レ点腫瘍学ノート

Top / 日記 / 2021年 / 10月18日

EGFRエクソン20挿入変異に対する高用量オシメルチニブのメモ

非小細胞肺癌ではEGFR ex20ins(エクソン20挿入変異)は古典的EGFR-TKI(エルロチニブ・ゲフィチニブなど)への体制変異と考えられていて、またオシメルチニブも有効性が乏しいためEGFR変異肺癌の中で治療開発が遅れた領域として課題視されていたようです。

uncommonなEGFR変異に対するオシメルチニブの治療効果に関する研究は下記のJCOの2019年の報告がありますが、エントリー基準で定義されているように、エクソン20の挿入変異の症例は(ほぼ)含まれていません(Eligible patients were age 19 years or older, with a histologically confirmed diagnosis of meta- static or recurrent NSCLC harboring EGFR mutations other than exon 19 deletion, L858R, T790M, or exon 20 in- sertion.)。

Osimertinib for Patients With Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09) - PubMed
Osimertinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring uncommon EGFR mutations.
https://pubmed.ncbi.nlm.nih.gov/31825714/

モボセルチニブやポジオチニブの話もありますが

最近では、モボセルチニブ*1やポジオチニブ*2の開発が進んでいます(ポジオチニブはEGFR ex20insもERBB2 ex20insも標的にするようです)。またオシメルチニブが高容量では有効ではないかという話もあって、それを評価する臨床試験も進んでいるようです。モボセルチニブやポジオチニブの話はまた改めて書くとして、オシメルチニブについてのツイートがあったのでそちらをメモしておきます。

EGFRエクソン20挿入変異に対する高用量オシメルチニブ

このたびLung cancer誌に掲載された国内第1/2相試験では14例に投与されたオシメルチニブ80mgの奏効率は0%だったようです。PFSは3.8ヶ月、OSは15.8ヶ月。

Title: A phase I/II study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer
EGFR exon 20 insertion (EGFR ex20ins) mutations comprise about 4-12% [1–4] of EGFR mutations, which is the third most common category of mutations detected in NSCLC. More than 60 types of EGFR exon 20 insertion mutations have been reported till date [5]. In-frame insertions at exon 20 push the C-helix into its inward position and promote the active conformation of EGFR, which induce ligand-independent activation of EGFR [2]. In clear contrast to common EGFR mutations such as the point mutation in exon 21 L858R and in-frame deletions in exon 19 of EGFR, EGFR ex20ins mutations are known to be resistant to clinically available first and second generation EGFR tyrosine kinase inhibitors (EGFR-TKIs).
https://www.lungcancerjournal.info/article/S0169-5002(21)00577-8/fulltext

一方で、米国のECOG-ACRIN 5162のP2(ECOG-ACRIN 5162)では160mgに増量したところ、ある程度奏効してCRも出ているようです。

ECOG-ACRIN 5162: A phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions. | Journal of Clinical Oncology
9513 Background: EGFR exon 20 insertions (ins20), which comprise 4-10% of EGFR-mutant NSCLC, are generally refractory to first- and second-generation EGFR TKIs. While the clinical activity of the third-generation EGFR TKI osimertinib against EGFR ins20 is unknown, preclinical studies suggest its favorable therapeutic window may allow for inhibition of EGFR isn20 at clinically-achievable doses (Hirano, Oncotarget 2015). We report the results of EA5162, a single-arm, phase II study of osimertinib 160 mg in NSCLC pts with EGFR ins20 (NCT03191149). Methods: Pts with advanced NSCLC with an EGFR ins20 mutation identified by any local, CLIA-certified tissue assay were treated with osimertinib 160 mg daily until progression, intolerable toxicity or withdrawal. At least one prior line of therapy was required; stable, asymptomatic brain metastases were allowed. The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival. The estimated sample size was 19 patients. Results: 21 pts were enrolled between 4/2018 and 7/2019 (median age 65; 15 female, 6 male; median 2 prior therapies); 1 patient did not meet eligibility criteria due to laboratory studies obtained 1 day out of window. As of 1/21/20, 6 pts remain on treatment. Among the 20 eligible pts, the best response was PR in 4 pts and CR in one pt, for a confirmed ORR of 25%; 12 (60%) pts had SD. The median PFS was 9.7 months (95% CI, 4.07, NA), median duration of response (DOR) was 5.7 months (95% CI, 4.73, NA.) Grade > 3 treatment-related adverse events (TRAE) observed in > 1 pt included anemia (n=2), fatigue (n=2), prolonged QT interval (n=2.) One pt had grade 4 respiratory failure, there were no grade 5 TRAEs. One pt discontinued study treatment due to grade 3 anemia. Conclusions: Osimertinib 160mg daily is well-tolerated and showed clinical activity in EGFR ins20-mutant NSCLC with a response rate of 25%, disease control rate of 85%, and mPFS of 9.7 months. The adverse events with osimertinib 160 mg QD in this cohort were consistent with other reports of this regimen; grade 3 rash and diarrhea were not observed. Clinical trial information: NCT03191149.
https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.9513

ECOG-ACRIN 5162: A phase II study of osimertinib 160 mg in EGFR exon 20 insertion mutations.
n=20
ORR 25%; DCR 85%; mDoR 5.7 months, mPFS 9.7 months
Toxicity in the expected range. #ASCO20 #LCSM @Exon20Group pic.twitter.com/5fIBVvddix

— Dr. Antonio Calles 🌈🫁🚭 (@Tony_Calles) May 30, 2020

投与量が80mgと160mgと違いますが、これが奏効率の差なのでしょうか。あるいは、エクソン20の中でも挿入部位によって感受性に違いが出るのか(だとすればBRCAのように変異塩基でその機能ダメージやpathogenicityを分類するようになるのか)。。。


この記事に対するコメント

このページには、まだコメントはありません。

お名前:


*1 JAMA oncol 2021 https://jamanetwork.com/journals/jamaoncology/fullarticle/2784882
*2 J Clin Oncol 2021 https://pubmed.ncbi.nlm.nih.gov/34550757/

更新日:2021-10-18 閲覧数:766 views.