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Efficacy and Safety of Afatinib in the Treatment of Advanced Non-Small-Cell Lung Cancer with EGFR Mutations: A Meta-Analysis of Real-World Evidence

Efficacy and Safety of Afatinib in the Treatment of Advanced Non-Small-Cell Lung Cancer with EGFR... Hindawi Journal of Oncology Volume 2021, Article ID 8736288, 16 pages https://doi.org/10.1155/2021/8736288 Research Article Efficacy and Safety of Afatinib in the Treatment of Advanced Non-Small-Cell Lung Cancer with EGFR Mutations: A Meta-Analysis of Real-World Evidence Lemeng Zhang , Yongzhong Luo , Jianhua Chen, Tianli Cheng, Hua Yang, Changqie Pan, Haitao Li, and Zhou Jiang oracic Medicine Department 1, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China Correspondence should be addressed to Yongzhong Luo; luoyongzhong@hnca.org.cn Received 21 October 2021; Accepted 29 November 2021; Published 18 December 2021 Academic Editor: Ozkan Kanat Copyright © 2021 Lemeng Zhang et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. )e purpose of this study was to explore the efficacy and safety of afatinib in advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations based on real-world evidence. Materials and Methods. Eligible real-world studies were identified from PubMed, Cochrane Library, and Embase. Cochrane guidelines were used to assess the quality of included studies. Cochran’s Q test and I statistics were used for the heterogeneity analysis. Results. Twenty-five studies were included in this meta-analysis; nine studies were included in the qualitative descriptive analysis. )e summarized disease control rate (DCR) was 87.6% (81.5%, 92.7%), and the overall response rate (ORR) was 58.9% (48.8%, 68.7%). )e pooled median progression-free survival (PFS) was 12.4 (10.3, 14.5) months, mean time to failure (TTF) was 15.4 (13.6, 17.2) months, and median overall survival (OS) was 31.6 (26.7, 36.5) months. )e total incidences of adverse events (AEs) for skin rashes, diarrhea, paronychia, and mucositis were 71.4% (64.4%, 77.9%), 70.4% (60.1%, 79.8%), 52.1% (41.9, 62.3%), and 36.5% (29.5%, 43.8%), respectively. )e incidences of severe adverse events (SAEs, Grade ≥3) for diarrhea, skin rashes, paronychia, and mucositis were 9.7% (6.8%, 13.1%), 5.8% (4.5%, 7.2%), 3.8% (2.0%, 6.2%), and 2.1% (1.0%, 3.6%), respectively. Differences in PFS and OS between the afatinib non-full-dose (<40 mg) and full-dose (>40 mg) groups were not significant (P> 0.05). However, the ORR in the full- dose group was 78.5% (66.7%, 88.4%), which was significantly higher than that in the non-full-dose group (67.8% [56.8%, 77.9%]). Conclusion. )e efficacy and safety of afatinib has been confirmed by real-world evidence in advanced NSCLC with EGFR mutation, consistent with randomized controlled trial results. In real-world setting, tolerability-guided dose adjustment might not affect the afatinib efficacy. Afatinib is an irreversible second-generation ErbB family 1. Introduction blocker [6], which has been approved as a first-line treat- Lung cancer is the leading cause of cancer-related deaths and ment for NSCLC patients with EGFR exon 19 deletions or a serious threat to human health [1]. Non-small-cell lung exon 21 L858R substitution mutations [7]. In 2013, afatinib cancer (NSCLC) accounts for more than 80% of lung cancer was approved worldwide as a first-line treatment for patients [2]. Epidermal growth factor receptor (EGFR) mutations with EGFR-mutant NSCLC [5, 8]. )e LUX-Lung 3/6/7 have been identified in approximately 50% of Asian and trials revealed that afatinib had obvious effects in the 10–15% of Caucasian lung adenocarcinoma patients [3, 4]. treatment of advanced EGFR-mutant NSCLC [9–12] and Currently, tyrosine kinase inhibitors (TKIs), including might provide a better curative effect than first-generation erlotinib, gefitinib, dacomitinib, afatinib, and osimertinib, EGFR-TKIs [13]. Moreover, a meta-analysis based on ran- are the standard first-line treatment for advanced NSCLC domized controlled trials (RCTs) has shown that afatinib patients with EGFR mutations [5]. prolonged progression-free survival (PFS), increased overall 2 Journal of Oncology survival (OS), and the overall response rate (ORR) [14]. 