Anti-EGFR Therapies: How to Select Patients

Anti-EGFR Therapies: How to Select Patients
Fred R. Hirsch
Tetsuya Mitsudomi
Pasi A. Jänne
Epidermal growth factor receptor (EGFR) inhibitors have proven effective in some patients with advanced non-small cell lung cancer (NSCLC) previously untreated and/or treated with chemotherapy.1 Most data are published on the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Objective response rates in phase II studies with gefitinib and erlotinib are 10% to 18% in western populations and up to 27% in Asian populations.2,3,4,5,6,7,8 In addition, a substantial fraction of NSCLC patients, who failed previous chemotherapy, achieve long-term stable disease (SD), leading to disease control rate (DCR) exceeding 50% of patients and often associated with symptomatic improvement and prolonged survival. Thus, developing a biomarker capable of predicting DCR is equally if not more important than one predicting only those who have objective response.
Two large placebo controlled randomized studies were performed with EGFR TKIs as second-or third-line therapy.6,7 The BR.21 study with erlotinib showed for the first time a survival benefit for a targeted therapy in NSCLC, whereas the Iressa Survival Evaluation in Lung Cancer (ISEL) study with gefitinib did not demonstrate a significant survival advantage, although subset analysis in the latter study did show survival benefit in certain clinical subgroups (i.e., never-smokers and Asians).7 In both studies, clinical effect of EGFR TKIs on survival was seen also in patients with “unfavorable” clinical characteristics (e.g., men, smokers, and patients with tumors of squamous histology).7,8 Thus, clinical features appear insufficient for identifying those patients who would and would not have survival benefit from these new agents.
After encouraging results of EGFR TKIs in relapsed patient categories, it was natural to test these drugs in combination with standard first-line chemotherapy of advanced NSCLC. In large prospective randomized studies, standard chemotherapy doublets were given in combination with EGFR TKIs or placebo, followed by maintenance with active drugs or placebo.9,10,11,12 No benefit from adding EGFR TKIs to standard chemotherapy was observed in any of the four studies, and again clinical characteristics (except for never-smoking status in the TRIBUTE study) could not identify subsets of patients who benefited from combination therapy.
Thus, the search for other measures (i.e., biomarkers) for selection of patients for the EGFR TKIs was mandatory.
The use of monoclonal antibodies, mainly cetuximab has been studied in NSCLC, and most recently the results from the FLEX (First Line in Lung Cancer with ErbituX) study, which is a comparison of cisplatin/vinorelbine with or without cetuximab in EGFR immunohistochemistry (IHC) positive was presented (see later).13 The latter study showed a survival benefit for patients having cetuximab added to the chemotherapy in first-line therapy for advanced NSCLC patients with EGFR protein-expressing tumors. Although the survival benefit (median survival, 11.3 vs. 10.1 months; hazard ratio [HR] = 0.87) was statistically significant, the efficacy seems not to be dramatically improved, and the study calls for a better biomarker selection of patients to this type of therapy. Another study (BMS 099), which compared chemotherapy with or without cetuximab as first-line therapy in advanced unselected NSCLC did not meet the primary end point of prolonged progression-free survival (PFS).14 Thus, selection of NSCLC patients to EGFR inhibitors based on EGFR markers might be crucial for outcome both with EGFR TKIs as well as with monoclonal antibodies. Potential clinical and molecular biomarkers for selection of patients to EGFR inhibitors for NSCLC is discussed later.
CLINICAL FACTORS
Early Clinical Trials In the phase I trials of gefitinib, tumor response was exclusively seen in NSCLC (4/16 in NSCLC and 0/48 in other types of cancer in United States/European study, 5/23 in NSCLC and 0/8 in other types of cancer in Japanese study).2,3 Especially in Japanese study, all four responders were with adenocarcinoma and three fourths were female patients.2
Two phase II trials of gefitinib, Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) 1 and 2, showed that certain patient subgroups appeared to have a higher response rate, namely women, adenocarcinoma, and Japanese.4,5 In IDEAL 1 conducted in Japan and European countries, 210 patients with one or two prior chemotherapy regimens were randomly assigned either to have 250 or 500 mg of gefitinib. Objective tumor response rate was similar between the two groups (18.4% and 19.0% for 250- and 500-mg group, respectively). In contrast, adverse events were more common in the 500-mg group. In the 250-mg group, 15.5% of the patients had AEs requiring a short-treatment interruption, and none required a dose reduction, 28.3% and 10.4% of the patients in the 500-mg group required a treatment interruption and a dose reduction, respectively. Response rate was higher for Japanese patients than non-Japanese patients (27.5% vs. 10.4%; p = 0.0023). Multivariate analysis revealed that performance status (PS), sex, histology, and prior immuno/hormonal therapy were significant predictive factors at the 10% significance level. A similarly designed randomized phase II trial conducted in the United States (IDEAL 2) revealed that overall response rate was 10% (12% in 250-mg group and 9% in 500- mg group). In this trial, patients with stage IIIB/IV diseases, for which they had received at least two chemotherapy regimens, were eligible. Response rate was again higher in women (19%) than in men (3%), in adenocarcinomas (13%) than other histologic types (4%).
