Cancer Chemother Pharmacol DOI 10.1007/s00280-015-2760-5
ORIGINAL ARTICLE
A phase II study of icotinib and whole‑brain radiotherapy in Chinese patients with brain metastases from non‑small cell lung cancer Yun Fan1 · Zhiyu Huang1 · Luo Fang1 · Lulu Miao1 · Lei Gong1 · Haifeng Yu1 · Haiyan Yang1 · Tao Lei1 · Weimin Mao1
Received: 2 January 2015 / Accepted: 24 April 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose Icotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. A phase II study was conducted to evaluate the efficacy and safety of icotinib in combination with whole-brain radiotherapy (WBRT) in Chinese NSCLC patients with brain metastases (BMs); the cerebrospinal fluid (CSF)/plasma concentrations of icotinib were also investigated. Methods Eligible patients had BMs from NSCLC, regardless of the EGFR status. Icotinib was administered at 125 mg orally 3 times/day until tumor progression or unacceptable toxicity, concurrently with WBRT (3.0 Gy per day, 5 days per week, to 30 Gy). CSF and plasma samples were collected simultaneously from 10 patients. Icotinib concentrations in the CSF and plasma were measured by high-performance liquid chromatography coupled with tandem mass spectrometry. Results Twenty patients were enrolled. The median follow-up time was 20.0 months. The overall response rate was 80.0 %. The median progression-free survival time was 7.0 months (95 % CI 1.2–13.2 months), and the median survival time (MST) was 14.6 months (95 % CI 12.5– 16.7 months). Of the 18 patients with known EGFR status, the MST was 22.0 months for those with an EGFR mutation and was 7.5 months for those with wild-type EGFR (P = 0.0001). The CSF concentration and penetration rate of icotinib were 11.6 ± 9.1 ng/mL and 1.4 ± 1.1 %, respectively. No patient experienced ≥grade 4 toxicity. * Weimin Mao [email protected] 1
Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology (Esophagus, Lung), Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou 310022, Zhejiang, People’s Republic of China
Conclusions Icotinib was well tolerated in combination with WBRT and showed efficacy in patients with BMs from NSCLC. This clinical benefit was related to the presence of activating EGFR mutations. Keywords Icotinib · Brain metastases · Non-small cell lung cancer · Whole-brain radiotherapy · Cerebrospinal fluid
Introduction Brain metastasis (BM) is one of the major reasons for the treatment failure of non-small cell lung cancer (NSCLC). Approximately 10 % of NSCLC patients present BMs when they are first diagnosed [1], and approximately 20–40 % patients at advanced stages will have a BM at some stage of the disease [2, 3]. To date, whole-brain radiotherapy (WBRT) remains the standard treatment for patients with multiple BMs. Surgery and stereotactic radiotherapy are suitable for patients with a more limited number of metastatic lesions. These local therapeutic measures are usually applied alone or in combination with other methods, yet the overall treatment effect is still unsatisfactory. The median overall survival (OS) time for patients with BMs from NSCLC who are treated with WBRT alone is only 3–5 months [4–6]. Due to the ineffectiveness of majority chemotherapeutic drugs penetrating the blood– brain barrier (BBB), it is difficult that chemotherapy combined with local treatment further improves the survival of patients with BMs. Many studies have indicated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib and gefitinib, can significantly raise the rate of survival of patients with advanced NSCLC [7, 8]. Since
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these inhibitors are able to penetrate the BBB to some extent [9], they also exhibit a certain efficacy in patients with BMs [10–13]. In particular, TKIs have significant effectiveness in patients with activating EGFR mutations [14]. Definite radiosensitization effect caused by combined erlotinib and radiotherapy is also shown through preclinical studies [15]. Icotinib is a new first-generation EGFR-TKI [16], with similiar molecular structure to erlotinib. A large-scale phase III randomized controlled study revealed that the progression-free survival (PFS) time of patients with advanced NSCLC who were treated with icotinib was not inferior to that of patients treated with gefitinib [17]. The purpose of the present phase II study was to evaluate the efficacy and safety of combined icotinib and WBRT in the treatment of NSCLC patients with BMs as well as the cerebrospinal fluid (CSF)/plasma concentrations of icotinib.
Patients and methods Patients and treatment methods The criteria for patient inclusion were as follows: NSCLC patients with BMs newly confirmed by magnetic resonance imaging (MRI); leptomeningeal involvement were not allowed; clearly confirmed NSCLC by pathology; patients who had not received EGFR-TKI treatment; patients who had not received WBRT; time from the last chemotherapy ≥4 weeks; evaluable lesions; multiple intracranial lesions or single lesion not suitable for surgery or stereotactic radiotherapy; age ≥18 and ≤75 years; Eastern Cooperative Oncology Group performance status (ECOG PS) score, 0–2; EGFR detection method using the amplification refractory mutation system (ARMS). This study was approved by the ethics committees of the researchers’ institutions, and all patients provided written informed consent before any study-related procedure (ClinicalTrials.gov Identifier: NCT01514877). After enrollment in the study, the patients were administered icotinib at 125 mg 3 times/day (TID); meanwhile, WBRT was implemented. After WBRT was completed, the patients continued to receive icotinib for maintenance treatment until disease progression or intolerable adverse events. If the patients had an adverse, ≥grade 3 reaction, such as skin rash or diarrhea, then the dose of icotinib was reduced to 75 mg TID. WBRT was delivered in 3 Gy fractions once per day, 5 days per week, to a total dose of 30 Gy. Sample collection an analysis After patients continued to receive icotinib orally for 5 days, the drug reached steady-state plasma concentrations. Then,
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Cancer Chemother Pharmacol
