Eye, Hepatobiliary, and Renal Disorders of Erlotinib in Patients with Non-Small-Cell Lung Cancer: A Meta-Analysis

Abstract

Background

Many molecular genetic alterations are involved in the pathogenesis and progression of lung cancer. The epidermal growth factor receptor (EGFR) mutation is a genetic alteration and frequently observed in patients with non-small-cell lung cancer (NSCLC) [1, 2]. Therefore, erlotinib and other EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib, afatinib, and osimertinib are the first-line therapies to treat EGFR mutation positive NSCLC in stage IIIB and IV [3].

The clinically important role and effectiveness of erlotinib have certainly been reported in lots of studies and published research. The information about its safety is also generally reported and well-known. Skin rash and diarrhea are the most common adverse events of erlotinib and the event rates were reported as 49.2% for skin rash and 20.3% for diarrhea in the SATURN study [4]. Dose reductions or delays due to these adverse effects may be required, but the first-line therapy remains erlotinib followed with monitoring and appropriate supportive care in many cases. That is, erlotinib-related skin rash and diarrhea have been evaluated carefully based on the clinical application and studies and how to manage about the adverse events are also well established.

Whereas, other erlotinib-related adverse events, such as eye, liver, or renal toxicities, have been considered less extensively, despite the fact that these risks have been reported continuously since the initial clinical trials of erlotinib [5, 6]. These adverse events occur less frequently and most of them are mild to moderate. But the event rates have a limitation in that they were reported individually as a unit of each study. Indeed, many studies have reported on the adverse events of erlotinib, but the results were inconsistent among studies. Shepherd et al. reported that an eye disorder occurred in 28 patients, but hepatic or renal events were not observed in a trial involving 485 participants [5]. In contrast, the liver-related event rate was 38.4% in a trial involving 276 participants and no ocular or renal disorders were reported [7]. This shows that, to date, there are no clear conclusions regarding the association of the aforementioned toxicity-related adverse events with erlotinib.

The aim of our study was to evaluate the eye, hepatobiliary, and renal disorders of erlotinib in patients with NSCLC and to integrate quantitatively the results through conducting a meta-analysis.

Methods

Search strategy and study selection

The MEDLINE (OVID and PubMed) and Cochrane Library were accessed for the literature searching in this meta-analysis. The following PubMed MeSH terms and related text terms were used: “erlotinib”, “cancer”, “neoplasm”, “carcinoma”, “clinical trials”, and “randomized clinical trials”. Searching for the bibliographies of all relevant articles were also performed. There was no publication limitation. The search was completed on 13 July 2018.

The review process for selecting article were conducted by same methods with our previously reported studied [8]. The inclusion criteria were described as below:

(1) Phase II, III, and IV trials in patients with NSCLC

(2) Participants who received daily erlotinib treatment

(3) Inclusion of the reported adverse events or toxicity related data

The study protocol for this meta-analysis has been registered in the International Prospective Register for Systematic Reviews (PROSPERO) CRD42018093758 on May 30, 2018.

Data extraction and quality assessment

The following data were extracted from each included study: the first author’s surname, publication year, study design, number of participants, type of cancer, treatments (dose regimen and periods), and toxicity related data.

The methodological quality of each study was evaluated by two authors according to the Jadad scale, which is using for the randomized controlled trials [9]. The scale evaluates as total 5 points about a description of the randomization, the appropriateness of the randomization method, a description of double blinding, the appropriateness of the double-blinding method, and a description of withdrawals and dropouts. Scores higher than 3 were considered high quality. Any discrepancies between the two authors were resolved by discussion.

Statistical analysis

The end point for this meta-analysis was the incidence of eye, hepatobiliary, and renal adverse events following monotherapy with erlotinib for NSCLC. As a sub-group analysis, the incidence of eye and hepatic disorders in the erlotinib treatment group were compared with the values in the control group with placebo or cytotoxic chemotherapy. To evaluate the heterogeneity of the included studies, the χ² test with Q statistics and quantified using I² measures were applied [10]. A fixed-effects model (Mantel–Haenszel method) or a random-effects model (DerSimonian–Laird method) was applied in the calculations based on the result of heterogeneity test in each analysis [11, 12].

