clinical studies. Here, we retrospectively screened next-generation sequencing (NGS) data from 24 468 lung cancer patients, and a total of 85 unique EGFR e20ins variants were identified in 547 cases (2.24%), with p.A767_V769dup (25.1%) and p.S768_D770dup (17.6%) being the most prevalent ones. Comprehensive genomic profiling revealed that TP53 mutations frequently coexisted with p.H773dup (77.8%, P = 0.0558) and p.A767_V769dup (62.8%, P = 0.0325), while RB1 mutations usually co-occurred with p.H773_V774insAH (33.3%, P = 0.0551), implying that different EGFR e20ins variants might require distinct genomic context for tumorigenesis and/or maintenance. Despite that treatment regimens were highly diverse for EGFR e20ins-positive patients, we observed an overall response rate of 14% and a disease control rate (DCR) of 38.4% in 65 patients who received at least one EGFR TKI. The progression-free survival (PFS) differs significantly in six representative EGFR e20ins variants (P = 0.017), and EGFR p.A763_Y764insF-QEA was associated with better PFS than other EGFR e20ins when treating with various EGFR TKIs. Some EGFR e20ins variants showed at least partial response to first-generation EGFR TKIs, including p.A767_V769dup, p.S768_D770dup, p.N771_H773dup, p.A763_Y764insF-QEA, and p.D770_N771insG. Poziotinib achieved higher DCR for p.S768_D770dup than for p.A767_V769dup, whereas osimertinib showed limited effects for these two insertions when used as the first-line treatment. Overall, our results demonstrated that EGFR e20ins were highly diversified in terms of insertion patterns and co-occurring mutations and these EGFR e20ins variants showed different clinical responses to various EGFR TKIs,

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Section: Discussionmentioning

confidence: 99%

Variability of EGFR exon 20 insertions in 24 468 Chinese lung cancer patients and their divergent responses to EGFR inhibitors

Qin

Hong

Tong³

et al. 2020

Molecular Oncology

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“…However, it should be noted that not all mutations lead to increased sensitivity to EGFR-TKIs 30. Mutations such as an exon 20 insertion, present in up to 9.2% of the EGFR mutations, induce a decreased EGFR-TKI sensitivity 31…”

Section: Introductionmentioning

confidence: 99%

Rapid clinical mutational testing ofKRAS,BRAFandEGFR: a prospective comparative analysis of the Idylla technique with high-throughput next-generation sequencing

et al. 2019

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AimsPrecision medicine therapy is remodelling the diagnostic landscape of cancer. The success of these new therapies is often based on the presence or absence of a specific mutation in a tumour. The Idylla platform is designed to determine the mutational status of a tumour as quickly and accurately as possible, as a rapid, accurate diagnosis is of the utmost importance for the treatment of patients. This is the first complete prospective study to investigate the robustness of the Idylla platform for EGFR, KRAS and BRAF mutations in non-small cell lung cancer, metastatic colorectal cancer and metastatic melanoma, respectively.MethodsWe compared prospectively the Idylla platform with the results we obtained from parallel high-throughput next-generation sequencing, which is the current gold standard for mutational testing. Furthermore, we evaluated the benefits and disadvantages of the Idylla platform in clinical practice. Additionally, we reviewed all the published Idylla performance articles.ResultsThere was an overall agreement of 100%, 94% and 94% between the next-generation panel and the Idylla BRAF, KRAS and EGFR mutation test. Two interesting discordant findings among 48 cases were observed and will be discussed together with the advantages and shortcoming of both techniques.ConclusionOur observations demonstrate that the Idylla cartridge for the EGFR, KRAS and BRAF mutations is highly accurate, rapid and has a limited hands-on time compared with next-generation sequencing.

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“…TAS6417, tarloxotinib (TH-4000) and luminespib (Hsp90 inhibitor; AUY922) are novel inhibitors of EGFR, especially directed to exon 20 insertions. [ 134 , 135 , 136 ].…”

Section: Tyrosine Kinase Receptor Inhibitors Developed For Cancer mentioning

confidence: 99%

Tyrosine Kinase Receptors in Oncology

Esteban-Villarrubia

Castillo

Pozas

et al. 2020

IJMS

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Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.

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TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations

Cited by 72 publications

References 35 publications

Variability of EGFR exon 20 insertions in 24 468 Chinese lung cancer patients and their divergent responses to EGFR inhibitors

Variability of EGFR exon 20 insertions in 24 468 Chinese lung cancer patients and their divergent responses to EGFR inhibitors

Rapid clinical mutational testing ofKRAS,BRAFandEGFR: a prospective comparative analysis of the Idylla technique with high-throughput next-generation sequencing

Tyrosine Kinase Receptors in Oncology

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