Cell Biochem Biophys DOI 10.1007/s12013-014-9955-y

ORIGINAL PAPER

Effects of Icotinib on Advanced Non-Small Cell Lung Cancer with Different EGFR Phenotypes Huiyun Pan • Rong Liu • Shengjie Li • Hui Fang • Ziwei Wang • Sheng Huang Jianying Zhou



Ó Springer Science+Business Media New York 2014

Abstract Icotinib is the first oral epidermal growth factor receptor (EGFR) tyrosine kinase receptor inhibitor, which has been proven to exert significant inhibitory effects on nonsmall cell lung cancer in vitro. Clinical evidence has showed that the efficacy of Icotinib on retreating advanced non-small cell lung cancer is comparable to Gefitinib. However, different phenotypes of EGFR can affect the therapeutic outcomes of EGFR tyrosine kinase receptor inhibitor. Therefore, our study focused on efficacy and safety of Icotinib in patients with advanced non-small cell lung cancer of different EGPR phenotypes. Clinical data of patients with advanced non-small cell lung cancer who received Icotinib treatment from August, 2011 to May, 2013 were retrospectively analyzed. Kaplan–Meier analysis was used for survival analysis and comparison. 18 wild-type EGFR and 51 mutant type were found in a total of 69 patients. Objective response rate of patients with mutant type EGFR was 54.9 % and disease control rate was 86.3 %. Objective response rate of wild-type patients was 11.1 % (P = 0.0013 vs mutant type), disease control rate was 50.0 % (P = 0.0017). Median progression-free survival (PFS) of mutant type and wild-

H. Pan  R. Liu  S. Li  H. Fang  Z. Wang Gerontology Center, The First Affiliated Hospital, Zhejiang University, No. 79, Qingchun Road, Hangzhou 310003, Zhejiang, China S. Huang Respiratory Department, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, Zhejiang, China J. Zhou (&) Respiratory Department, The First Affiliated Hospital, Zhejiang University, No. 79, Qingchun Road, Hangzhou 310003, Zhejiang, China e-mail: [email protected]

type patients were 9.7 and 2.6 months, respectively (P \ 0.001). Median PFS of exon 19 mutated mutant patients was 11.3 months, mean PFS of exon 21 L858R mutated mutant patients was 8.7 months (P = 0.3145). Median overall survival (OS) of EGFR mutated patients had not reached. OS time of 13 wild-type patients was 12.9 months (P \ 0.001). The common adverse reactions of Icotinib included rash, diarrhea, itching skin with occurrence rates of 24.6 % (17/69), 13.0 % (9/69), and 11.6 % (8/69), respectively. Most adverse reactions were grade I–II. Icotinib has great efficacy in EGFR mutated patients, making it an optimal regimen to treat EGFR mutated patients. Furthermore, most of adverse reactions associated with Icotinib treatment were tolerable. Keywords mutation

Icotinib  Non-small lung cancer  EGFR

Introduction Lung cancer is a worldwide malignancy with high morbidity and mortality. Non-small cell lung cancer (NSCLC) accounts for 80 % of lung cancer cases and 50 % of NSCLC cases are diagnosed at relative advanced stage [1, 2]. The prognosis of NSCLC remains poor, which is associated with a 5-year survival rate of approximate 15 %. Currently, the first-line treatment of NSCLC is platiniferous drugs combined with chemotherapy. However, the clinical outcomes remain unsatisfactory with response rate of only 15–36 %, overall survival time of 8–10 months and 1-year survival rate of 30–40 % [2]. Molecular targeted therapeutic drugs have provided new therapeutic strategies to NSCLC patients who are irresponsive to conventional chemotherapy. Clinical data demonstrated that molecular

