Osimertinib for Patients With Non–Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09)

Cho, Jae Yong; Lim, Sung Hee; An, Ho Jung; Kim, Ki Hwan; Park, Keon Uk; Kang, Eun Joo; Choi, Yoon Hee; Ahn, Mi Sun; Lee, Myung Hee; Sun, Jong Mu; Lee, Se‐Hoon; Ahn, Jin Seok; Park, Keunchil; Ahn, Myung Ju

doi:10.1200/jco.19.00931

Cited by 264 publications

(254 citation statements)

References 34 publications

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“…In the phase II study of osimertinib for EGFR -TKI naïve patients with uncommon EGFR mutation-positive NSCLC (KCSG-LU15-09), 22 of the 36 patients received osimertinib as the 1L treatment [ 14 ]. A total of 14 patients received osimertinib as a sequential treatment after failing the 1L treatment, except for EGFR -TKIs.…”

Section: Discussionmentioning

confidence: 99%

Treatment and Outcomes of Metastatic Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: Are They Different from Those with Common EGFR Mutations?

Jung

Park

Sun

et al. 2020

Biology

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Approximately 10% of the epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are uncommon EGFR mutations. Although the efficacy of second (2G) or third generation (3G) EGFR tyrosine kinase inhibitors (EGFR-TKIs) in the patients with uncommon EGFR mutation has been proven, further studies are warranted to define the optimal treatment approach for uncommon EGFR mutation-positive NSCLC. This study retrospectively investigated the treatment patterns and outcomes of patients with uncommon EGFR mutation-positive NSCLC from January 2011 to December 2019 at the Samsung Medical Center, Seoul, Korea. During the study, 2121 patients with EGFR mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. Of this, 135 (6.4%) patients harbored uncommon EGFR mutations. Of 135, 54 (40%, 54/135) patients had overlapping mutations with major EGFR mutations. The objective response rate (ORR) for the 1L EGFR-TKI was 63.3%. The median progression-free survivals (PFSs) were 8.6 months (95% CI: 3.8–13.5), 11.7 months (95% CI: 6.6–16.7), 7.7 months (95% CI: 4.9–17.4), and 5.0 months (95% CI: 3.7–6.1) for major uncommon EGFR mutation (G719X, L861Q), compound mutation with major EGFR mutation (Del 19 or EGFR exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The median overall survivals (OSs) were 25.6 months (16.9–34.2), 28.8 (95% CI: 24.4–33.4), 13.5 months (95% CI: 7.4–27.8), and 9.4 months (95% CI: 3.4–10.5) for major uncommon EGFR mutation (G719X), compound mutation with major EGFR mutation (Del 19 or EGFR exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The response rate, median PFS, and OS were 63.3%, 16.3 months (95% CI: 15.6–16.9), and 37.5 months (95% CI: 35.4–39.6) for common EGFR mutation-positive NSCLC. After failing 1L EGFR-TKI, repeated tissue or liquid biopsy were carried out on 44.9% (35/78) of patients with T790M detected in 10/35 (28.6%) patients. With subsequent 3G EGFR-TKI after failing the first-line EGFR-TKI, the ORR and PFS for 3G EGFR-TKI were 80% and 8.9 months (95% CI: 8.0–9.8). These patients showed a median OS of 34.6 months (95% CI: 29.8–39.4). The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common EGFR mutations. T790M was detected in 28.6% of the uncommon EGFR mutation-positive patients for whom prior 1G/2G EGFR-TKIs failed and underwent repeat biopsy at the time of progression.

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Section: Discussionmentioning

confidence: 99%

Treatment and Outcomes of Metastatic Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: Are They Different from Those with Common EGFR Mutations?

Jung

Park

Sun

et al. 2020

Biology

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“…It is reported that approximately 10% of patients with epidermal growth factor receptor (EGFR) mutation-positive NSCLC harbor uncommon mutations, and EGFR tyrosinekinase inhibitor (KTI) are currently used as the standard first-line treatment options for NSCLC patients harboring sensitizing EGFR mutations. 2 Osimertinib is the first FDA approved third-generation EGFR-TKI that selectively targets the T790M mutated EGFR and is now marketavailable in China. Osimertinib can irreversibly bind to NSCLC cell lines with EGFR mutation (T790M, L858R and exon 19 deletion), with a weak inhibitory effect on wild- type EGFR protein.…”