Sensitivity analysis was conducted to improve the reliability of meta-analysis. The meta-analytic calculations were repeatedly performed after each study was excluded in turn. To examine potential publication bias, the Begg’s test and Egger’s test [13, 14] were applied. All statistical analysis and calculations were performed using the Comprehensive Meta-Analysis software, version 2 (CMA 26526; Biostat, Englewood, NJ USA). All statistical tests were two-sided and P-value < 0.05 was considered to indicate statistical significance.

Results

Study quality and characteristics

In total, 1,511 articles were identified in the literature search. After the removal of duplicates, the titles and abstracts of 1,148 articles were screened. Of these, 934 articles were excluded, and the full texts of the remaining 214 articles were assessed for eligibility. A further 154 articles were excluded because of insufficient data, overlapped data, or because they were unsuitable based on the inclusion criteria. The remaining 60 studies were included in this meta-analysis. The study selection process was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [15].

 The characteristics of the 60 studies are listed in Table 1. Patients with stage IIIB and IV NSCLC were enrolled in the included 61 studies and only one study was performed in patients with IIB and IIIA NSCLC [58]. Using the Jadad score, 37 studies were classified as low quality (a score of 2 and or less), whereas 23 studies were classified as high quality (a score of 3 or greater) (Table 1).

Incidence and relative risk of erlotinib-induced eye disorders

Forty-four of the 60 studies were assessed for the incidence of eye disorders in 20,964 participants treated with erlotinib (Table 1). In total, 611 eye-related adverse events of any grades were reported, and thirty three of the 611 adverse events were classified as grade 3–4. The incidence of eye disorders in each study was between 0.00% and 45.7%. The index of eye disorders mainly included dry eye, conjunctivitis, blurry vision, and other ocular adverse events.

The overall incidence (event rate) of eye disorders for any grade was 3.30% (95% confidence interval [CI] 2.20%–5.00%) using the random-effects model (Table 2).

Four studies were assessed for the specific contribution of erlotinib to the development of eye disorders by comparing erlotinib-treatment groups and control groups (placebo or other treatment). The risk ratios (RR) and 95% CI of the comparison between the two groups were 2.91 and 1.70–4.98, respectively (Figure 1). Reanalysis using a random-effects model revealed the significant differences (RR = 3.34; 95% CI 1.32–8.45). This result indicated that patients who received erlotinib had significantly increased the risk of ocular toxicities.

Incidence and relative risk of erlotinib-induced hepatobiliary disorders

Fifty-two of the 60 studies were assessed for the incidence of hepatobiliary disorders in 21,339 participants treated with erlotinib (Table 1). The index of hepatobiliary disorders mainly included alanine transaminase (ALT) or aspartate transaminase (AST) elevations, alkaline phosphatase elevation, hyperbilirubinemia, and other hepatobiliary adverse events. In detail, 751 ALT increases, 456 bilirubin increases, and 1,025 other adverse events of any grade were reported and 301 of them were classified as grade 3–4. The incidence in each study of the ALT increase ranged from 0.00% to 50.9% and the incidence of bilirubin increase ranged from 0.00% to 38.9%.

The overall incidence (event rate) of ALT and bilirubin increases were 6.40% (95% CI 3.90–10.4) and 3.8% (95% CI 2.30%–6.10%), respectively, using the random-effects model (Table 2). The overall incidence of other adverse events except ALT and bilirubin increases were 1.00 % (95% CI 0.60%–1.80%). The incidence of any hepatobiliary disorders of grade 3–4 was 2.20% (95% CI 1.50%–3.10%) (Table 2).

Five studies were included to compare the liver toxicity of erlotinib, representing as ALT elevation, between erlotinib-treatment groups and control groups (placebo or other treatment). The RR and 95% CI of the comparison between the two groups were 1.319 and 0.913–1.904, respectively, using the fixed-effects model (Figure 2). Reanalysis using a random-effects model revealed no significant differences. This result indicated that patients who received erlotinib had no significantly increased risk of liver-related toxicities.

Incidence of erlotinib-induced renal disorders

Forty-three studies were assessed for erlotinib-induced renal disorders in 10,367 participants treated with erlotinib (Table 1). In total, 218 renal adverse events of any grade were reported and nine of the 218 adverse events were classified as grade 3–4. The incidence of renal disorders in each study ranged from 0.00% to 25.4%. The index of renal disorders mainly included elevated serum creatinine, proteinuria, renal failure, and other renal adverse events.