Miller et al.15 were the first to report that smoking history as well as bronchioloalveolar pathologic subtypes predict sensitivity to gefitinib. Overall, a partial radiographic response was observed in 21 (15%) of 139 patients with advanced NSCLC. Never-smokers have a significantly higher response rate than former/current smokers (36% vs. 8%; p <0.001).15 In addition, adenocarcinoma with bronchioloalveolar features had higher response rate (38%) than other adenocarcinomas (14%, p <0.001).5 Multivariate analysis confirmed that these two factors were independent predictors of response (p = 0.006 and 0.004, respectively). However, gender was not identified as a significant predictor in both univariate and multivariate analyses. The authors speculated that this was because of comigration of smoking and gender.15
Subsequent Studies Following this observation, various groups confirmed that response to gefitinib or erlotinib very much affected patients’ clinical backgrounds. In observation of over 4000 patients taken from previously published literature (Table 49.1), TKI response was dependent on smoking history (never-smokers 38% vs. former/current smokers 10%), gender (men 13% vs. women 36%), histologic type (adenocarcinoma 27% vs. nonadenocarcinoma 7%), and ethnicity (East Asians 29% vs. others 8%).
Several authors further showed that higher response rate was linked to longer survival in each patient subset. For example, Ando et al.16 showed that median survival time (MST) after gefitinib treatment was 16.6 and 7.7 months in female and male patients, 15.6 and 7.6 months in never-smokers and former/current smokers, and 12.1 and 6.3 months in patients with adenocarcinoma and with other histologic types, respectively. In addition, multivariate analysis by the Cox regression model revealed that women, no smoking history, adenocarcinoma as well as absence of metastatic disease, good PS, previous chest surgery are independent prognostic factors.16
Clinical Predictors in Randomized Phase III Trials Aforementioned trends were also seen in randomized controlled clinical trials. In four randomized trials comparing TKI plus platinum doublet chemotherapy versus platinum doublet chemotherapy, namely Iressa NSCLC Trial Assessing Combination Treatment (INTACT) 1 and 2 using gefitinib, TALENT and TRIBUTE using erlotinib, addition of TKI did not yield survival advantage over platinum doublet.9,10,11,12 However, subgroup analysis of TRIBUTE showed that addition of erlotinib to carboplatin plus paclitaxel confer an advantage in overall survival in patients who reported never smoking (MST, 23 vs. 10 months; HR, 0.49; 95% confidence interval [CI], 0.28 to 0.85).12 None of other factors including gender, race, PS, or histology were predictive for overall survival.12 The favorable predictive role of never smoking was also demonstrated for patients with bronchioloalveolar carcinomas (BAC).17
In a randomized, placebo-controlled trial to determine whether erlotinib prolongs survival in NSCLC patients after the failure of first-or second-line chemotherapy (BR.21), erlotinib significantly prolongs survival with MST of 6.7 versus 4.7 months (HR, 0.70; p <0.001).6In this trial, tumor response was significantly better in never-smokers than former/current smokers (25% vs. 4%; p <0.001).12 Furthermore, smoking history was an independent prognostic factor (p = 0.048), as well as erlotinib treatment (p = 0.002), Asian ethnicity (p = 0.01), and adenocarcinoma histology (p = 0.004). In their exploratory subgroup analyses, a benefit from erlotinib was dependent on smoking history, with HR of 0.9 (p = 0.14) in former/current smokers and 0.4 (p <0.001) in never-smokers.6
In contrast, similar placebo-controlled randomized trial using gefitinib in place of erlotinib, ISEL trial, failed to show overall survival advantage in gefitinib treatment group (median survival, 5.6 vs. 5.1 months; p = 0.087).7 However, gefitinib prolongs survival in never-smokers (MST, 8.9 vs. 6.1 months; p = 0.012) as well as in Asian patients (MST, 9.5 vs. 5.5 months; p = 0.010) in preplanned subset analyses.7
The results of two randomized phase II trials comparing gefitinib with docetaxel were recently reported. V15-32 conducted in Japan failed,18 but similarly designed Iressa Non-small cell lung cancer Trial Evaluating REsponse and Survival against Taxotere (INTEREST)19 was able to show noninferiority of gefitinib to docetaxel in patients with NSCLC having been treated with one or two chemotherapy regimens. None of clinical parameters such as sex, PS, smoking status, age, ethnicity (INTEREST only) significantly affected overall survival in the both trials.18,19 These somewhat unexpected observations are at least partly attributed to high crossover rate especially in V15-32, that is, 53% of patients with docetaxel arm received gefitinib upon progression and 36% of patients with gefitinib arm received docetaxel,18 whereas the rates were 31% and 37% in INTEREST,19 respectively. Other concern was that rates of nonsmokers were not equal in V15-32 (i.e., 29% of gefitinib arm were nonsmokers, whereas 36% of docetaxel arm were nonsmokers).18
TABLE 49.1 Relationship between Tumor Response and Clinical Parameters in Patients with Lung Cancer Treated with EGFR TKI