5-mL peripheral blood samples and 20-mL CSF samples were collected 2 h after receiving oral icotinib to measure the icotinib concentrations in the plasma and CSF using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC–MS). The MS device was an Agilent 6410B (Agilent Technologies, Beijing, China). All blood and CSF specimens were obtained in the period of WBRT. Patient evaluation All patient baseline evaluations were completed within 4 weeks of systemic treatment. The baseline evaluations included a comprehensive physical examination, a complete blood count, serum biochemistry, thoracic and abdominal enhanced computed tomography (CT), and contrast-enhanced magnetic resonance images (MRIs) of the brain. Four weeks after treatment initiation, MRIs and thoracic and abdominal CT examinations were conducted again to evaluate the short-term efficacy. Next, efficacy and adverse reaction evaluations were performed every 8 weeks and when the disease progressed until the patient died or was lost to follow-up. The objective tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, which was divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Adverse reactions were evaluated based on the CTCAE 3.0 edition (Common Terminology Criteria for Adverse Events version 3.0) once a week during treatment and then every 8 weeks at follow-up visits. Statistical analyses The sample size calculation was based on a one-sample mean test which was designed to detect any increase in the median survival time from 4.8 months in the historical control group [6] to 6.0 months with this therapeutic approach. The patients were stratified according to EGFR mutation status. The primary endpoint was the median PFS (including intracranial and extracranial lesions); the secondary endpoints were the OS, the overall response rate (ORR) of intracranial lesions, and safety. In addition, the cerebrospinal fluid (CSF)/plasma concentrations of icotinib of icotinib were evaluated. Fisher’s exact test and the Chi-square test were performed to compare the clinical and demographic characteristics of patients with and without an EGFR mutation. PFS and OS curves were established using the Kaplan–Meier method. The log-rank test was applied to compare PFS and OS in patients with a known EGFR status (wild type vs. mutated). Statistical tests were based on a two-sided significance level of 0.05. All statistical analyses were performed using SPSS 20.0.0 for Windows (IBM Corp, Armonk, NY, USA). Survival data were
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censored at the time of the last visit for patients who were still alive at the final analysis. The data cutoff date for all analyses was June 15, 2014.
Results Patients and EGFR mutation status From February 2012 to March 2013, 20 patients in the Zhejiang Cancer Hospital were enrolled in this study. The patients had pathologically confirmed NSCLC and had newly diagnosed BMs with imaging evidence. The patients’ clinical characteristics are listed in Table 1. The median age
was 62 years (range 39–75 years), and males accounted for 60 % of the patient sample. The ECOG PS scores of 75 % of the patients were 0–1, and half of the patients had a smoking history. Adenocarcinoma accounted for 80.0 % of the tumors, and 90 % of the patients had active extracranial lesions as the BMs were diagnosed. Nine patients had corresponding nervous system symptoms while the BMs were confirmed; other patients had asymptomatic BMs that were found during routine examinations. A single patient had an isolated BM; the diameter of the brain lesion that located in the cerebellum was 4.5 cm. Two patients had 2–3 intracranial lesions; 17 patients had ≥3 intracranial lesions. Two patients (10 %) were treated for the first time and had activating EGFR mutations. Ninety percent of the patients had
Table 1 Patient characteristics (n = 20) Characteristics Gender Male Female Age, years Median Range ECOG PS 0–1 2 Smoking status Prior Never Current Tumor histology Adenocarcinoma Squamous Unknown Number of intracranial lesions 1–3 ≥3 RTOG GPA 0–1 1.5–2.5 3 3.5–4.0 Previous treatment None First- to second-line chemotherapy Active extracranial disease at study entry Yes No
All patients (n = 20)
EGFR mutant (n = 10)
EGFR wild type (n = 8)
P 0.188
12 (60.0 %) 8 (40.0 %)
4 (40.0 %) 6 (60.0 %)
6 (75.0 %) 2 (25.0 %)
62 39–75
60 39–72
54 39–75
15 (75.0 %) 5 (25.0 %)
8 (80.0 %) 2 (20.0 %)
6 (75.0 %) 2 (25.0 %)
9 (45.0 %) 10 (50.0 %) 1 (5.0 %)
3 (30.0 %) 7 (70.0 %) 0
4 (50.0 %) 3 (37.5 %) 1 (12.5 %)
16 (80.0 %) 1 (5.0 %) 3 (15.0 %)
9 (90.0 %) 1 (10.0 %) 0
6 (75.0 %) 0 2 (25.0 %)
3 (15.0 %) 17 (85.0 %)
1 (10.0 %) 9 (90.0 %)
1 (12.5 %) 7 (87.5 %)
12 (60.0 %) 8 (40.0 %) 0 0
8 (80.0 %) 2 (20.0 %)
4 (50.0 %) 4 (50.0 %)
2 (10.0 %) 18 (90.0 %)
2 (20.0 %) 8 (80.0 %)
0 8 (100.0 %)
18 (90.0 %)
9 (90.0 %)
7 (87.5 %)
2 (10.0 %)
1 (10.0 %)
1 (12.5 %)
0.515
1.000
0.350
0.181
1.000
0.321
0.477
1.000
EGFR epidermal growth factor receptor, ECOG PS Eastern Cooperative Oncology Group performance status, RTOG GPA Radiation Therapy Oncology Group graded prognostic assessment
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Cancer Chemother Pharmacol
received first- or second-line chemotherapy. The first-line chemotherapy regimens were all platinum-containing, twodrug regimens, and the majority of the regimens were cisplatin or carboplatin combined with gemcitabine and taxanes. Five patients received pemetrexed combined with platinum treatment. Our study planned to enroll 40 patients, and preplanned interim analysis was conducted for the median PFS data of 20 patients. The study was terminated due to a significantly shorter median PFS of patients with wildtype EGFR in comparison with patients who had EGFR mutations. In total, 18 patients provided tissue samples for the examination of EGFR mutations using the amplification refractory mutation system (ARMS) method. Ten patients exhibited activating EGFR mutations, and eight patients had wild-type EGFR. The most common mutation was a deletion in exon 19 (six patients), followed by deletion in exon 21 (four patients). No rare mutations were detected. The comparison of clinical and pathological characteristics between patients with an EGFR mutation and those with wild-type EGFR did not reveal any significant difference.