The overall incidence (event rate) of renal disorders was 3.10% (95% CI 1.90%–5.00%), using the random-effects model (Table 2). The incidence of renal disorder of grade 3–4 was 1.10% (95% CI 0.70%–1.60%), using the fixed-effects model (Table 2). Reanalysis using a random-effects model showed the same result.

Sensitivity analysis and publication bias

As the results of sensitivity analysis, no significant differences were observed (data available on request). The results of publication bias through the Begg’s rank correlation test and Egger’s regression test are shown in Table 2 and 3.

Discussion

This meta-analysis was conducted to evaluate the eye, hepatobiliary, and renal toxicities of erlotinib in patients with EGFR positive NSCLC. The present meta-analysis quantitatively integrated the inconsistent results of reported clinical studies.

In the present meta-analysis, phase I studies were not included due to divergence from the dosage regimens in phase II, III, and IV studies. The reason is that the dose regimen of erlotinib is a highly associating factor in assessing the toxicity of erlotinib. The most common toxicities associated with erlotinib in phase I studies were also dose-dependent rash and diarrhea which were similarly observed in the included phase II, III, or IV studies [74, 75]. Other reported adverse events included mucositis, nausea, vomiting, and headaches that were observed less frequently [74].

Warnings and precautions were described as pulmonary toxicity, renal failure, hepatotoxicity, cardiovascular events, and ocular disorders, according to the approved drug information for erlotinib. Those adverse events were less common, but mostly severe. The bigger issue is that the information is still not enough to refer for effective monitoring and study. Thus, the present meta-analysis is a meaningful and useful approach for erlotinib therapy.

Firstly, in the meta-analysis of the incidence of erlotinib-induced ocular disorders, the overall incidence was 3.30% and the incidence of grade 3–4 disorders was 0.40% in patients with NSCLC cancers (Table 2). Comparing to the control groups, the risk of eye toxicities was significantly higher in the erlotinib group (Figure 1). EGFR is present in the eyes (corneal and conjunctival epithelial cells) and is also expressed in the sebaceous glands and hair follicle sheaths [76, 77]. EGFR in the above tissue plays an important role in regulating cell proliferation, apoptosis, and differentiation [78]. Whereas, erlotinib, as an EGFR inhibitor, interferes with the regulatory mechanism of EGFR and the eye toxicity is thought to be linked to the EGFR inhibition [6, 79, 80]. Erlotinib-induced eye disorders can be relieved by discontinuation of the treatment, but some cases may be more severe and manifest as advanced or irreversible diseases. Thus, regular follow-up relating to ocular disorders should be considered in all patients treated with erlotinib for prevention, early diagnosis, and treatment.

Secondly, in the evaluation of the incidence of erlotinib-induced hepatobiliary disorders, the overall incidence of ALT and bilirubin elevations were 6.40% and 3.80%, respectively. But, the risk of hepatobiliary toxicities was not significantly increased in the erlotinib group, compared to the control group. It was reported that liver function test abnormalities were common (1% to 10%) adverse events in the post-marketing data with over 400,000 patients with NSCLC having received erlotinib [81]. The events were mainly mild to moderate, transient, or associated with liver metastasis. Both the present meta-analysis and post-marketing data similarly indicate that ALT or bilirubin elevations are frequently observed, but not critical toxicity necessary to factor into treatments with erlotinib. However, the erlotinib-induced hepatotoxicity could be increased by other risks or features patients may have. A recent retrospective study showed that concomitant use of CYP3A4 inducers and H2-antagonist/PPIs, liver metastasis, and age ≥65 were risk factors of erlotinib-induced hepatotoxicity [82]. Therefore, a monitoring strategy for hepatobiliary toxicities of erlotinib should be recommended persistently in patients with these risk factors mentioned above.

Lastly, the overall incidence of renal disorder was evaluated. Kidney-related toxicity of erlotinib has not been extensively researched because erlotinib is mainly metabolized by CYP3A4, CYP1A1, and CYP1A2, in the liver. Safety concerns for patients with renal failure have rarely been reported, but one pharmacokinetic study showed that erlotinib was hardly affected by renal function and hemodialysis in patients with NSCLC and chronic renal failure [83]. Regarding this, a laboratory study has reported interesting results that erlotinib preserved renal function and prevented salt retention in nephrotic rats [84]. Another laboratory study has reported similar conclusions that erlotinib attenuated the progression of chronic kidney disease in rats with remnant kidney [85]. Further clinical studies will hopefully provide answers about this issue.