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targeted therapeutic drugs can significantly improve the patient life quality and prolong survival time of some patients [3]. Epidermal growth factor receptor (EGFR) signaling pathway is closely associated with the carcinogenesis and progression of NSCLC. Activation of EGFR signaling pathway can promote cancer cell proliferation, differentiation, metastasis, angiogenesis, and apoptosis inhibition. Therefore, EGFR is considered an ideal target for biologically targeted therapy of NSCLC. EGFR inhibitors such as Imatinib, Gefitinib, and Erlotihib have been widely employed in clinical settings. Among these agents, the effects of Gefitinib in the treatment of NSCLC have been well studied. IDEAL1 and 2 research have reported that as second-line drug or third-line drug, the response rate of in treating NSCLC is 9–19 %. These results demonstrated that the effects of Gefitinib last longer compared to chemotherapy, and the median duration of response was up to 7–13 months [4, 5]. Icotinib hydrochloride is a specific small molecules EGFR inhibitor with great efficacy, which has been approved to be used in the treatment of advanced NSCLC in August, 2011 in China. Icotinib has similar chemical structure, molecular mechanism, and clinical efficacy to Gefitinib and Erlotihib while better safety profile. Lynch and Paez found that efficacy of EGFR inhibitor in treating NSCLC was often related to EGFR mutation, which made detection of cancer cell EGFR gene mutation an important basis for individualized personal therapy [6, 7]. In the past 2 years, Icotinib has become more and more widely used in treating NSCLC. However, the clinical outcomes differed a lot between individuals, which may be related to EGFR mutation. Therefore, we investigate the relationship of clinical efficacy of Icotinib and EGFR mutation in this study.

stage IV, irresponsive to second-line or third-line therapy, and naı¨ve to EGFR TKI treatment. (4) Only EGFR TKI was applied after chemotherapy failure. Exclusion criteria in our study included: (1) Patients with unknown EGFR mutation. (2) No measurable clinical lesion. (3) Patients received other treatment which might affect the evaluation of efficacy, such as chemotherapy or interventional therapy except Icotinib. (4) Patient ECOG (Eastern Cooperative Oncology Group) score was more than 3. Treatment All patients completed the following examinations before treatment: enhanced CT examination of chest, enhanced MRI of brain, whole body isotope bone scan, blood routine test, liver and kidney function, electrolyte, total protein, albumin, blood glucose, immune function, electrocardiogram (ECG), pulmonary function test, and arterial blood gas analysis. Oral Icotinib (manufactured by Zhejiang BetaPharma Co., Ltd.) 125 mg three times per day was administrated. The indication to stop treatment was disease progressed, death or intolerance to treatment. Evaluation of Therapeutic Outcomes Therapeutic responses were evaluated from 1 month after Icotinib initiation. CT or other imaging examinations were performed to evaluate the responses every 2 months if response was stable or treatment was effective. Responses were classified as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to RECIST 1.1 criteria. Recent effective rate included response rate (RR). Disease control rate was the total of complete response, partial response, and stable disease (CR ? PR ? SD, DCR).

Patients and Methods Toxicity and Adverse Effects Selection of Patients 216 NSCLC patients aged from 33 to 78 (137 male cases and 79 female cases) who had received second-line or third-line therapy between August, 2011 and May, 2013 were included in this study. Inclusion criteria of this study were as follows: (1) all patients were diagnosed as NSCLC with confirmed pathological type. Pathological types of include patients included adenocarcinoma, squamous carcinoma, squamous adenocarcinoma, large cell carcinoma, or unclassified. (2) Pathological sections (Surgical pathology tissue and slice, lung puncture or biopsy sections, liquid-based cytology test of phlegm, puncture or biopsy specimens of lymph nodes or other metastasis, liquid-based cytology test of fiberoptic bronchoscopy biopsy, and brush or lavage) were obtained. (3) Patients were in stage III or