experiencing disease progression, seven patients exhibited the progression of extracranial lesions (five showed progression of only extracranial lesions, and two showed progression of both intracranial and extracranial lesions). The median PFS time of all the patients was 7.0 months (95 % CI 1.2–13.2 months; Fig. 1a). The median PFS times differed according to the EGFR mutation status: 4.0 months (95 % CI 2.7–5.3 months) for the EGFR wild-type group and 12.0 months (95 % CI 5.8–18.2 months) for the EGFR mutation group (P = 0.0001) (Fig. 1b). The median survival time (MST) in the whole group was 14.6 months (95 % CI 12.5–16.7 months; Fig. 1c). The MST of patients with EGFR mutations was 22.0 months (95 % CI 14.6–29.4), which was significantly longer than the 7.5 months (95 % CI 4.7 5–10.3 months; P = 0.0001) for the wild-type EGFR patients (Fig. 1d). The MST for patients received no treatments, firstline chemotherapy and second-line chemotherapy was 19.0 months (95 % CI 14.4–23.6 months), 18.0 months (95 % CI 13.2–22.6 months), and 13.0 months (95 % CI 7.6–18.5 months), separately.
Treatment response and patients survival
CSF/plasma concentrations of icotinib
The objective tumor ORR of the intracranial lesions was evaluated in all patients. Among them, 5 achieved CR, 11 achieved PR, and 3 achieved SD, yielding a response rate of 80.0 % and a disease control rate (CR + PR + SD) of 95.0 %. For different statuses of EGFR mutations, there was no remarkable difference in terms of ORR and CR (P = 0.275 and 0.092, respectively) (Table 2). Five patients were alive at the time of this analysis, and the median follow-up time was 20 months (range 4–25 months). All surviving patients exhibited EGFR mutations. Of the eight patients with wild-type EGFR
Detection of icotinib concentrations in the CSF and plasma was performed in 10 patients. The detailed data are listed in Table 3. The median icotinib concentrations in the plasma and CSF were 940.6 ± 503.8 and 11.6 ± 9.1 ng/mL, respectively. The CSF/plasma concentrations of icotinib were approximately 1.4 ± 1.1 %.
Table 2 Response of brain metastases to icotinib combined with WBRT All patients (%)
EGFR mutant EGFR wild (%) type (%)
Patient number
20
10
8
CR PR CR + PR SD
5 (25.0 %) 11 (55.0 %) 16 (80.0 %) 3 (15.0 %)
4 (40.0 %) 5 (50.0 %) 9 (90.0 %) 1 (10.0 %)
0 5 (62.5 %) 5 (62.5 %) 2 (25.0 %)
0.092 0.664 0.275 0.559
PD
1 (5.0 %)
0
1 (12.5 %)
0.444
P
EGFR epidermal growth factor receptor, CR complete response, PR partial response, SD stable disease, PD progressive disease
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Toxicity The combination of icotinib plus WBRT was well tolerated by all 20 patients, and no grade 4/5 treatment-related toxicity was observed. The adverse events during treatment are summarized in Table 4. During the icotinib-combined WBRT, 45.0 % of patients had nausea, 35.0 % of patients experienced headaches, and 10 % of patients had vomiting, which were grade 1 adverse reactions. The most common AEs reported during icotinib alone therapy were rash (40.0 %), diarrhea (15.0 %), and increased AST/ALT (15.0 %). These were predominantly of grade 1/2, with only one case of increased AST/ALT reported as grade 3. After symptomatic treatment, the patient continued icotinib treatment. There was no occurrence of interstitial pneumonia. Only one patient had obvious cognitive impairment after 21 months of WBRT treatment; the brain MRIs did not show any signs of recurrence. Three patients with longterm survival (survival time >12 months) had mild-degree memory decline.
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Fig. 1 Disease-free survival and overall survival after treatment of brain metastases with whole-brain radiation therapy and icotinib. a Disease-free survival for all patients (n = 20); b overall survival for
all patients; c disease-free survival by epidermal growth factor receptor (EGFR) mutation (n = 10) and wild type (n = 8); d overall survival by EGFR mutation status
Table 3 CSF and plasma concentrations of icotinib and response of the central nervous system metastases Case
CSF concentrations (ng/mL)
Plasma concentrations (ng/mL)
CSF/plasma CNS response concentrations (%)
1 2 4 6 8 9 10 11 12 14
26.95 17.68 5.40 12.28 2.85 4.61 5.40 4.67 11.38 26.32
632.2 1098 1120 1348 151 378.3 742 714 1475 1747
4.26 complete response 1.61 partial response 0.48 partial response 0.91 complete response 1.89 partial response 1.22 stable disease 0.72 complete response 0.65 stable disease 0.77 partial response 1.51 partial response
Mean ± SD
11.8 ± 9.1
940.6 ± 503.8
1.4 ± 1.1 %
CNS central nervous system, CSF cerebrospinal fluid
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Table 4 Treatment-related toxicities Adverse events
Any N %
1 N %
2 N %
3 N %
4 N %
Nausea Vomiting Headache Dizziness Diarrhea Acneiform rash
9 (45.0 %) 2 (10.0 %) 7 (35.0 %) 2 (10.0 %) 3 (15.0 %) 8 (40.0 %)
9 (45.0 %) 2 (10.0 %) 7 (35.0 %) 2 (10.0 %) 2 (10.0 %) 4 (20.0 %)
0 0 0 1 (5.0 %) 4 (20.0 %)
0 0 0 0 0 0
0 0 0 0 0 0
Increased 3 (15.0 %) AST/ALT
2 (10.0 %)
0
1 (5.0 %)
0
Increased bilirubin
1 (5.0 %)
0
0
0
1 (5.0 %)
AST aspartate aminotransferase, ALT alanine aminotransferase