Overall

Smoking

Gender

Histology

Ethnicity

Author Year

TKI

Design

N

CR+PR

RR

N

CR+PR

RR

N

CR+PR

RR

N

CR+PR

RR

N

CR+PR

RR

Fukuoka et al. 20034

G

Rand P-II

208

38

18

%

N/A

N/A

N/A

Asian

102

29

28

%

Other

108

11

10

%

Kris et al. 20035

G

Rand P-II

216

22

10

%

N/A

Male

123

4

3

%

Adeno

146

19

13

%

Female

93

18

19

%

Other

70

3

4

%

Perez-Soler 20048

E

P-II

57

7

12

%

Adeno

35

4

11

%

Other

22

3

14

%

Takano et al. 2004158

G

Retro

98

32

33

%

NS

32

20

63

%

Male

66

15

23

%

Adeno

81

31

38

%

Asian

98

32

33

%

S

66

12

18

%

Female

32

17

53

%

Other

17

1

6

%

Kaneda et al. 200430

G

Retro

101

20

20

%

NS

55

15

33

%

Male

64

6

9

%

Adeno

81

20

25

%

Asian

101

20

20

%

S

46

5

9

%

Female

37

14

38

%

Other

20

0

0

%

Huang et al. 200468

G

Retro

16

9

56

%

NS

12

7

58

%

Male

4

2

50

%

Adeno

15

9

60

%

Asian

16

9

56

%

S

4

2

50

%

Female

12

5

42

%

Other

1

0

0

%

Miller et al. 200415

G

Retro

139

21

15

%

NS

36

13

36

%

Male

48

4

8

%

Adeno

108

21

19

%

S

103

8

8

%

Female

91

17

19

%

Other

31

0

0

%

Other

139

21

15

%

Kris et al. 200417

E

Retro

59

15

25

%

NS

19

7

37

%

S

21

4

19

%

Lim 2005154

G

Retro

110

35

32

%

NS

66

31

47

%

Male

52

10

19

%

Asian

110

35

47

%

S

44

4

%

Female

58

25

43

%

Shepherd et al. 20056

E

P-III

427

38

9

%

NS

93

23

25

%

Male

281

17

6

%

Adeno

209

29

14

%

Asian

53

10

19

%

S

311

12

4

%

Female

146

21

14

%

Other

218

9

4

%

Other

374

28

8

%

Kim et al. 200531

G

Retro

80

20

25

%

NS

17

10

59

%

Male

61

12

20

%

Adeno

39

16

41

%

Asian

80

20

25

%

S

63

10

16

%

Female

19

8

42

%

Other

41

4

10

%

Lee et al. 200520

G

P-II

36

25

69

%

NS

36

25

69

%

Male

3

1

33

%

Adeno

36

25

69

%

Asian

36

25

69

%

S

0

0

0

%

Female

33

24

73

%

Other

%

Mitsudomi et al. 200567

G

Retro

50

26

52

%

NS

25

17

68

%

Male

27

11

41

%

Adeno

43

25

58

%

Asian

50

26

52

%

S

25

9

36

%

Female

23

15

65

%

Other

7

1

14

%

Takano et al. 200561

G

Retro

66

35

53

%

NS

43

28

65

%

Male

40

17

43

%

Adeno

62

34

55

%

Asian

66

35

53

%

S

23

7

30

%

Female

26

18

69

%

Other

4

1

25

%

Cappuzzo et al. 200540

G

Prospective plus EAP

102

14

14

%

NS

15

6

40

%

Male

67

4

6

%

Adeno

63

11

17