2.2. Inclusion and Exclusion Criteria. In the present study, However, whether afatinib is effective in particular sub- the inclusion criteria employed were as follows: (i) the groups remains controversial due to the RCT exclusion subjects were patients with advanced EGFR-mutated criteria [14, 15]. Furthermore, the adverse effects of afatinib NSCLC diagnosed by histology and cytology; (ii) the study limit its clinical application [16]. )us, a dose-adjustment reported the efficacy (ORR, disease control rate (DCR), OS, strategy guided by tolerability can yield clinical benefits PFS, and time to failure (TTF)) or safety (adverse reactions/ based on RCT data [14, 16], which need to be demonstrated serious adverse reactions) of afatinib in the treatment of through real-world evidence (RWE)-based data. NSCLC; (iii) the study reported the difference in efficacy and It is undeniable that the credibility of RCTs can be safety based on different groups, including different afatinib inferred from causality and is thus considered the gold doses (full dose (40 mg/day for 6 months or more) vs. non- standard of clinical research; however, RCTs may not reflect full dose (<40 mg/day for 6 months or 40 mg/day for a real-world practice due to strict inclusion criteria [17]. reduction in the first 6 months)), mutation type (exon 19 Patients in the real-world may differ in numerous charac- deletion vs. uncommon, exon 21 L858R vs. uncommon, exon 19 deletion vs. exon 21 L858R), ECOG-PS (0–1 vs. 2–4), and teristics from those in RCTs. RWE-based studies collect data of patients treated as a whole in clinical practice according to brain metastases; (iv) the research type was RWE. local government regulations, overcoming inherent limita- )e exclusion criteria were as follows: (i) nontreatment tions of RCTs, and can assess the efficacy and safety in- studies, including letters, reviews, and comments; (ii) the formation of patients in the real world [18, 19]. )erefore, it study lacked parameters required for quantitative analysis is crucial to confirm the efficacy and safety of afatinib by (including mean, sample size, standard deviation of the using RWE data. Additionally, a previous study based on experimental group and the control group required for real-world data proved that afatinib dose adjustment de- continuous variable meta-analysis) and could not be ob- creases the intensity and frequency of adverse drug reactions tained through the conversion of other data in the study without affecting the efficacy [20]. Although RWE con- (enrolled as the qualitative description study); (iii) the study tributes to the evaluation of certain clinical influential fac- lacked baseline information such as gender, age, tumor classification, and ECOG-PS, reporting only the efficacy tors, the impact of dose adjustment, brain metastasis, mutation type, and Eastern Cooperative Oncology Group (PFS and TTF) of afatinib (enrolled as the qualitative de- Performance Status (ECOG-PS) on the efficacy and safety of scription study); (iv) the research type was RCT. Further- afatinib remains elusive. more, only one study (containing complete information) Accordingly, we performed a meta-analysis based on was extracted if more than one study was published using the real-world afatinib data in advanced NSCLC with EGFR same data. mutations. To the best of