Discussion The present phase II study showed that WBRT with concurrent icotinib for NSCLC produced longer overall survival compared with that of historical controls [4–6], with particular benefit evident for patients with EGFR mutations; the median PFS and MST were as long as 12.0 and 22.0 months, respectively. Several retrospective and prospective studies reported that gefitinib and erlotinib are effective for intracranial metastatic lesions [10–14, 18]; however, the results varied greatly. The overall respond rate for intracranial lesions ranged from 10 to 87.8 % [11, 14], and the PFS ranged from 2.3 to 14.5 months [14, 18]. An analysis of these studies revealed that the major reason for this discrepancy was the selection of patients for treatment. By continuously treating 41 non-selected Caucasian patients with BMs using gefitinib, Cereoli et al. [11] obtained a relatively low efficacy and disease control rate only about 10.0 and 27.0 %, respectively. Choosing adenocarcinoma and non-smoking Asian patients as the treatment population, Kim et al. [13] used gefitinib or erlotinib alone without combination with WBRT to treat BMs and reported that the intracranial lesion response rate was 73.9 %, the PFS was 7.1 months, and the OS was 18.8 months. As for the treatment of the BM population with EGFR mutations using single gefitinib, Iuchi et al. [14] reported that the intracranial lesion response rate reached 87.8 %, the PFS was 12.4 months, and the OS was 21.9 months. Our study also observed that the EGFR mutation subgroup had a higher response rate and longer survival time than the wild-type subgroup. The efficacy of the mutation subgroup patients was basically consistent with the results of Iuchi et al. [14], which further confirmed that the EGFR mutation was an efficacy predictive factor for using EGFR-TKIs to treat NSCLC patients with
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BMs. For patients with BMs, the selection of EGFR-TKI treatment should still be based on their gene mutation status. Cause of the first treatment failure in patients with wildtype EGFRs showed that all seven patients with extracranial lesions had immediate progression. Currently, many randomized studies have confirmed that EGFR-TKI treatment has minimal effects on the efficacy of patients with wild-type EGFRs [19–21]. Meta-analysis results have also revealed that the response rate and PFS of wild-type EGFR patients treated with EGFR-TKIs are much worse than those treated with chemotherapy [22]. The blockade of EGFR signaling in vitro has been shown to sensitize cells to the effects of radiation. Furthermore, blockade of the wild-type EGFR has also been demonstrated to reduce radiation tolerance by reducing DNA repair, blocking antiapoptosis pathways, and inhibiting proliferation in wildtype patients [15]; however, these results have not been confirmed in clinical studies. As small molecule substances, the molecular weight of icotinib is 427.88 [16]. The results revealed that the CSF concentration and CSF/plasma concentrations of icotinib were 11.6 ± 9.1 ng/mL and 1.4 ± 1.1 %, respectively, which is similar to the 1.1 % CSF/plasma concentrations of gefitinib as reported in the literature [10]. This result indicates that icotinib can penetrate the BBB to reach intracranial metastatic lesions, which may partially explain the effectiveness of icotinib in BM patients with EGFR mutations. Concurrent icotinib combined with WBRT treatment or icotinib alone therapy all had rather good safety, which is proved by our study. Among all the patients with long-term survival, one patient had significant cognitive impairment, and three patients had mild-degree memory decline, which was considered to be associated with the application of WBRT. For BM patients with activating EGFR mutations, long-term survival can be obtained after EGFR-TKI treatment, and the adverse events of WBRT on the brain have a higher chance of manifesting. Iuchi et al. [14] reported that the treatment with a single dose of gefitinib had improved efficacy of BM patients with EGFR mutations and approximately half of the patients postponed the implementation of WBRT; thus, the development of WBRT-associated cognitive impairment is reduced. But a meta-analysis reported that upfront cranial radiotherapy may improve intracranial disease control and survival outcomes compared with TKI alone [23]. Aiming to compare the PFS between the firstline icotinib and WBRT treatments, a phase III randomized controlled study is currently being conducted in BM patients with EGFR mutations in China [24]. The results of this phase III study might solve the issue of selecting the first-line treatment for BM patients with EGFR mutations.
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Although the present prospective clinical study seems to have significant findings, there were certain limitations. As shown, this was a single group with a small sample size and a non-randomized study which indicates that largescale, multicenter, and randomized controlled studies are necessary to validate these results. In summary, the present prospective phase II study demonstrated that the treatment of NSCLC patients with BMs using icotinib combined with WBRT had significant efficacy. The effectiveness for patients with activating EGFR mutations was significantly better than that for those with wild-type EGFR. The concurrent icotinib combined with WBRT treatment yielded good tolerance. Whether icotinib can be used as a first-line single-drug treatment in BM patients with activating EGFR mutations should be further investigated by randomized controlled studies.