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Toxicity and adverse effects were categorized according to ‘‘the Standard of Adverse Reaction’’ (the third version of CTC) established by National Cancer Institute of America, including 5 grades from 0 to 4. Detection of EGFR Mutation Pyrophosphate sequencing method was applied to test EGFR mutation, sections tested included 19 surgical section, 35 biopsy sections, and 15 sections of other tissue. Follow-up Follow-up was completed in 69 patients. Progression-free survival (PFS) of which was obtained by clinic or phone,

Cell Biochem Biophys

median follow-up period was 11.2 months, the last followup time was Oct 30, 2013. Overall survival (OS) presented the period that initiate treatment to death or last follow-up time. PFS was defined as Icotinib initiation to confirmed disease progression. Statistical Analysis SPSS17.0 was used for statistical analysis. Kaplane-Meier analysis was used to analyze median PFS and OS. P \ 0.05 was considered statistically significant.

Results

Table 1 General characteristic of 69 patients Variables

All (n = 69)

EGFR mutation (n = 51)

EGFR wild type (n = 18)

38

25

13

31

26

5

0–1

42

32

10

2

27

19

8

Median

56

56

57

\65

45

33

12

C65

24

18

6

Yes

26

19

7

No

43

32

11

Gender Male Female Performance status

General Characteristics of Patients and EGFR Phenotype 69 patients completed EGFR phenotype analysis and follow-up. 38 cases were male and 31 cases were female. 61 cases were adenocarcinoma and 8 cases were other pathological type. 6 cases were in stage III and 63 cases were in stage IV. 51 cases were EGFR mutated type and 18 cases were EGFR wild type. Among EGFR mutated patients, 27 cases were exon 19 deletion, 18 cases were exon 21 L858R mutation, and 6 cases were other mutation. Age, gender, and course of disease between EGFR mutated and wildtype patients were not significantly different, as shown in Table 1.

Stage

PFS and Overall Survival Median PFS of 69 patients was 8.6 months, whereas PFS of mutated patients was 9.7 months. For EGFR mutated patients, median PFS of exon 19 mutated patients was 11.3 months and median PFS of exon 21 L858R mutated patients was 8.7 months. PFS of patients with different EGFR mutation was not significantly different (P = 0.3145) (Fig. 1; Table 3). Median PFS of wild-type patients was 2.6 months, which was significantly different compared to PFS of mutated patients (P \ 0.001) (Fig. 2). Among mutated patients, PFS of 17 brain metastasis patients was 8.8 months, while PFS of non-brain metastasis patients was 9.7 months(P = 0.7016) (Fig. 3). Among 51

0.5910

0.8806

0.9021

0.6723

III

6

4

2

IV

63

47

16

61 8

46 5

15 3

Histology Adenocarcinoma Non-adenocarcinoma

0.4343

Table 2 Comparison between EGFR and wild-type patients Best response

EGFR mutation [n (%)]

EGFR wildtype [n (%)]

Complete response

0 (0)

0 (0)

Partial response

28 (54.9)

2 (11.1)

Stable disease Progressive disease

16 (31.4) 7 (13.7)

7 (38.9) 9 (50.0)

Evaluation of Clinical Response For 51 EGFR mutated patients, the objective rate was 54.9 % and the disease control rate was 86.3 %. For 18 EGFR wild-type patients, the objective rate was 11.1 %, and the disease control rate was 50.0 %. Objective response rate and disease control rate were significantly different, as shown in Table 2.

0.0889

Age (year)

Smoking

P

P

Response rate

54.9 %

11.1 %

0.0013

Disease control rate

86.3 %

50.0 %

0.0017

Median progression-free survival (month)

9.7

2.6

\0.001

Median overall survival (month)



13.1

\0.001

patient with mutated EGFR, 29 received first-line therapy, 22 cases received second-line and third-line therapy. PFS of first-line and retreated patients was 9.7 and 8.6 months, respectively (P = 0.4125). Among 18 wild-type patients, median PFS of 9 disease-controlled patients was 5.7 months, while median PFS of 9 progressed patients was 1.3 months (P \ 0.001). Until Oct 30, 2013, 32 patients died including 22 mutated patients and 10 wild-type patients. Median OS of EGFR mutated patients had not reached. OS of 13 wild-type patients was 12.9 months