%

S

87

8

9

%

Female

35

10

29

%

Other

39

3

8

%

Other

102

14

14

%

Han et al. 200570

G

Retro

90

22

24

%

NS

43

15

35

%

Male

54

8

15

%

Adeno

58

20

34

%

Asian

90

22

24

%

S

47

7

15

%

Female

36

14

39

%

Other

32

2

6

%

Zhang et al. 2005159

G

Retro

98

31

32

%

NS

58

25

43

%

Male

56

11

20

%

Adeno

75

31

41

%

Asian

98

31

32

%

S

37

6

16

%

Female

39

20

51

%

Other

20

0

0

%

Tokumo et al. 200569

G

Retro

21

10

48

%

NS

8

6

75

%

Male

13

6

46

%

Adeno

15

9

60

%

Asian

21

10

48

%

S

13

4

31

%

Female

8

4

50

%

Other

6

1

17

%

Thatcher et al. 20057

G

P-III

959

77

8

%

NS

204

37

18

%

Male

5

%

Adeno

11.9

%

Asian

209

26

12

%

S

755

40

5.3

%

Female

15

%

Other

4.8

%

Other

750

51

7

%

Tomizawa et al. 2005155

G

Retro

20

14

70

%

NS

11

10

91

%

Male

9

5

56

%

Adeno

18

13

72

%

Asian

20

14

70

%

S

9

4

44

%

Female

11

9

82

%

Other

2

1

50

%

Other

0

0

0

%

Ando et al. 200616

G

Retro

1713

348

20

%

NS

653

225

35

%

Male

1086

126

12

%

Adeno

1288

311

24

%

Asian

20

14

70

%

S

1012

116

12

%

Female

627

222

35

%

Other

414

34

8

%

Other

0

0

0

%

Niho et al. 2006160

G

P-II first line

40

12

30

%

NS

8

6

75

%

Male

24

3

13

%

Adeno

30

11

37

%

Asian

40

12

30

%

S

32

6

19

%

Female

16

9

56

%

Other

10

1

10

%

Suzuki et al. 2006156

G

P-II first line

34

9

27

%

NS

11

5

46

%

Male

21

2

10

%

Adeno

25

7

28

%

Asian

34

9

27

%

S

23

4

17

%

Female

13

7

54

%

Other

9

2

22

%

Satouchi et al. 2007157

G

Retro

221

54

24

%

NS

89

37

42

%

Male

142

20

14

%

Adeno

196

52

27

%

Asian

221

54

24

%

S

131

17

13

%

Female

79

34

43

%

Other

25

2

8

%

Other

0

0

0

%

Tamura et al. 200734

E

P-II

106

30

28

%

NS

51

%

Male

17

%

Adeno

Asian

106

30

28

%

S

14

%

Female

50

%

Other

Other

0

0

0

%

Total

4232

964

23

%

NS

1515

561

37

%

Male

2241

284

13

%

Adeno

2623

698

26.6

%

Asian

1571

463

29

%

S

2852

285

10

%

Female

1434

511

36

%

Other

988

68

7

%

Other

1473

125

8

%

CR, complete response; E, erlotinib; EAP, expanded access program; G, gefitinib; N/A, not applicable; NS, non-smoker; P-II, phase II study; P-III, phase III study; PR, partial response; Rand P-II, randomized phase II study; RR, response rate; S, smokers; TKI, tyrosine kinase inhibitor.

