Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia

Okahisa, Masanobu; Udagawa, Hibiki; Matsumoto, Shingo; Kato, Terufumi; Yokouchi, Hiroshi; Furuya, Naoki; Kanemaru, Ryota; Toyozawa, Ryo; Nishiyama, Akihiro; Ohashi, Kadoaki; Miyamoto, Shingo; Nishino, Kazumi; Nakamura, Atsushi; Iwama, Eiji; Niho, Seiji; Oi, Hajime; Sakai, Tetsuya; Shibata, Yuji; Izumi, Hiroki; Sugiyama, Eri; Nosaki, Kaname; Umemura, Shigeki; Zenke, Yoshitaka; Yoh, Kiyotaka; Kah Mun Low, Grace; Zhuo, Jianmin; Goto, Koichi

doi:10.1016/j.lungcan.2024.107798

Cited by 4 publications

(2 citation statements)

References 21 publications

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“…Moreover, not all Exon 20ins mutations respond similarly to TKIs. Studies have indicated that some mutations may confer resistance or reduced sensitivity to certain TKIs, while others may exhibit greater responsiveness, depending on the structural domains where the insertion mutations occur ( 30 ). It is evident that the differences in mutations at different sites highlight the subtleties in understanding treatment outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of exon 20 insertions induces an “αC-in” conformational shift in the α-C helix, thereby fostering constitutive activation and downstream signaling. Positioned distinctively outside the α-C helix, these mutations evade the adenosine triphosphate (ATP) binding pocket, typically exerting their effects through covalent binding to the ATP pocket and competitive inhibition of downstream signaling, rendering them refractory to conventional EGFR tyrosine kinase inhibitors (TKIs) save for the A763–764insFQEA mutation ( 30 ). Prior investigations have established that over 90% of insertion mutations occur within adjacent loops following the α-C helix within the intracellular domain of the receptor, with approximately 70% involving proximal loop insertions and 30% involving distal loop insertions, notably clustering between amino acids 766 and 775 and typically involving insertions or duplications of one to four amino acids ( 31 ).…”

Section: Methods For the Detection Of Egfr Ex20insmentioning

confidence: 99%

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The current landscape, advancements, and prospects in the treatment of patients with EGFR exon 20 insertion mutations warrant scientific elucidation

Man,

Sun,

Chen

et al. 2024

Front. Oncol.

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Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most prevalent mutation in non-small cell lung cancer (NSCLC), following the 19del and L858R mutations. The unique nature of the EGFR ex20ins mutation poses challenges for the effectiveness of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). As a result, chemotherapy remains the primary and more effective treatment approach. However, with advancements in time and technology, numerous experimental studies have revealed the potential of novel drugs and therapies to have stronger inhibitory effects on EGFR ex20ins mutations. In this comprehensive review, we provide an overview of the current treatment landscape, recent advancements, and the prospects for patients with advanced NSCLC characterized by EGFR ex20ins mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Methods For the Detection Of Egfr Ex20insmentioning

confidence: 99%

The current landscape, advancements, and prospects in the treatment of patients with EGFR exon 20 insertion mutations warrant scientific elucidation

Man,

Sun,

Chen

et al. 2024

Front. Oncol.

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A phase 2 study of mobocertinib as first-line treatment in Japanese patients with non-small cell lung cancer harboring EGFR exon 20 insertion mutations

Yoh,

Azuma,

Hayashi

et al. 2024

Int J Clin Oncol

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Background Mobocertinib is a novel, synthetic, orally administered tyrosine kinase inhibitor that inhibits many activated forms of epidermal growth factor receptor (EGFR), including those containing exon 20 insertion (ex20ins) mutations. This study aimed to assess the efficacy of mobocertinib in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR ex20ins mutations. Methods This was a phase 2, open-label study. Patients with NSCLC harboring EGFR ex20ins mutations who had not had previous systemic treatment received mobocertinib 160 mg once daily. The primary endpoint was the confirmed objective response rate. A planned interim analysis was completed for the first 14 patients with a centrally confirmed EGFR ex20ins mutation, with enrollment stopped if the number of patients with an objective response was five or fewer. Results In total, 33 patients were enrolled into the study (63.6% women; median age: 66 years). At the interim analysis, the objective response rate evaluated by a central independent review committee was 28.6% (4/14, 90% confidence interval: 10.4–54.0); therefore, enrollment was stopped for futility. In the full analysis set, the objective response rate was 18.2% (6/33, 95% confidence interval: 7.0–35.5); of the six responders, one patient (3.0%) had a complete response and five patients (15.2%) had partial responses. The most common treatment-related adverse events were diarrhea, paronychia, stomatitis, and nausea. Conclusion Although study enrollment was terminated early owing to futility, our results showed modest activity of mobocertinib in Japanese patients with NSCLC with EGFR ex20ins mutations with no additional safety concerns.

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Efficacy of immune checkpoint inhibitors plus platinum-based chemotherapy as 1st line treatment for patients with non-small cell lung cancer harboring HER2 mutations: Results from LC-SCRUM-Asia

Kato,

Udagawa,

Matsumoto

et al. 2024

Lung Cancer

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Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia

Cited by 4 publications

References 21 publications

The current landscape, advancements, and prospects in the treatment of patients with EGFR exon 20 insertion mutations warrant scientific elucidation

The current landscape, advancements, and prospects in the treatment of patients with EGFR exon 20 insertion mutations warrant scientific elucidation

A phase 2 study of mobocertinib as first-line treatment in Japanese patients with non-small cell lung cancer harboring EGFR exon 20 insertion mutations

Efficacy of immune checkpoint inhibitors plus platinum-based chemotherapy as 1st line treatment for patients with non-small cell lung cancer harboring HER2 mutations: Results from LC-SCRUM-Asia

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