The inevitable limitation of meta-analysis is that analysis should be performed based on previously reported studies and those studies are not necessarily complete or accurate. Likewise, there was a lack of original data in the present meta-analysis, and the studies differed substantially with regard to dosage regimens and study periods. Despite these limitations, the strength of current meta-analysis is that more than 1,500 articles were reviewed and a sufficient number of studies were included in the analysis.

Conclusions

We examined the overall incidence of the erlotinib-induced eye, hepatobiliary, and renal disorders in patients with NSCLC. Based on the results, careful monitoring of eye toxicity in patients receiving erlotinib should be recommended and close monitoring including liver function tests should be suggested in patients with hepatic toxicity-related risk factors.

Declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

All data generated or analysed during this study are included in this published article (and its supplementary information files).

Funding

This research was supported by the 2018 Yeungnam University Research Grant; This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) founded by the Ministry of Science, ICT and Future Planning (2017R1C1B5017085).

The funding institutions had no role in the study design, methods, data collections, analysis and manuscript preparation in relation to this work.

Competing Interests

The authors declare that they have no competing interests

Authors’ contributions

Study design: Choi HD

Data acquisition: Choi HD and Chang MJ

Data anaysis and interpretation: Choi HD and Chang MJ

Statistical anaysis: Choi HD

Manuscript preparation: Choi HD

Manuscript editing and review: Choi HD and Chang MJ

Acknowledgements

Not applicable

References

1. Gullick WJ. Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers. Br Med Bull. 1991;47:87–98.
2. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.
3. Non-small cell lung cancer. NCCN Clinical practice guidelines in oncology (NCCN guidelines). 2019.
4. Coudert B, Ciuleanu T, Park K. et al. Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy. Ann Oncol. 2012;23:388–94.
5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–32.
6. Methvin AB, Gausas RE. Newly recognized ocular side effects of erlotinib. Ophthal Plast Reconstr Surg. 2007;23:63–5.
7. Urata Y, Katakami N, Morita S, et al. Randomized Phase III Study Comparing Gefitinib With Erlotinib in Patients With Previously Treated Advanced Lung Adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016;34:3248–57.
8. Choi HD, Chang MJ. Cardiac toxicities of lapatinib in patients with breast cancer and other HER2-positive cancers: a meta-analysis. Breast Cancer Res Treat. 2017;166:927–36.
9. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;7:1–12.
10. Cochran WG. The combination of estimates from different experiments. Biometrics. 1954; 10:101–29.
11. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective sties of diseases. J Natl Cancer Inst. 1959;22:719–48.
12. DerSimonian R, Larid N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.
13. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometircs. 1994;50:1088–101.
14. Egger M, Smith GD, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34.
15. Moher D, Liberati A, Tetzlaff J, et al. Preferred Reporting Items for Systematic Reviews and Meta-Analysis: The PRISMA Statement. PLoS Med. 2009;6:e1000097.
16. Arrieta O, Martinez-Barrera L, Trevino S, et al. Wood-smoke exposure as a response and survival predictor in erlotinib-treated non-small cell lung cancer patients: an open label phase II study. J Thorac Oncol. 2008;3:887–
17. Felip E, Rojo F, Reck M, et al. A phase II pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy. Clin Cancer Res. 2008;14:3867–
18. Hesketh PJ, Chansky K, Wozniak AJ, et al. Southwest Oncology Group phase II trial (S0341) of erlotinib (OSI-774) in patients with advanced non-small cell lung cancer and a performance status of 2. J Thorac Oncol. 2008;3:1026–
