Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation

Koba, Taro; Kijima, Takashi; Takimoto, Takayuki; Hirata, Haruhiko; Naito, Yujiro; Hamaguchi, Maki; Otsuka, Tomoyuki; Kuroyama, Muneyoshi; Nagatomo, Izumi; Takeda, Yoshito; Kida, Hiroshi; Kumanogoh, Atsushi

doi:10.1097/md.0000000000006087

Cited by 22 publications

(15 citation statements)

References 30 publications

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“…First, it penetrates the bloodbrain barrier very well ( Figure 1A). While our studies were on mice, osimertinib has been shown elsewhere to penetrate the human brain as well [19,[24][25][26][27]. Second, osimertinib is an irreversible inhibitor of EGFR tyrosine kinase, so its inhibition of EGFRvIII signaling is longlasting.…”

Section: Discussionmentioning

confidence: 91%

Efficacy of osimertinib against EGFRvIII+ glioblastoma

et al. 2020

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Epidermal Growth Factor Receptor variant III (EGFRvIII) is an active mutant form of EGFR that drives tumor growth in a subset of glioblastoma (GBM). It occurs in over 20% of GBMs, making it a promising receptor for small molecule targeted therapy. We hypothesize that poor penetration of the blood-brain barrier by previously tested EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as afateninb, erlotinib, gefitinib, and lapatinib played a role in their limited efficacy. The present study examined the effects of osimertinib (previously known as AZD9291) on EGFRvIII+ GBM models, both in vitro and in vivo. Therefore, a panel of six GBM stem cells (GSCs) expressing EGFRvIII+ was evaluated. The EGFRvIII+ GSC differed in the expression of EGFRvIII and other key genes. The GSC line D317, which expresses high levels of EGFRvIII and has robust tyrosine kinase activity, was selected for assessing osimertinib's efficacy. Herein, we report that osimertinib inhibits the constitutive activity of EGFRvIII tyrosine kinase with high potency (<100 nM) while also inhibiting its downstream signaling. Further, osimertinib inhibited D317's growth in vitro and in both heterotopic and orthotopic xenograft models. Additional preclinical studies are warranted to identify EGFRvIII+ GBM's molecular signature most responsive to osimertinib.

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Section: Discussionmentioning

confidence: 91%

Efficacy of osimertinib against EGFRvIII+ glioblastoma

et al. 2020

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“…Several cases of LM treated with osimertinib have been reported. Koba et al 19 observed a rapid response to osimertinib, within 2 weeks of its administration in patients with brain metastases. Hata et al 20 observed that osimertinib efficiently passes the BBB.…”

Section: Discussionmentioning

confidence: 99%

Non-small cell lung cancer leptomeningeal metastases treated with intrathecal therapy plus osimertinib and temozolomide and whole-brain radiation therapy: a case report

Wang¹,

Wei²,

Yan³

et al. 2018

OTT

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RationaleLeptomeningeal metastasis (LM) is an important cause of mortality in patients with non-small cell lung cancer (NSCLC). As the symptoms of LM and its early clinical manifestations are nonspecific, early diagnosis of LM is difficult. However, there are few treatment options for LM, which leads to a poor prognosis; thus, increased clinical attention is necessary. The effects of most systemic chemotherapies on metastatic brain tumors (brain metastases and LMs) are limited as they cannot pass the blood–brain barrier; therefore, whole-brain radiation therapy is a therapeutic option. Osimertinib is a potent and irreversible third-generation oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It binds to EGFR with high affinity when the EGFR T790M mutation is present together with sensitizing mutations. The clinical efficacy of osimertinib in NSCLC patients carrying the T790M mutation has been demonstrated in clinical trial NCT02468661. Intrathecal injection of chemotherapeutic drugs can be directed to a specific lesion. Temozolomide is one such drug, and its effect has been confirmed.Patient and interventionsWe treated a 38-year-old patient with NSCLC who carried the EGFR L858R mutation. We administered a combination of oral osimertinib and oral temozolomide plus an intrathecal injection of cytarabine and whole-brain radiation therapy for symptomatic multiple brain metastases.OutcomesThe patient showed a marked response to this combination therapy. To date (after ~18 months), no recurrence or new lesions have been observed and he is asymptomatic. His disease-free survival surpasses that achieved with any monotherapy for LM.LessonsThis is the first report to demonstrate the response to combination therapy in an NSCLC patient with LM. These findings indicate the potential utility of chemotherapy combined with radiotherapy combined with targeted therapy combined with local treatment, as each treatment acts via a different mechanism, enhancing their therapeutic effects.

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“…In the preclinical study, osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib, or afatinib [ 94 ]. There were several reports of dramatic intracranial response to osimertinib in patients with EGFR T790M lung cancer [ 94 , 95 ]. A phase I study (BLOOM, NCT02228369), which has enrolled pretreated EGFR -mutant NSCLC patients with leptomeningeal metastasis treated with 160 mg osimertinib once daily, is ongoing.…”

Section: Introductionmentioning

confidence: 99%

Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer

Wu¹,

Shih²

2018

Mol Cancer

543

456

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Recent advances in diagnosis and treatment are enabling a more targeted approach to treating lung cancers. Therapy targeting the specific oncogenic driver mutation could inhibit tumor progression and provide a favorable prognosis in clinical practice. Activating mutations of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) are a favorable predictive factor for EGFR tyrosine kinase inhibitors (TKIs) treatment. For lung cancer patients with EGFR-exon 19 deletions or an exon 21 Leu858Arg mutation, the standard first-line treatment is first-generation (gefitinib, erlotinib), or second-generation (afatinib) TKIs. EGFR TKIs improve response rates, time to progression, and overall survival. Unfortunately, patients with EGFR mutant lung cancer develop disease progression after a median of 10 to 14 months on EGFR TKI. Different mechanisms of acquired resistance to first-generation and second-generation EGFR TKIs have been reported. Optimal treatment for the various mechanisms of acquired resistance is not yet clearly defined, except for the T790M mutation. Repeated tissue biopsy is important to explore resistance mechanisms, but it has limitations and risks. Liquid biopsy is a valid alternative to tissue re-biopsy. Osimertinib has been approved for patients with T790M-positive NSCLC with acquired resistance to EGFR TKI. For other TKI-resistant mechanisms, combination therapy may be considered. In addition, the use of immunotherapy in lung cancer treatment has evolved rapidly. Understanding and clarifying the biology of the resistance mechanisms of EGFR-mutant NSCLC could guide future drug development, leading to more precise therapy and advances in treatment.

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Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation

Cited by 22 publications

References 30 publications

Efficacy of osimertinib against EGFRvIII+ glioblastoma

Efficacy of osimertinib against EGFRvIII+ glioblastoma

Non-small cell lung cancer leptomeningeal metastases treated with intrathecal therapy plus osimertinib and temozolomide and whole-brain radiation therapy: a case report

Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer

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