References 1. Sørensen JB, Hansen HH, Hansen M, Dombernowsky P (1988) Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 6:1474–1480 2. Mujoomdar A, Austin JH, Malhotra R, Powell CA, Pearson GD, Shiau MC, Raftopoulos H (2007) Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma: primary tumor size, cell type, and lymph node metastases. Radiology 242(3):882–888 3. Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer surveillance system. J Clin Oncol 22:2865–2872 4. Knisely JP, Berkey B, Chakravarti A, Yung AW, Curran WJ Jr, Robins HI, Movsas B, Brachman DG, Henderson RH, Mehta MP (2008) A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). Int J Radiat Oncol Biol Phys 71:79–86 5. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG, Byhardt R (1997) Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745–751 6. Khuntia D, Brown P, Li J et al (2006) Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 24:1295–1304 7. Shepherd FA, Pereira JR, Ciuleanu T et al (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353(2):123–132 8. Mok TS, Wu YL, Thongprasert S et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957 9. Togashi Y, Masago K, Masuda S et al (2012) Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 70:399–405
10. Wu YL, Zhou C, Cheng Y et al (2011) Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG0803). Lancet Oncol. 12:735–742 11. Ceresoli GL, Cappuzzo F, Gregorc V et al (2004) Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol 15:1042–1047 12. Welsh JW, Komaki R, Amini A et al (2013) Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol 31:895–902 13. Kim JE, Lee DH, Choi Y et al (2009) Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastases. Lung Cancer 65:351–354 14. Iuchi T, Shingyoji M, Sakaida T et al (2013) Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer 82:282–287 15. Chinnaiyan P, Huang S, Vallabhaneni G et al (2005) Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res 65:3328–3335 16. Tan F, Shen X, Wang D et al (2012) Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efficacy in preclinical studies. Lung Cancer 76:177–182 17. Shi Y, Zhang L, Liu X et al (2013) Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 14:953–961 18. Namba Y, Kijima T, Yokota S et al (2004) Gefitinib in patients with brain metastases from non-small-cell lung cancer: review of 15 clinical cases. Clin Lung Cancer. 6:123–128 19. Garassino MC, Martelli O, Broggini M et al (2013) Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 14:981–988 20. Kawaguchi T, Ando M, Asami K et al (2014) Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol 32:1902–1908 21. Zhou Q, Cheng Y, Yang JJ et al (2014) Pemetrexed versus gefitinib as a second-line treatment in advanced nonsquamous nonsmall-cell lung cancer patients harboring wild-type EGFR (CTONG0806): a multicenter randomized trial. Ann Oncol 25:2385–2391 22. Lee JK, Hahn S, Kim DW et al (2014) Epidermal growth factor receptor tyrosine kinase inhibitors vs. conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. JAMA 311:1430–1437 23. Soon YY, Leong CN, Koh WY et al (2015) EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant nonsmall cell lung cancer with brain metastases: a systematic review and meta-analysis. Radiother Oncol 114(2):167–172 24. Icotinib treat the patient with brain metastases epidermal growth factor receptor (EGFR) mutant non small cell lung cancer comparing with whole brain radiotherapy. http://www.ClinicalTrials. gov (NCT01724801)
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ORIGINAL ARTICLE
A phase II study of icotinib and whole‑brain radiotherapy in Chinese patients with brain metastases from non‑small cell lung cancer Yun Fan1 · Zhiyu Huang1 · Luo Fang1 · Lulu Miao1 · Lei Gong1 · Haifeng Yu1 · Haiyan Yang1 · Tao Lei1 · Weimin Mao1
Received: 2 January 2015 / Accepted: 24 April 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose Icotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. A phase II study was conducted to evaluate the efficacy and safety of icotinib in combination with whole-brain radiotherapy (WBRT) in Chinese NSCLC patients with brain metastases (BMs); the cerebrospinal fluid (CSF)/plasma concentrations of icotinib were also investigated. Methods Eligible patients had BMs from NSCLC, regardless of the EGFR status. Icotinib was administered at 125 mg orally 3 times/day until tumor progression or unacceptable toxicity, concurrently with WBRT (3.0 Gy per day, 5 days per week, to 30 Gy). CSF and plasma samples were collected simultaneously from 10 patients. Icotinib concentrations in the CSF and plasma were measured by high-performance liquid chromatography coupled with tandem mass spectrometry. Results Twenty patients were enrolled. The median follow-up time was 20.0 months. The overall response rate was 80.0 %. The median progression-free survival time was 7.0 months (95 % CI 1.2–13.2 months), and the median survival time (MST) was 14.6 months (95 % CI 12.5– 16.7 months). Of the 18 patients with known EGFR status, the MST was 22.0 months for those with an EGFR mutation and was 7.5 months for those with wild-type EGFR (P = 0.0001). The CSF concentration and penetration rate of icotinib were 11.6 ± 9.1 ng/mL and 1.4 ± 1.1 %, respectively. No patient experienced ≥grade 4 toxicity. * Weimin Mao [email protected] 1
Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology (Esophagus, Lung), Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou 310022, Zhejiang, People’s Republic of China
Conclusions Icotinib was well tolerated in combination with WBRT and showed efficacy in patients with BMs from NSCLC. This clinical benefit was related to the presence of activating EGFR mutations. Keywords Icotinib · Brain metastases · Non-small cell lung cancer · Whole-brain radiotherapy · Cerebrospinal fluid
Introduction Brain metastasis (BM) is one of the major reasons for the treatment failure of non-small cell lung cancer (NSCLC). Approximately 10 % of NSCLC patients present BMs when they are first diagnosed [1], and approximately 20–40 % patients at advanced stages will have a BM at some stage of the disease [2, 3]. To date, whole-brain radiotherapy (WBRT) remains the standard treatment for patients with multiple BMs. Surgery and stereotactic radiotherapy are suitable for patients with a more limited number of metastatic lesions. These local therapeutic measures are usually applied alone or in combination with other methods, yet the overall treatment effect is still unsatisfactory. The median overall survival (OS) time for patients with BMs from NSCLC who are treated with WBRT alone is only 3–5 months [4–6]. Due to the ineffectiveness of majority chemotherapeutic drugs penetrating the blood– brain barrier (BBB), it is difficult that chemotherapy combined with local treatment further improves the survival of patients with BMs. Many studies have indicated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib and gefitinib, can significantly raise the rate of survival of patients with advanced NSCLC [7, 8]. Since
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these inhibitors are able to penetrate the BBB to some extent [9], they also exhibit a certain efficacy in patients with BMs [10–13]. In particular, TKIs have significant effectiveness in patients with activating EGFR mutations [14]. Definite radiosensitization effect caused by combined erlotinib and radiotherapy is also shown through preclinical studies [15]. Icotinib is a new first-generation EGFR-TKI [16], with similiar molecular structure to erlotinib. A large-scale phase III randomized controlled study revealed that the progression-free survival (PFS) time of patients with advanced NSCLC who were treated with icotinib was not inferior to that of patients treated with gefitinib [17]. The purpose of the present phase II study was to evaluate the efficacy and safety of combined icotinib and WBRT in the treatment of NSCLC patients with BMs as well as the cerebrospinal fluid (CSF)/plasma concentrations of icotinib.