Clinical Trials for Patients Selected by Clinical Factors Prompted by these observations, Lee et al.20 conducted phase II trial to evaluate the efficacy of gefitinib as a first-line therapy in never-smokers with advanced or metastatic adenocarcinoma in Korea. Out of 36 patients who were assessable for response, 25 patients (69%) had partial response and 4 (19%) had stable disease, yielding 88% of disease control rate.16 This amazingly high rate could be achieved possibly because patients had a combination of three predictors of good response. Interestingly, they did not see difference in response between adenocarcinoma with bronchioloalveolar features (3/7, 43%) and that without bronchioloalveolar features (22/29, 76%) (p = 0.16).20
Although the contribution of each factor to the positive results is unknown, this study clearly supports the further study of EGFR TKI as a first-line therapy in certain subsets of NSCLC patients. This was prospectively investigated in Iressa Pan-Asia Study (IPASS), a phase III trial investigating gefitinib versus carboplatin/paclitaxel doublet chemotherapy as first-line treatment in selected subjects with stage IIIB/IV adenocarcinoma having no or light smoking history in East and South East Asia.21 The result was recently reported to be positive and details were discussed later in this chapter.
Histology As shown in Tables 49.1, response rate for patients with adenocarcinoma was 27% compared with 7% in patients with other histologic types. As discussed earlier, Miller et al.15 reported that patients with bronchioloalveolar histologic type predict sensitivity to gefitinib. Out of 139 NSCLC patients they reviewed, 21 (15%; 95% CI, 9% to 21%) experienced a partial radiographic response. In this study, the authors defined NSCLC of bronchioloalveolar subtype as adenocarcinoma with bronchioloalveolar features, bronchioloalveolar carcinoma with focal invasion, or pure bronchioloalveolar cancer. However, this definition of bronchioloalveolar features are not strictly followed to World Health Organization (WHO) criteria in which bronchioloalveolar cell carcinoma is defined as noninvasive, in situ carcinoma.15 However, these observations do not preclude patients with nonadenocarcinoma histology from candidates of EGFR-TKI therapy. In aforementioned BR.21 trial comparing erlotinib with best supportive care, patients with nonadenocarcinoma histology also had a survival benefit with an HR of 0.8 (p = 0.07).6
Adenosquamous carcinoma is defined as having components of both squamous cell carcinoma and adenocarcinoma with each comprising at least 10% of the tumor. Although the majority of patients with this histologic type are smokers, several investigators reported similar incidence of EGFR mutation in adenosquamous cell carcinoma, one of putative predictive markers as discussed later. For example, Kang et al.,22 Toyooka et al.,23 and Sasaki et al.24 reported that EGFR mutation was present in 11/25, 3/11, and 4/26 adenosquamous carcinomas, respectively. Although most patients were not treated with EGFR TKI, patients with adenosquamous histology harboring EGFR mutation can be candidates for EGFR-TKI therapy. Interestingly, these authors agree in that identical EGFR mutation is present in both squamous and adenocarcinoma components in the same adenosquamous tumor.22,23,24 In addition, at least a part of patients with squamous cell carcinoma who responded to EGFR TKI in the literature may, in fact, be those with squamous cell carcinoma with adenocarcinoma component with EGFR mutation.
Similarly, Fukui et al.25 reported that one of six patients with combined small cell carcinoma and adenocarcinoma of the lung had EGFR L858R mutation. This mutation was again present in both small cell and adenocarcinoma components.
Skin Toxicity Skin toxicity is most common adverse event relating to EGFR-TKI therapy. For example, during treatment with gefitinib 250 mg/day or erlotinib 150 mg/day, skin toxicity occurred in 62%4 and 75% of the patients.26 In a phase II trial of erlotinib, skin rash correlated with tumor response and overall survival. MSTs for patients without rash, those with grade 1, and those with grade 2 or 3 were 1.5, 8.5, and 19.6 months, respectively.8 Similarly, Jänne et al.27 reported a correlation between skin rash and survival in patients on an expanded access study. MST for patients with skin toxicity of any grade was 10 months that was significantly longer than 4.5 months for patients without skin toxicity (p = 0.0001).27