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Fig. 2 Comparison between PFS of EGFR mutation and wild-type patients (9.7 vs. 2.6 months, P \ 0.001) Fig. 1 Comparison of exon19 deficient patients and exon 21 L858Rdeficient EGFR mutation patients (11.3 vs. 8.7 months, P = 0.3145) Table 3 Relation analysis between PFS of 51 EGFR mutation patients and influence factors Variables

Median PFS (month)

95 % CI

8.9

6.8–10.3

9.6

7.7–11.5

0–1

10.7

8.7–12.1

2

7.2

6.1–8.4

Gender Male Female Performance status

0.3217

0.0625

Age(year)

0.2584

\65

8.6

7.6–10.8

C65

10.5

9.5–12.2

Yes

8.8

5.6–12.0

No

9.6

8.0–11.3

III

7.6

8.1–11.5

IV

10.1

6.5–13.6

8.8

7.2–10.4

9.7

6.7–13.9

0

9.3

7.8–11.1

C1

8.2

6.6–10.8

Exon 19

11.3

8.1–13.2

Other

8.7

7.0–11.6

Smoking

0.7109

Stage

0.2249

Brain metastasis Yes No Prior chemotherapy

0.7016

0.3810

Mutation type

123

P

Fig. 3 Comparison between PFS of EGFR brain metastasis and nonbrain metastasis patients (8.8 vs. 9.7 months, P = 0.7016)

(P \ 0.001). OS of disease-controlled patients in wild-type patients had no statistically different (P = 0.0628). Adverse Effects

0.3145

The most common adverse effects included rash, diarrhea, and skin itching with occurrence rate of 24.6 % (17/69), 13.0 % (9/69), and 11.6 % (8/69), respectively. Most

Cell Biochem Biophys

adverse effects were grade I – II and could be relieved after treatment. Other adverse effects included 3 cases anorexia (4.3 %), 2 cases nausea (2.9 %), 1 case dental ulcer (1.4 %), 1 case liver function impairment (1.4 %), and 1 case thrombus (1.4 %). Patients presented with abnormal transaminase markers backed to normal liver function after supportive live therapy, and the treatment was not affected.

Discussions Studies on EGFR mutation and its relationship with clinical response of EGFR TKI in NSCLC have opened new era of lung cancer molecular target therapy [6–8]. EGFR dimer induces protein tyrosine kinase activation, leading to autophosphorylation and consequently downstream signal activation to promote cell proliferation, angiogenesis, and cell apoptosis inhibition. Tyrosine kinase inhibitors (such as Gefitinib and Erlotinib) target at ATP combining site and prevent activation of internal tyrosine kinase to selectively inhibit EGFR signaling pathway [9]. Currently, EGFR TKIs was used as standard drug for treating patients with advanced NSCLC of specific gene phenotype in clinic. Icotinib is the third approved EGFR TKIs drug worldwide. Icotinib has similar chemical structure, molecular mechanism, and therapeutic effects as Gefitinib and Erlotihib, whereas better safety profile. The clinical responses of NSCLC patients with EGFR mutation to Icotinib treatment were analyzed. The median PFS of patients was 9.7 months, objective response rate was 54.9 %, and disease control rate was 86.3 %, which are comparable to the clinical data of Gefitinib [10, 11]. These results indicated that Icotinib had good efficacy on EGFR mutation patients. For the 18 patients with wild-type EGFR, PFS was 2.6 months, objective response rate was 11.1 %, and disease control rate was 50.0 %, indicating that Icotinib was partially effective in wild-type patients. Analysis of EGFR mutation patients in ICOGEN research reported that median PFS of Icotinib was 7.8 months [12]. PFS of EGFR mutation patients in our study was longer, which may be caused by better PS score of the patients in this study. Previous studies have showed that prescription dosage (150 mg/day) of Eriotinib inhibited the growth of wild-type cell lines, while Gefitinib was lack of the inhibitory effect on cell growth [8]. Early in vitro study on Icotinib showed that its effects were similar to Eriotinib on wild-type cell line [13]. In our study, median PFS of 18 patients with EGFR wild type was 2.6 months, which was consistent with 2.4 month PFS of wild-type patients in TAILOR study [14], indicating that Icotinib provided clinical benefits to wild-type patients. wild-type exon 19 deletion mutation and exon 21 L858R mutation are the main mutation types of EGFR. We found