Patients and methods Patients and treatment methods The criteria for patient inclusion were as follows: NSCLC patients with BMs newly confirmed by magnetic resonance imaging (MRI); leptomeningeal involvement were not allowed; clearly confirmed NSCLC by pathology; patients who had not received EGFR-TKI treatment; patients who had not received WBRT; time from the last chemotherapy ≥4 weeks; evaluable lesions; multiple intracranial lesions or single lesion not suitable for surgery or stereotactic radiotherapy; age ≥18 and ≤75 years; Eastern Cooperative Oncology Group performance status (ECOG PS) score, 0–2; EGFR detection method using the amplification refractory mutation system (ARMS). This study was approved by the ethics committees of the researchers’ institutions, and all patients provided written informed consent before any study-related procedure (ClinicalTrials.gov Identifier: NCT01514877). After enrollment in the study, the patients were administered icotinib at 125 mg 3 times/day (TID); meanwhile, WBRT was implemented. After WBRT was completed, the patients continued to receive icotinib for maintenance treatment until disease progression or intolerable adverse events. If the patients had an adverse, ≥grade 3 reaction, such as skin rash or diarrhea, then the dose of icotinib was reduced to 75 mg TID. WBRT was delivered in 3 Gy fractions once per day, 5 days per week, to a total dose of 30 Gy. Sample collection an analysis After patients continued to receive icotinib orally for 5 days, the drug reached steady-state plasma concentrations. Then,
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5-mL peripheral blood samples and 20-mL CSF samples were collected 2 h after receiving oral icotinib to measure the icotinib concentrations in the plasma and CSF using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC–MS). The MS device was an Agilent 6410B (Agilent Technologies, Beijing, China). All blood and CSF specimens were obtained in the period of WBRT. Patient evaluation All patient baseline evaluations were completed within 4 weeks of systemic treatment. The baseline evaluations included a comprehensive physical examination, a complete blood count, serum biochemistry, thoracic and abdominal enhanced computed tomography (CT), and contrast-enhanced magnetic resonance images (MRIs) of the brain. Four weeks after treatment initiation, MRIs and thoracic and abdominal CT examinations were conducted again to evaluate the short-term efficacy. Next, efficacy and adverse reaction evaluations were performed every 8 weeks and when the disease progressed until the patient died or was lost to follow-up. The objective tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, which was divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Adverse reactions were evaluated based on the CTCAE 3.0 edition (Common Terminology Criteria for Adverse Events version 3.0) once a week during treatment and then every 8 weeks at follow-up visits. Statistical analyses The sample size calculation was based on a one-sample mean test which was designed to detect any increase in the median survival time from 4.8 months in the historical control group [6] to 6.0 months with this therapeutic approach. The patients were stratified according to EGFR mutation status. The primary endpoint was the median PFS (including intracranial and extracranial lesions); the secondary endpoints were the OS, the overall response rate (ORR) of intracranial lesions, and safety. In addition, the cerebrospinal fluid (CSF)/plasma concentrations of icotinib of icotinib were evaluated. Fisher’s exact test and the Chi-square test were performed to compare the clinical and demographic characteristics of patients with and without an EGFR mutation. PFS and OS curves were established using the Kaplan–Meier method. The log-rank test was applied to compare PFS and OS in patients with a known EGFR status (wild type vs. mutated). Statistical tests were based on a two-sided significance level of 0.05. All statistical analyses were performed using SPSS 20.0.0 for Windows (IBM Corp, Armonk, NY, USA). Survival data were
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censored at the time of the last visit for patients who were still alive at the final analysis. The data cutoff date for all analyses was June 15, 2014.
Results Patients and EGFR mutation status From February 2012 to March 2013, 20 patients in the Zhejiang Cancer Hospital were enrolled in this study. The patients had pathologically confirmed NSCLC and had newly diagnosed BMs with imaging evidence. The patients’ clinical characteristics are listed in Table 1. The median age
was 62 years (range 39–75 years), and males accounted for 60 % of the patient sample. The ECOG PS scores of 75 % of the patients were 0–1, and half of the patients had a smoking history. Adenocarcinoma accounted for 80.0 % of the tumors, and 90 % of the patients had active extracranial lesions as the BMs were diagnosed. Nine patients had corresponding nervous system symptoms while the BMs were confirmed; other patients had asymptomatic BMs that were found during routine examinations. A single patient had an isolated BM; the diameter of the brain lesion that located in the cerebellum was 4.5 cm. Two patients had 2–3 intracranial lesions; 17 patients had ≥3 intracranial lesions. Two patients (10 %) were treated for the first time and had activating EGFR mutations. Ninety percent of the patients had
Table 1 Patient characteristics (n = 20) Characteristics Gender Male Female Age, years Median Range ECOG PS 0–1 2 Smoking status Prior Never Current Tumor histology Adenocarcinoma Squamous Unknown Number of intracranial lesions 1–3 ≥3 RTOG GPA 0–1 1.5–2.5 3 3.5–4.0 Previous treatment None First- to second-line chemotherapy Active extracranial disease at study entry Yes No
All patients (n = 20)
EGFR mutant (n = 10)
EGFR wild type (n = 8)
P 0.188
12 (60.0 %) 8 (40.0 %)
4 (40.0 %) 6 (60.0 %)
6 (75.0 %) 2 (25.0 %)
62 39–75
60 39–72
54 39–75
15 (75.0 %) 5 (25.0 %)
8 (80.0 %) 2 (20.0 %)
6 (75.0 %) 2 (25.0 %)
9 (45.0 %) 10 (50.0 %) 1 (5.0 %)
3 (30.0 %) 7 (70.0 %) 0
4 (50.0 %) 3 (37.5 %) 1 (12.5 %)
16 (80.0 %) 1 (5.0 %) 3 (15.0 %)
9 (90.0 %) 1 (10.0 %) 0
6 (75.0 %) 0 2 (25.0 %)
3 (15.0 %) 17 (85.0 %)
1 (10.0 %) 9 (90.0 %)
1 (12.5 %) 7 (87.5 %)
12 (60.0 %) 8 (40.0 %) 0 0
8 (80.0 %) 2 (20.0 %)
4 (50.0 %) 4 (50.0 %)
2 (10.0 %) 18 (90.0 %)
2 (20.0 %) 8 (80.0 %)
0 8 (100.0 %)
18 (90.0 %)
9 (90.0 %)
7 (87.5 %)
2 (10.0 %)
1 (10.0 %)
1 (12.5 %)
0.515
1.000
0.350
0.181
1.000
0.321
0.477
1.000
EGFR epidermal growth factor receptor, ECOG PS Eastern Cooperative Oncology Group performance status, RTOG GPA Radiation Therapy Oncology Group graded prognostic assessment
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received first- or second-line chemotherapy. The first-line chemotherapy regimens were all platinum-containing, twodrug regimens, and the majority of the regimens were cisplatin or carboplatin combined with gemcitabine and taxanes. Five patients received pemetrexed combined with platinum treatment. Our study planned to enroll 40 patients, and preplanned interim analysis was conducted for the median PFS data of 20 patients. The study was terminated due to a significantly shorter median PFS of patients with wildtype EGFR in comparison with patients who had EGFR mutations. In total, 18 patients provided tissue samples for the examination of EGFR mutations using the amplification refractory mutation system (ARMS) method. Ten patients exhibited activating EGFR mutations, and eight patients had wild-type EGFR. The most common mutation was a deletion in exon 19 (six patients), followed by deletion in exon 21 (four patients). No rare mutations were detected. The comparison of clinical and pathological characteristics between patients with an EGFR mutation and those with wild-type EGFR did not reveal any significant difference.