our knowledge, this is the first meta-analysis based on RWE to explore the efficacy and 2.3. Data Extraction and Quality Assessment. In the present safety of afatinib in advanced NSCLC with EGFR mu- study, two independent researchers participated in data tations. In this study, related RWE from Embase, extraction. )e available data included first author name, PubMed, and Cochrane Library databases were analyzed. year of publication, gender, sample size, history, country, Herein, we aimed to comprehensively analyze the efficacy age, stage, ORR, DCR, OS, PFS, TTF, and adverse reactions. and safety of afatinib in NSCLC patients with advanced )e extraction tables were exchanged after both researchers EGFR mutations based on real-world evidence. Fur- had completed the above data extraction work. Any in- thermore, we explored the impact of tolerability-guided consistencies in extracted results were resolved through dose adjustment, brain metastasis, mutation type, and discussion. ECOG-PS. 2.4. Statistical Analysis. STATA software (version 11.0) was 2. Materials and Methods used for statistical analysis. )e incidence rate (IR) and 95% confidence interval (CI) were used as the effect size to )is meta-analysis was performed following the guidelines evaluate the incidence of ORR, DCR, AEs, and SAEs in of the meta-analyses (PRISMA) statement [21]. patients with NSCLC administering afatinib. )e median (95% CI) was used to assess the months of PFS, OS, and TTF, while weighted mean difference (WMD) and 95% CI were 2.1. Data Sources. Relevant studies were searched and identified in electronic databases, including Embase, utilized as combined indices of effect quantity. )e relative risk (RR) and 95% CI were used as the combined indices of PubMed, and Cochrane Library (updated to December 31, 2020). )e main search keywords included “afatinib,” “non- effect quantity to comprehensively evaluate differences in small cell lung cancer,” NSCLC, “lung adenocarcinoma,” ORR, DCR, and incidence of adverse reactions between the and “adenosquamous carcinoma” )e search was performed two groups. Moreover, the risk of OS/PFS was analyzed based on a combination of subject and free words. Addi- using hazard risk (HR) and 95% CI. If the study did not tionally, a manual search of references in identified literature directly report the HR (95% CI) of OS and PFS but reported was performed to obtain additional information regarding the median survival and log-rank P-value in non-full dose vs. full dose of afatinib, the HR (95% CI) could be converted the procedure. No language restrictions were applied to the current meta-analysis. using the method described before [22]. Journal of Oncology 3 Cochran’s Q test and I statistics were used to perform (95% CI [13.6–17.2]). )e difference in TTF between the the heterogeneity analysis [23]. A random-effects model was first-line-only group (15.7 months, 95% CI [13.4, 18.0]) and used if heterogeneity was obtained (P< 0.05, I > 50%); the mixed group (14.4 months, 95% CI [11.5, 17.3]) was not conversely, a fixed-effects model was employed. Moreover, significant (P> 0.05). Seven studies reported the OS out- to assess the effect of the above factors on the combined comes in patients treated with afatinib (Figure 3(c)). )e results of PFS, a subgroup analysis was conducted on PFS heterogeneity test among these seven studies was statistically based on the timing of afatinib administration and data significant (I > 50%, P< 0.05). )e combined median OS sources (direct reports in study or obtained by conversion). was 31.6 months (95% CI [26.7–36.5]). Furthermore, a sensitivity analysis was undertaken to assess In total, 12 studies reported the incidence of diarrhea, the effect of combined results by analyzing the relevant mucositis, and skin rashes and 10 studies reported the total studies individually. Finally, the Egger test [24] was used to incidence of paronychia, including any grade (Figures 4(a)– analyze publication bias between the two groups. 