19. Kubota K, Nishiwaki Y, Tamura T, et al. Efficacy and safety of erlotinib monotherapy for Japanese patients with advanced non-small cell lung cancer: a phase II study. J Thorac Oncol. 2008;3:1439–
20. Lee DH, Kim SW, Suh C, Yoon DH, Yi E, Lee JS. Phase II study of erlotinib as a salvage treatment for non-small-cell lung cancer patients after failure of gefitinib treatment. Ann Oncol. 2008;19:2039–
21. Lilenbaum R, Axelrod R, Thomas S, et al. Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2. J Clin Oncol. 2008;26:863–
22. Akerley W, Boucher KM, Bentz JS, Arbogast K, Walters, T. A phase II study of erlotinib as initial treatment for patients with stage IIIB-IV non-small cell lung cancer. J Thorac Oncol. 2009;4:214–
23. Reck M, van Zandwijk N, Gridelli C, et al. Erlotinib in advanced non-small cell lung cancer: efficacy and safety findings of the global phase IV Tarceva Lung Cancer Survival Treatment study. J Thorac Oncol. 2010; 5:1616–
24. Rossi D, Dennetta D, Ugolini M, et al. Activity and safety of erlotinib as second- and third-line treatment in elderly patients with advanced non-small cell lung cancer: a phase II trial. Target Oncol. 2010; 5:231–
25. Stathopoulos GP, Trafalis D, Dimitroulis J, Athanasiou A, Koutantos J, Anagnostopoulos A. Erlotinib treatment in pretreated patients with non-small cell lung cancer: A Phase II study. Oncol Lett. 2010;1:335–
26. Takahashi T, Yamamoto N, Nukiwa T, et al. Phase II study of erlotinib in Japanese patients with advanced non-small cell lung cancer. Anticancer Res. 2010;30:557–
27. Yoshioka H, Hotta K, Kiura K, et al. A phase II trial of erlotinib monotherapy in pretreated patients with advanced non-small cell lung cancer who do not possess active EGFR mutations: Okayama Lung Cancer Study Group trial 0705. J Thorac Oncol. 2010;5:99–
28. Choi DR, Lee DH, Choi CM, Kim SW, Suh C, Lee JS. Erlotinib in first-line therapy for non-small cell lung cancer: a prospective phase II study. Anticancer Res. 2011;31:3457–
29. Lee DH, Kim SW, Suh C, Han YH, Lee JS. Phase II study of erlotinib for chemotherapy-naive patients with advanced or metastatic non-small cell lung cancer who are ineligible for platinum doublets. Cancer Chemother Pharmacol. 2011;6:35–
30. Matsuura S, Inui N, Ozawa Y, et al. Phase II study of erlotinib as third-line monotherapy in patients with advanced non-small-cell lung cancer without epidermal growth factor receptor mutations. Jpn J Clin Oncol. 2011;41:959–
31. Mita AC, Papadopoulos K, de Jonge MJ, et al. Erlotinib 'dosing-to-rash': a phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer. Br J Cancer. 2011;105:938–
32. Natale RB, Thongprasert S, Greco FA, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2011;29:1059–
33. Ramalingam SS, Spigel DR, Chen D, et al. Randomized phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer. J Clin Oncol. 2011;29:4574–
34. Sequist LV, Pawel J, Garmey EG, et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin Oncol, 2011;29:3307–
35. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12:735–
36. Ciuleanu T, Stelmakh L, Cicenas S, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012;13:300–
37. Kobayashi T, Koizumi T, Agatsuma T, et al. A phase II trial of erlotinib in patients with EGFR wild-type advanced non-small-cell lung cancer. Cancer Chemother Pharmacol. 2012;69:1241–
38. Lee SM, Khan I, Upadhyay S, et al. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2012;13:1161–
39. Pérol M, Chouaid C, Pérol D, et al. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012;30:3516–
40. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–
41. Scagliotti GV, Krzakowski M, Szczesna A, et al. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. J Clin Oncol. 2012;30:2070–
42. Schaake EE, Kappers I, Codrington HE, et al. Tumor response and toxicity of neoadjuvant erlotinib in patients with early-stage non-small-cell lung cancer. J Clin Oncol. 2012;30:2731–
43. Witta SE, Jotte RM, Konduri K, et al. Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy. J Clin Oncol. 2012;30:2248–
44. Wu YL, Kim JH, Park K, Zaatar A, Klingelschmitt G, Ng C. Efficacy and safety of maintenance erlotinib in Asian patients with advanced non-small-cell lung cancer: a subanalysis of the phase III, randomized SATURN study. Lung Cancer. 2012;77:339–