experiencing disease progression, seven patients exhibited the progression of extracranial lesions (five showed progression of only extracranial lesions, and two showed progression of both intracranial and extracranial lesions). The median PFS time of all the patients was 7.0 months (95 % CI 1.2–13.2 months; Fig. 1a). The median PFS times differed according to the EGFR mutation status: 4.0 months (95 % CI 2.7–5.3 months) for the EGFR wild-type group and 12.0 months (95 % CI 5.8–18.2 months) for the EGFR mutation group (P = 0.0001) (Fig. 1b). The median survival time (MST) in the whole group was 14.6 months (95 % CI 12.5–16.7 months; Fig. 1c). The MST of patients with EGFR mutations was 22.0 months (95 % CI 14.6–29.4), which was significantly longer than the 7.5 months (95 % CI 4.7 5–10.3 months; P = 0.0001) for the wild-type EGFR patients (Fig. 1d). The MST for patients received no treatments, firstline chemotherapy and second-line chemotherapy was 19.0 months (95 % CI 14.4–23.6 months), 18.0 months (95 % CI 13.2–22.6 months), and 13.0 months (95 % CI 7.6–18.5 months), separately.
Treatment response and patients survival
CSF/plasma concentrations of icotinib
The objective tumor ORR of the intracranial lesions was evaluated in all patients. Among them, 5 achieved CR, 11 achieved PR, and 3 achieved SD, yielding a response rate of 80.0 % and a disease control rate (CR + PR + SD) of 95.0 %. For different statuses of EGFR mutations, there was no remarkable difference in terms of ORR and CR (P = 0.275 and 0.092, respectively) (Table 2). Five patients were alive at the time of this analysis, and the median follow-up time was 20 months (range 4–25 months). All surviving patients exhibited EGFR mutations. Of the eight patients with wild-type EGFR
Detection of icotinib concentrations in the CSF and plasma was performed in 10 patients. The detailed data are listed in Table 3. The median icotinib concentrations in the plasma and CSF were 940.6 ± 503.8 and 11.6 ± 9.1 ng/mL, respectively. The CSF/plasma concentrations of icotinib were approximately 1.4 ± 1.1 %.
Table 2 Response of brain metastases to icotinib combined with WBRT All patients (%)
EGFR mutant EGFR wild (%) type (%)
Patient number
20
10
8
CR PR CR + PR SD
5 (25.0 %) 11 (55.0 %) 16 (80.0 %) 3 (15.0 %)
4 (40.0 %) 5 (50.0 %) 9 (90.0 %) 1 (10.0 %)
0 5 (62.5 %) 5 (62.5 %) 2 (25.0 %)
0.092 0.664 0.275 0.559
PD
1 (5.0 %)
0
1 (12.5 %)
0.444
P
EGFR epidermal growth factor receptor, CR complete response, PR partial response, SD stable disease, PD progressive disease
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Toxicity The combination of icotinib plus WBRT was well tolerated by all 20 patients, and no grade 4/5 treatment-related toxicity was observed. The adverse events during treatment are summarized in Table 4. During the icotinib-combined WBRT, 45.0 % of patients had nausea, 35.0 % of patients experienced headaches, and 10 % of patients had vomiting, which were grade 1 adverse reactions. The most common AEs reported during icotinib alone therapy were rash (40.0 %), diarrhea (15.0 %), and increased AST/ALT (15.0 %). These were predominantly of grade 1/2, with only one case of increased AST/ALT reported as grade 3. After symptomatic treatment, the patient continued icotinib treatment. There was no occurrence of interstitial pneumonia. Only one patient had obvious cognitive impairment after 21 months of WBRT treatment; the brain MRIs did not show any signs of recurrence. Three patients with longterm survival (survival time >12 months) had mild-degree memory decline.