4(d)) and Grade ≥3 (Figures 5(a)–5(d)), respectively. )e results revealed that the most common AEs were diarrhea, mucositis, skin rashes, and paronychia, with an incidence of 3. Results 70.4% (95% CI [60.1%, 79.8%]) (Figure 4(a)), 36.5% (95% CI 3.1. Literature Review and Characteristics of Included Studies. [29.5%, 43.8%]) (Figure 4(b)), 71.4% (95% CI [64.4%, In total, 994, 990, and 281 studies were explored in the 77.9%]) (Figure 4(c)), and 52.1% (95% CI [41.9%, 62.3%]) Embase, PubMed, and Cochrane Library databases, re- (Figure 4(d)), respectively. Meanwhile, the incidences of spectively (Figure 1). After eliminating duplicate studies, a common SAEs (Grade ≥3) for diarrhea, mucositis, skin total of 1525 studies were obtained, with 1479 studies further rashes, and paronychia were 9.7% (95% CI [6.8%, 13.1%]) excluded as these failed to meet the inclusion criteria after (Figure 5(a)), 2.1% (95% CI [1.0%, 3.6%]) (Figure 5(b)), 5.8% assessing the abstract and title. Among the remaining 46 (95% CI [4.5%, 7.2%]) (Figure 5(c)), and 3.8% (95% CI studies, 12 relevant studies were identified after reading the [2.0%, 6.2%]) (Figure 5(d)), respectively. full text. Manual retrieval did not detect any study that could Additionally, the total incidence of fatigue was 15.1% be included in the current analysis. Finally, a total of 25 (95% CI [4.1, 30.9], Supplementary Figure 1A) and the studies [20, 25–33] with sufficient data were included (Ta- incidence of severe fatigue was 0.8% (95% CI [0.0, 2.2], ble 1). A total of nine studies [34–41] were included in the Supplementary Figure 2A). )e total and severe alanine current qualitative descriptive analysis (Table 2). aminotransferase (ALT) levels elevated were 8.3% (95% CI [0.0%, 31.0%]) (Supplementary Figure 1B) and 0.7% (95% CI [0.0%, 2.3%]) (Supplementary Figure 2B), respectively. )e 3.2. Study Characteristics. )e 25 enrolled studies were incidence of total and severe aspartate aminotransferase published between 2014 and 2020. )e study areas were (AST) levels elevated was 6.2% (95% CI [0.0%, 34.3%]) primarily in Asia. Moreover, 19, 1, and 5 studies were en- (Supplementary Figure 1C) and 0.3% (95% CI [0.0%, 1.5%]) rolled in first-line, second-line, and mixed population (Supplementary Figure 2C), respectively. )e incidence of groups, respectively. total and severe interstitial lung disease (ILD) was 1.1% (95% CI [0.1%, 2.9%]) (Supplementary Figure 1D) and 0.7% (95% 3.3.Meta-AnalysisforEfficacyandSafetyofAfatinibBasedon CI [0.0%, 2.3%]) (Supplementary Figure 2D), respectively. RWE. A total of 15 studies presented the outcomes of DCR Finally, except for skin rashes and fatigue, significant het- (Figure 2(a)) and ORR (Figure 2(b)). Among these 15 erogeneity was observed among all studies that contained 2 2 studies, the heterogeneity was statistically significant (I other indicators (I > 50%, P< 0.05). 50%, P< 0.001), and the combined result of DCR was 87.6% (95% CI [81.5%, 92.7%]), and the difference between the 3.4. Effect of Tolerability-Guided Afatinib Dose Adjustment. first-line-only group (90.8%; 95% CI [86.2%, 94.6%]) and second-line group (74.8%; 95% CI [52.5%, 92.0%]) was not Compared with the full dose of 40 mg/day, 57.8% (1917/ 3319) patients administered non-full dose of afatinib (Ta- significant (P> 0.05). )e combined ORR was 58.9% (95% CI [48.8%, 68.7%]). )e difference in ORR between the first- ble 1). Seven studies (8 sets of research data) reported PFS between the non-full-dose and full-dose groups line-only group (70.8%; 95% CI [67.2%, 74.3%]) and second- line group (22.7%; 95% CI [16.8%, 