45. Goto K, Nishio M, Yamamoto N, et al. A prospective, phase II, open-label study (JO22903) of first-line erlotinib in Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC). Lung Cancer. 2013;82:109–
46. Groen HJ, Socinski MA, Grossi F, et al. A randomized, double-blind, phase II study of erlotinib with or without sunitinib for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC). Ann Oncol. 2013;24:2382–
47. Wu YL, Zhou C, Cheng Y, et al. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803). Ann Oncol. 2013;24:993–
48. Yamada K, Takayama K, Kawakami S, et al. Phase II trial of erlotinib for Japanese patients with previously treated non-small-cell lung cancer harboring EGFR mutations: results of Lung Oncology Group in Kyushu (LOGiK0803). Jpn J Clin Oncol. 2013;43:629–
49. Brahmer JR, Lee JW, Traynor AM, et al. Dosing to rash: a phase II trial of the first-line erlotinib for patients with advanced non-small-cell lung cancer an Eastern Cooperative Oncology Group Study (E3503). Eur J Cancer. 2014;50:302–
50. Gemma A, Kudoh S, Ando M, et al. Final safety and efficacy of erlotinib in the phase 4 POLARSTAR surveillance study of 10 708 Japanese patients with non-small-cell lung cancer. Cancer Sci. 2014;105:1584–
51. Gitlitz BJ, Bernstein E, Santos ES, et al. A randomized, placebo-controlled, multicenter, biomarker-selected, phase 2 study of apricoxib in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Thorac Oncol. 2014;9:577–
52. Horiike A, Yamamoto N, Tanaka H, et al. Phase II study of erlotinib for acquired resistance to gefitinib in patients with advanced non-small cell lung cancer. Anticancer Res. 2014;34:1975–
53. Kawaguchi T, Ando M, Asami K, et al. 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. 2014;32:1902–
54. Matsumoto Y, Maemondo M, Ishii Y, et al. A phase II study of erlotinib monotherapy in pre-treated non-small cell lung cancer without EGFR gene mutation who have never/light smoking history: re-evaluation of EGFR gene status (NEJ006/TCOG0903). Lung Cancer. 2014;86:195–
55. Morise M, Taniguchi H, Saka H, et al. Phase II study of erlotinib for previously treated patients with EGFR wild-type non-small-cell lung cancer, following EGFR mutation status reevaluation with the Scorpion Amplified Refractory Mutation System. Mol Clin Oncol. 2014;2:991–
56. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15:1236–
57. Yoshioka H, Komuta K, Imamura F, Kudoh S, Seki A, Fukuoka M. Efficacy and safety of erlotinib in elderly patients in the phase IV POLARSTAR surveillance study of Japanese patients with non-small-cell lung cancer. Lung Cancer. 2014;86:201–
58. Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2015;33:4007–
59. Minemura H, Yokouchi H, Azuma K, et al. A phase II trial of erlotinib monotherapy for pretreated elderly patients with advanced EGFR wild-type non-small cell lung cancer. BMC Res Notes. 2015;8:220.
60. Reckamp KL, Koczywas M, Cristea MC, et al. Randomized phase 2 trial of erlotinib in combination with high-dose celecoxib or placebo in patients with advanced non-small cell lung cancer. Cancer. 2015;121:3298–
61. Wu YL, Zhou C, Liam CK, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analysis from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015;26:1883–
62. Yamada K, Aono H, Hosomi Y, et al. A prospective, multicentre phase II trial of low-dose erlotinib in non-small cell lung cancer patients with EGFR mutations pretreated with chemotherapy: Thoracic Oncology Research Group 0911. Eur J Cancer. 2015;51:1904–
63. De Greve J, Van Meerbeeck J, Vansteenkiste JF, et al. Prospective Evaluation of First-Line Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Carrying an Activating EGFR Mutation: A Multicenter Academic Phase II Study in Caucasian Patients (FIELT). PLoS One. 2016;11:e0147599.
64. Lara Jr PN, Moon J, Hesketh PJ, et al. SWOG S0709: Randomized Phase II Trial of Erlotinib versus Erlotinib Plus Carboplatin/Paclitaxel in Patients with Advanced Non-Small Cell Lung Cancer and Impaired Performance Status as Selected by a Serum Proteomics Assay. J Thorac Oncol. 2016;11:420–