that EGFR TKIs treatment showed better clinical response in exon 19 deletion patients than exon 21 L858R patients [15]. However, there was no statistically significant difference, which may result from the small sample size of this study. In most studies, EGFR TKIs treatment showed similar clinical efficacy in chemo-naı¨ve or retreated patients with EGFR mutation [16]. In this study, the clinical response chemo-naı¨ve or retreated patients to Icotinib treatment was not significantly different. A clinical study has reported that Erlotinib and Gefitinib showed good efficacy in brain metastasis patients, especially in patients with EGFR mutation [17, 18]. In this study, 16 brain metastasis patients with EGFR mutation received Icotinib treatment in our study. Our results showed that median PFS of brain metastasis patients with EGFR mutation was 8.8 months, which was in accordance with previous study, indicating that Icotinib had good efficacy in EGFR mutation brain metastasis patients. In safety analysis, our results shows that common adverse effects included rash and diarrhea, and the occurrence rate of adverse effects was similar to ICOGEN study [19, 20]. However, the occurrence rate of adverse effects associated with Icotinib treatment was lower than that of Gefitinib and Erlotinib [20, 21], indicating that Icotinib was better tolerated. As a retrospective analysis, only 69 patients were included in our study and the small sample size could be an issue of this study. Moreover, EGFR mutation was mainly detected using sequencing and ARMS (amplification refractory mutation system) methods. Sensitivity of the former was relatively low, which may lead to false negative to some extent. Pyrophosphate sequencing method was used in our research. However, false negative wild-type patients could occur, which may lead to good efficacy in wild-type patients in our study. EGFR TKIs combined with chemotherapy or radiotherapy can improve the therapeutic outcome in patients with NSCLC. In a phase II clinical trial, Casal et al report a therapeutic strategy of combining chemotherapy and radiotherapy with oral Erlotinib for 6 months in patients with stage III unresectable NSCLC [22]. Their results showed that CR 22.2 %, PR 12.8 %, SD 55.6 %, and PD 9.4 %, effective rate and control rate were up to 35 and 90.6 %, median PFS was 7.3 months, median OS was 18.7 months, the most common Erlotinib related side effects were rash 30.6 % and diarrhea 16.7 % [23, 24]. This before-mentioned clinical data demonstrated that Erlotinib combined with radiotherapy and chemotherapy was an effective and tolerable therapy for stage III unresectable NSCLC. Clinical response analysis of 69 EGFR confirmed lung cancer patients showed that Icotinib effective in advanced NSCLC Chinese patients, especially for EGFR mutation advanced NSCLC patients. In addition, most of adverse

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effects are well tolerated. As a drug newly marketed, more clinical trials should be conducted to fully evaluated the clinical efficacy and safety profile of Icotinib, especially on clinical response and safety in combination with chemotherapy and radiotherapy. Acknowledgments This work was funded by grants from Public Welfare Project of Zhejiang Province (No. 2012C23074), Natural Science Foud of Zhejiang Province (No. Y2110167), and Medical Foud of Zhejiang Province (No. 2008B067).

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Effects of icotinib on advanced non-small cell lung cancer with different EGFR phenotypes.

Icotinib is the first oral epidermal growth factor receptor (EGFR) tyrosine kinase receptor inhibitor, which has been proven to exert significant inhi...
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