40.2%]) was significant (Figure 6(a)). Among them, HRs (95% CI) in four studies (five sets of data) were obtained by conversion. )e het- (P< 0.05). Moreover, a total of 12 studies indicated the PFS out- erogeneity for these data was not significant (I < 0.0%, P> 0.05). For the combined results, the HR was 1.2 (95% CI comes of afatinib (Figure 3(a)), and the heterogeneity was [0.9, 1.5]; P> 0.05) (Table 3, Figure 6(a)), which indicated statistically significant (I > 50%, P< 0.05). )e combined median PFS was 12.4 months (95% CI [10.3, 14.5]). For PFS, that dose reduction does not impact the therapeutic efficacy in terms of PFS. )e PFS of the non-full-dose group was the difference between the first-line-only group (13.6 months; 95% CI [12.4, 14.7]) and second-line group (6.1 5.0–14.2 months, while the PFS in the full-dose group was 3.0–15.7 months. For the combined results, the WMD was months; 95% CI [2.3, 9.9]) was significant (P< 0.05). Fur- thermore, four studies reported TTF outcomes (Figure 3(b)). −1.6 months (95% CI [−5.7, 2.5]) (Figure 6(b)). Two studies reported the difference in OS risk between the non-full-dose )e heterogeneity was statistically significant (I > 50%, P< 0.05), and the combined median TTF was 15.4 months and full-dose groups (Figure 6(c)). )e result of the 4 Journal of Oncology Records identified through database (n=2215) PubMed (n=990), Embase (n=944), The Cochrane library (n=281) Records after duplicates removed (n = 1525) Records screened Records excluded (n = 1479) title/abstract (n = 1525) Full-text articles excluded with Full-text articles assessed reasons (n = 12) 6 without interested outcomes; for eligibility (n = 46) 5 RCTs; 1 Review. Studies included in Articles excluded with reasons quantitative synthesis (n = 9) (meta-analysis) 9 without available data for (n = 34) meta-analyses. Studies included in quantitative synthesis (meta-analysis) (n = 25) Figure 1: Flow diagram of the screening process for eligible studies. heterogeneity test indicated that the heterogeneity between Two studies reported differences in total AEs based on the two groups was not significant (I < 0.0%, P> 0.05); thus, the full-dose and non-full-dose groups. Significant het- for the combined result, the HR was 1.03 (95% CI [0.69, 1.5]; erogeneity in the total AEs was observed in diarrhea and P> 0.05), which indicated that dose reduction did not affect skin rashes (I > 50.0%; P< 0.05) but was not observed in the therapeutic efficacy in terms of OS. mucositis and paronychia (I > 50.0%, P< 0.05) )ree studies reported the difference between DCR and (Figure 8(a)). )e heterogeneity of diarrhea, skin rashes, ORR based on different afatinib doses. )e heterogeneity of and paronychia (Grade ≥3) was not significant (I > 50.0%, DCR in these studies was significant (I > 50%, P> 0.05). )e P< 0.05) (Figure 8(b)). )e incidence of total AEs and non-full-dose group (95.1% [88.0%, 99.4%]) presented a SAEs, including diarrhea, skin rash, mucositis, paronychia, DCR similar to the full-dose group [95.6% (90.3, 99.1%)]. dry skin, and pruritus, showed a decreased trend in the For the combined results, the RR was 0.9 (95% CI [0.8, 1.0]; non-full-dose group (Table 4), which indicated the toler- P> 0.05) (Figure 7(a)). Moreover, the results of the het- ability-guided dose adjustment alleviated afatinib-related erogeneity test for ORR were I < 50% and P> 0.05. )e adverse effects. non-full-dose group (67.8 [56.8%, 77.9%]) presented a significantly lower ORR than the full-dose group (78.5 3.5. Effect of Subgroup on Efficacy and Safety of Afatinib. [66.7%, 88.4%]). For the combined results, the RR was 0.8 (95% CI [0.7, 0.9]; P> 0.05) (Figure 7(b)). Although the Two studies reported differences in the DCR and ORR in brain metastases. )e DCRs in the without metastases group