65. Neal JW, Dahlberg SE, Wakelee HA, et al. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016;17:1661–
66. Papadimitrakopoulou V, Jack LeeJ, Wistuba II, et al. The BATTLE-2 study: a biomarker-integrated targeted therapy study in previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol. 2016;34:3638–
67. Park K, Yu CJ, Kim SW, et al. First-Line Erlotinib Therapy Until and Beyond Response Evaluation Criteria in Solid Tumors Progression in Asian Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer: The ASPIRATION Study. JAMA Oncol. 2016;2:305–
68. Yamada K, Azuma K, Takeshita M, et al. Phase II Trial of Erlotinib in Elderly Patients with Previously Treated Non-small Cell Lung Cancer: Results of the Lung Oncology Group in Kyushu (LOGiK-0802). Anticancer Res. 2016;36:2881–
69. Ciuleanu TE, Ahmed S, Kim JH, et al. Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer. Br J Cancer. 2017;117:757–
70. Ikezawa Y, Asahina H, Oizumi S, et al. A randomized phase II trial of erlotinib vs. S-1 as a third- or fourth-line therapy for patients with wild-type EGFR non-small cell lung cancer (HOT1002). Cancer Chemother Pharmacol. 2017;80:955–
71. Leighl NB, Rizvi NA, de Lima Jr LG, et al. Phase 2 Study of Erlotinib in Combination With Linsitinib (OSI-906) or Placebo in Chemotherapy-Naive Patients With Non-Small-Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations. Clin Lung Cancer. 2017;18:34–
72. Miyawaki M, Naoki K, Yoda S, et al. Erlotinib as second- or third-line treatment in elderly patients with advanced non-small cell lung cancer: Keio Lung Oncology Group Study 001 (KLOG001). Mol Clin Oncol. 2017;6:409–
73. Yang JJ, Zhou Q, Yan HH, et al. A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer. 2017;116:568–
74. Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001;19:3267–79.
75. Milton DT, Azzoli CG, Heelan RT, et al. A phase I/II study of weekly high dose erlotinib in previously treated patients with non-small cell cancer. Cancer. 2006;107:1034–41.
76. Liu Z, Carvajal M, Carraway CA, et al. Expression of the receptor tyrosine kinases, epidermal growth factor receptor, erbb2, and erbb3, in human ocular surface epithelia. Cornea. 2001;20:81–5.
77. Zieske JD, Wasson M. Regional variation in distribution of EGF receptor in developing and adult corneal epithelium. J Cell Sci. 1993;106:145–52.
78. Nakamura Y, Sotozono C, Kinoshita S. The epidermal growth factor receptor (EGFR): role in corneal wound healing and homeostasis. Exp Eye Res. 2001;72:511–7.
79. Zhang G, Basti S, Jampol LM. Acquired trichomegaly and symptomatic external ocular changes in patients receiving epidermal growth factor receptor inhibitors. Cornea. 2007;26:858–60.
80. Borkar DS, Lacouture ME, Basti S. Spectrum of ocular toxicities from epidermal growth factor receptor inhibitors and their intermediate-term follow-up: a five-year review. Support Care Cancer. 2013;21:1167–74.
81. Reck M, Mok T, Wolf J, Heigener D, Wu YL. Reviewing the safety of erlotinib in non-small cell lung cancer. Expert Opin Drug Saf. 2011;10:147–57.
82. Kim MK, Yee J, Cho YS, Jang HW, Han JM, Gwak HS. Risk factors for erlotinib-induced hepatotoxicity: a retrospective follow-up study. BMC Cancer. 2018;18:988.
83. Togashi Y, Masago K, Fukudo M. Pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small cell lung cancer and chronic renal failure who are undergoing hemodialysis. J Thorac Oncol. 2010;5:601–5.
84. Bou Matar RN, Klein JD, Sands JM, et al. Erlotinib preserves renal function and prevents salt retention in doxorubicin treated nephrotic rats. PLoS One. 2013;8:e54738.
85. Yamamoto Y, Iyoda M, Tachibana S, et al. Erlotinib attenuates the progression of chronic kidney disease in rats with remnant kidney. Nephrol Dial Transplant. 2018;33:598–606.

Tables

Table 1. General characteristics of the included studies

Abbreviations: ALT, alanine aminotransferase; NR, not reported.

Table 2 Incidence (event rate) of ocular, hepatobiliary, and renal disorders, test of heterogeneity and publication bias

Table 3 Test of heterogeneity and publication bias in comparisons between the erlotinib-treatment group and control group