In general, data from multiple studies with cetuximab and erlotinib show a consistent relationship between rash and response/survival in NSCLC as well as other tumor types.28 However, this relationship is less consistent for gefitinib, reason for this discrepancy is currently not known.28
Other Clinical Factors Related to Efficacy of EGFR TKIs Several other factors are reported to be associated with response/survival of patients treated with gefitinib or erlotinib. These included absence of metastatic disease,16 good performance status,4,16,26,27,29,30 previous chest surgery,16 younger age,7,13 presence of prior platinum chemotherapy.6
Interstitial Lung Disease In Japan, considerable fraction of patients with gefitinib treatment suffer from fatal interstitial lung disease (ILD).32 Large multi-institutional retrospective analysis conducted by West Japan Clinical Oncology Group (WJOG) revealed that 70 (3.5%) cases and 31 deaths (1.6%) from gefitinib induced ILD among 1976 patients.16 In a prospective study conducted by AstraZeneca Japan, incidence of ILD was 5.81% (193/3322) and 83 died of disease (2.5% mortality).33 In combined analysis of two phase II studies of erlotinib monotherapy in Japan, ILD was observed 5 of 108 (4.6%).34 In WJOG study, gefitinib-induced ILD was significantly associated with male sex, smoking history, and coincidence of interstitial pneumonia.16 In AstraZeneca study, poor PS, smoking history, preexisting ILD, and prior history of chemotherapy were independently associated with ILD.33
However, incidence of ILD appears to be lower in other Asian countries than Japan except Taiwan. Chiu et al.35 from Taiwan reported that four patients with NSCLC having brain metastases out of 76 patients (5.8%) developed ILD. In contrast, ILD was observed in 3/485 patients treated with erlotinib compared with 3/242 patients in the placebo group in BR.21 study in which about 13% of patients are of Asian ethnicity.6 Similarly, the number of patients experiencing ILD as higher in Asian population than in the overall population; however, no difference was observed between the gefitinib and placebo groups (3% vs. 4%) in ISEL study in which about 20% of patients are of Asian ethnicity. 7 From Korea, no cases of gefitinib-related ILD was observed in 111 patients with advanced NSCLC on expanded access program. 29 It is difficult to understand difference of incidence of ILD among countries especially among several East Asian countries. However, variability in the criteria for ILD should exist making it difficult to estimate true incidence of gefitinib or erlotinib induced ILD among different countries. Therefore, eliminating patients with multiple risk factors for ILD from candidates of EGFR-TKI therapy is important for patient selection at least in several East Asian countries including Japan.
EGFR GENE COPY NUMBER
In breast cancer patients, amplification of the HER-2 gene (HER-2 is a member of the EGFR family) detected by fluorescence in situ hybridization (FISH) is a strong predictive factor for treatment benefit from anti-HER-2 monoclonal antibody, trastuzumab, and recommended for use in clinical practice.36 EGFR is an important signaling pathway for lung carcinogenesis37 and was demonstrated to have a negative prognostic impact.38,39 Thus, it was hypothesized that genomic gain of EGFR is a factor contributing to growth advantage of NSCLC cells and may be an important biomarker of sensitivity to EGFR TKIs. Investigators from the University of Colorado Cancer Center developed an original scoring system for EGFR gene copy number assessed by FISH in which tumors were classified into six categories, based on ascending number of gene copies per cell.40 FISH-negative samples were classified as those with no or low genomic gain (≥ four copies of the gene per cell in <40% of cells), and FISH-positive samples were defined as tumors with high gene copy number (≥ four copies of the gene per cell in ≥40% of cells) or gene amplification (tight gene clusters and a ratio of gene/chromosome per cell ≥2, or ≥15 gene copies per cell in ≥10% of the cells). To date, several major studies have addressed the association between EGFR gene copy number by FISH and treatment outcome to EGFR TKIs. All the published studies demonstrated clinically important treatment benefit in patients with high EGFR gene copy number with EGFR TKIs versus placebo, and this test is now being validated in prospective clinical studies in enriched population of NSCLC patients.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Aug 25, 2016 | Posted by in CARDIOLOGY | Comments Off on Anti-EGFR Therapies: How to Select Patients

Full access? Get Clinical Tree

Get Clinical Tree app for offline access