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Fig. 1 Disease-free survival and overall survival after treatment of brain metastases with whole-brain radiation therapy and icotinib. a Disease-free survival for all patients (n = 20); b overall survival for
all patients; c disease-free survival by epidermal growth factor receptor (EGFR) mutation (n = 10) and wild type (n = 8); d overall survival by EGFR mutation status
Table 3 CSF and plasma concentrations of icotinib and response of the central nervous system metastases Case
CSF concentrations (ng/mL)
Plasma concentrations (ng/mL)
CSF/plasma CNS response concentrations (%)
1 2 4 6 8 9 10 11 12 14
26.95 17.68 5.40 12.28 2.85 4.61 5.40 4.67 11.38 26.32
632.2 1098 1120 1348 151 378.3 742 714 1475 1747
4.26 complete response 1.61 partial response 0.48 partial response 0.91 complete response 1.89 partial response 1.22 stable disease 0.72 complete response 0.65 stable disease 0.77 partial response 1.51 partial response
Mean ± SD
11.8 ± 9.1
940.6 ± 503.8
1.4 ± 1.1 %
CNS central nervous system, CSF cerebrospinal fluid
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Table 4 Treatment-related toxicities Adverse events
Any N %
1 N %
2 N %
3 N %
4 N %
Nausea Vomiting Headache Dizziness Diarrhea Acneiform rash
9 (45.0 %) 2 (10.0 %) 7 (35.0 %) 2 (10.0 %) 3 (15.0 %) 8 (40.0 %)
9 (45.0 %) 2 (10.0 %) 7 (35.0 %) 2 (10.0 %) 2 (10.0 %) 4 (20.0 %)
0 0 0 1 (5.0 %) 4 (20.0 %)
0 0 0 0 0 0
0 0 0 0 0 0
Increased 3 (15.0 %) AST/ALT
2 (10.0 %)
0
1 (5.0 %)
0
Increased bilirubin
1 (5.0 %)
0
0
0
1 (5.0 %)
AST aspartate aminotransferase, ALT alanine aminotransferase
Discussion The present phase II study showed that WBRT with concurrent icotinib for NSCLC produced longer overall survival compared with that of historical controls [4–6], with particular benefit evident for patients with EGFR mutations; the median PFS and MST were as long as 12.0 and 22.0 months, respectively. Several retrospective and prospective studies reported that gefitinib and erlotinib are effective for intracranial metastatic lesions [10–14, 18]; however, the results varied greatly. The overall respond rate for intracranial lesions ranged from 10 to 87.8 % [11, 14], and the PFS ranged from 2.3 to 14.5 months [14, 18]. An analysis of these studies revealed that the major reason for this discrepancy was the selection of patients for treatment. By continuously treating 41 non-selected Caucasian patients with BMs using gefitinib, Cereoli et al. [11] obtained a relatively low efficacy and disease control rate only about 10.0 and 27.0 %, respectively. Choosing adenocarcinoma and non-smoking Asian patients as the treatment population, Kim et al. [13] used gefitinib or erlotinib alone without combination with WBRT to treat BMs and reported that the intracranial lesion response rate was 73.9 %, the PFS was 7.1 months, and the OS was 18.8 months. As for the treatment of the BM population with EGFR mutations using single gefitinib, Iuchi et al. [14] reported that the intracranial lesion response rate reached 87.8 %, the PFS was 12.4 months, and the OS was 21.9 months. Our study also observed that the EGFR mutation subgroup had a higher response rate and longer survival time than the wild-type subgroup. The efficacy of the mutation subgroup patients was basically consistent with the results of Iuchi et al. [14], which further confirmed that the EGFR mutation was an efficacy predictive factor for using EGFR-TKIs to treat NSCLC patients with
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BMs. For patients with BMs, the selection of EGFR-TKI treatment should still be based on their gene mutation status. Cause of the first treatment failure in patients with wildtype EGFRs showed that all seven patients with extracranial lesions had immediate progression. Currently, many randomized studies have confirmed that EGFR-TKI treatment has minimal effects on the efficacy of patients with wild-type EGFRs [19–21]. Meta-analysis results have also revealed that the response rate and PFS of wild-type EGFR patients treated with EGFR-TKIs are much worse than those treated with chemotherapy [22]. The blockade of EGFR signaling in vitro has been shown to sensitize cells to the effects of radiation. Furthermore, blockade of the wild-type EGFR has also been demonstrated to reduce radiation tolerance by reducing DNA repair, blocking antiapoptosis pathways, and inhibiting proliferation in wildtype patients [15]; however, these results have not been confirmed in clinical studies. As small molecule substances, the molecular weight of icotinib is 427.88 [16]. The results revealed that the CSF concentration and CSF/plasma concentrations of icotinib were 11.6 ± 9.1 ng/mL and 1.4 ± 1.1 %, respectively, which is similar to the 1.1 % CSF/plasma concentrations of gefitinib as reported in the literature [10]. This result indicates that icotinib can penetrate the BBB to reach intracranial metastatic lesions, which may partially explain the effectiveness of icotinib in BM patients with EGFR mutations. Concurrent icotinib combined with WBRT treatment or icotinib alone therapy all had rather good safety, which is proved by our study. Among all the patients with long-term survival, one patient had significant cognitive impairment, and three patients had mild-degree memory decline, which was considered to be associated with the application of WBRT. For BM patients with activating EGFR mutations, long-term survival can be obtained after EGFR-TKI treatment, and the adverse events of WBRT on the brain have a higher chance of manifesting. Iuchi et al. [14] reported that the treatment with a single dose of gefitinib had improved efficacy of BM patients with EGFR mutations and approximately half of the patients postponed the implementation of WBRT; thus, the development of WBRT-associated cognitive impairment is reduced. But a meta-analysis reported that upfront cranial radiotherapy may improve intracranial disease control and survival outcomes compared with TKI alone [23]. Aiming to compare the PFS between the firstline icotinib and WBRT treatments, a phase III randomized controlled study is currently being conducted in BM patients with EGFR mutations in China [24]. The results of this phase III study might solve the issue of selecting the first-line treatment for BM patients with EGFR mutations.
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Although the present prospective clinical study seems to have significant findings, there were certain limitations. As shown, this was a single group with a small sample size and a non-randomized study which indicates that largescale, multicenter, and randomized controlled studies are necessary to validate these results. In summary, the present prospective phase II study demonstrated that the treatment of NSCLC patients with BMs using icotinib combined with WBRT had significant efficacy. The effectiveness for patients with activating EGFR mutations was significantly better than that for those with wild-type EGFR. The concurrent icotinib combined with WBRT treatment yielded good tolerance. Whether icotinib can be used as a first-line single-drug treatment in BM patients with activating EGFR mutations should be further investigated by randomized controlled studies.
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