Section: Discussionmentioning

confidence: 99%

“…1 The epidermal growth factor receptor (EGFR) is the major therapeutic target for NSCLC, and EGFR tyrosine kinase inhibitors (TKIs) are very efficient for EGFR mutation-positive patients. 2 To date, TKIs have been regarded as the standard first-line treatment options for these patients. Although the first and second-generation of EGFR-TKIs were originally developed to target wild-type (WT) EGFR, they are also effective for some EGFR mutations.…”

Section: Introductionmentioning

confidence: 99%

Effects of avitinib on the pharmacokinetics of osimertinib in vitro and in vivo in rats

Jiang

Wang

et al. 2020

Thoracic Cancer

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Background: Avitinib is one type of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of nonsmall cell lung cancer (NSCLC) with EGFR mutations. The purpose of this study was to investigate the effect of avitinib on the pharmacokinetics of osimertinib, one FDA approved third-generation TIKI, both in vitro and in vivo. Methods: The in vitro metabolic stability and inhibitory effect of avitinib on osimertinib were assessed with rat liver microsomes (RLM) to determine its IC 50 values. For the in vivo study, 18 Sprague-Dawley rats were randomly divided into three groups: the avitinib multiple dose group (30 mg/kg avitinib once daily for seven days), the avitinib single dose group (PEG200 once daily for six days and a dose of 30 mg/kg avitinib in PEG200 on day 7) and the control group (equal amounts of PEG200 once daily for seven days). Next, all rats were given osimertinib at a dosage of 10 mg/kg. UPLC/MS-MS was used for the determination of the concentration of osimertinib in plasma. Results: In vitro analysis revealed that the IC 50 value of osimertinib in rat liver microsomes was 27.6 μM. When rats were pretreated with avitinib, the values of AUC and MRT of the osimertinib were increased, and its C max and T max were significantly extended, whereas the values of CLz/F were significantly decreased (P < 0.05). Conclusions: Both in vitro and in vivo results demonstrated that a drug-drug interaction between avitinib and osimertinib occurred and more attention should be paid when avitinib and osimertinib are synchronously administered in clinic.

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“…Recently, a first prospective multicentre phase II trial demonstrated osimertinib activity towards uncommon EGFR mutations. The CNS response rate was reported as 40% (two of five patients), with a complete CNS response in a patient harbouring the G719X mutation [42]. As both prospective analyses of afatinib and osimertinib included limited numbers of patients (n = 100 and 36, respectively), conclusions about CNS activity cannot be drawn and additional studies are needed [39,42].…”

Section: Case Reports In Oncological Medicinementioning

confidence: 99%

Complete Remission of Multiple Brain Metastases in a Patient with EGFR-Mutated Non-Small-Cell Lung Cancer Treated with First-Line Osimertinib without Radiotherapy

Ameku¹,

Higa

2020

Case Reports in Oncological Medicine

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Osimertinib has demonstrated efficacy against stable or asymptomatic central nervous system (CNS) metastases of epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in phase 2 and 3 clinical trials that allowed prior CNS radiotherapy. However, the efficacy of osimertinib only or the optimal treatment combination or sequence of radiotherapy has not been investigated. A 74-year-old woman diagnosed with T4N1M1c Stage IVB lung adenocarcinoma with EGFR mutation presented with a left upper lobe mass and multiple bilateral lung metastases. A total of more than 20 asymptomatic multiple brain metastases with a maximum diameter of 12 mm were diagnosed simultaneously. Osimertinib was administered as first-line treatment. Whole brain radiotherapy was deferred because she had no neurological symptoms. After 5 weeks, the multiple brain metastases disappeared completely, together with the response in the lung lesions. This case demonstrated that first-line treatment with osimertinib could even achieve complete remission of multiple brain metastases comprising as many as twenty lesions of EGFR-mutated NSCLC without radiation therapy. Radiation therapy for brain metastases can be deferred or even withheld. A new treatment strategy for EGFR mutated NSCLC with CNS metastases should be investigated using osimertinib, especially regarding optimal combination or sequence of radiotherapy.

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Osimertinib for Patients With Non–Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09)

Cited by 264 publications

References 34 publications

Treatment and Outcomes of Metastatic Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: Are They Different from Those with Common EGFR Mutations?

Treatment and Outcomes of Metastatic Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: Are They Different from Those with Common EGFR Mutations?

Effects of avitinib on the pharmacokinetics of osimertinib in vitro and in vivo in rats

Complete Remission of Multiple Brain Metastases in a Patient with EGFR-Mutated Non-Small-Cell Lung Cancer Treated with First-Line Osimertinib without Radiotherapy

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