difference in PFS and OS was not significant, the ORR was and the brain metastases group were 94.6% (91.3%, 97.3%) significantly higher in the full-dose group compared with the non-full-dose group. and 89.1% (82.2%, 94.6%), respectively. )e ORRs in the Included Eligibility Screening Identification Journal of Oncology 5 Table 1: Characteristics of 25 included studies in this meta-analysis. Age, years, ECOG- Dose Female, Clinical Study Area Afatinib N median Mutations PS, 0–1/ Histology reduce, n (%) stage (range) ≧2 no/yes Brat, K First-line 12 IIIB, 135 Czech 147 96 (65.3) 62.8± 11.1 EGFR mutation 147/0 145 AD, 2 other NR/NR 2020 only IV 17 Del19, 4 Chen YH, First-line Taiwan 23 15 (65.2) 42–81 L858R, 2 23 advanced NR NR NR/NR 2019 only uncommon del Re M, First-line 34 Del19, 7 Italy 41 20 (48.8) 70.5± 11.3 2 IIIB, 39 IV NR NR 26/15 2019 only L858R Halmos B, First-line 138 67.0 178 Del19, 49 12 IIIB, 216 192/27 (9 226 AD, 1 SCC, Global 228 51/173 2019 only (60.5) (32.0–90.0) L858R IV missing) 1 NOS 68 Del19, 11 Ho GF, First-line Malaysia 85 47 (55.3) 59.1± 10.8 L858R, 6 4 IIIB, 81 IV 69/16 82 AD, 3 SCC 49/26 2019 only uncommon Hsieh YY, First-line 424 43 IIIB, 708 735 AD, 16 Taiwan 751 62.5± 11.2 EGFR mutation 678/73 NR/NR 2019 only (56.5) IV other Igawa S, First-line 29 Del19, 19 36 IV, 12 Japan 48 27 (56) 67 (35–85) 24/24 NR 21/27 2020 only L858R recurrence 141 Del19, 47 39 IA-IIIA, Ito K, 102 203/12 (3 208 AD, 10 Japan Mixed 218 64.3 (34–87) L858R, 30 11 IIIB, 168 NR/NR 2020 (46.8) missing) non-AD uncommon IV Second- 15 Del19, 13 58 AD, 1 SCC, 2 Kan F, United 50/12 (1 line or 63 37 (58.7) 64 (29–83) L858R, 4 63 IV NOS, 1 large 33/31 2014 Kingdom missing) more uncommon cell, 1 unknown 114 Del19, 37 Kim, Y First-line Korea 165 80 (48.5) 57 (30–79) L858R, 14 165 IV 156/9 NR 53/112 2019 only uncommon 41 Del19, 20 Lau SC, First-line Canada 70 44 (63) 62 (34–84) L858R, 9 70 advanced 68/2 66 AD, 4 other NR/NR 2019 only uncommon Li YL, First-line 52 Del19, 35 31/10 (46 USA 87 62 (71.3) 69 (62–81) 2 IIIB, 85 IV 86 AD, 1 SCC NR/NR 2019 only L858R missing) 81 Del19, 24 Liang SK, First-line 4 IIIB, 136 Taiwan 140 87 (62.1) 61 (28–87) L858R, 35 129/11 140 AD 81/59 2017 only IV uncommon 151 Del19, 53 Liang SK, First-line 157 259 Taiwan 259 62 (28–87) L858R, 55 240/19 259 AD 139/120 2018 only (60.6) advanced uncommon 59 Del19, 23 Lin YT, First-line 60 (53–71) 95 AD, 4 non- Taiwan 99 61 (61.6) L858R, 13 99 advanced 92/7 NR/NR only IQR AD uncommon 73 Del19, 61 Liu CY, First-line 16 IIIB, 130 Taiwan 146 78 (53.4) 63.2± 11.3 L858R, 12 123/23 146 AD 79/67 2017 only IV uncommon Shen YC, First-line Taiwan 24 15 (62.5) 59 (33–86) 24 uncommon 1 IIIB, 23 IV 19/5 24 AD 24/NR 2017 only 5 I-IIIA, 5 42 Del19, 15 Sonehara First-line IIIB, 40 IV, 61 AD, 1 Japan 62 36 (58.1) 67 (46–85) L858R, 3 57/5 23/39 K, 2019 only 13 unclassified uncommon recurrence 1554 AD, 14 94 IIIB, 1206 1020 Del19, 421 SCC, 2 NOS, 1 Tamura K, 947 IV, other 580/ Japan Mixed 1602 67 (34–90) L858R, 137 1381/221 large cell, 32 2019 (59.1) 301, 1 1008 uncommon others, 1 missing unknown 87 Del19, 27 Tan WL, First-line 121 AD, 1 SCC, Singapore 125 61 (48.8) 62 (26–86) L858R, 11 125 IV NR 62/62 2018 only 3 NOS uncommon 6 Journal of Oncology Table 1: Continued. Age, years, ECOG- Dose Female, Clinical Study Area Afatinib N median Mutations PS, 0–1/ Histology reduce, n (%) stage (range) ≧2 no/yes 46 Del19, 28 9 IIIB, 45 IV, First-line 74 AD, 1 SCC, 1 76 52 (68.4) 68 (42–88) L858R, 2 22 67/9 18/58 only NOS Tanaka H, uncommon recurrence Japan 2019 Second- 29 Del19, 21 line or 52 41 (78.9) 65 (39–90) L858R, 2 46/6 51 AD, 1 SCC NR/NR recurrence more uncommon 58< 65 58 Del19, 23 Tu CY, First-line years/ 3 IIIB, 101 Taiwan 104 65 (62.5) L858R, 23 93/11 104 AD 67/31 2018 only 46> 65 IV uncommon years 44 Del19, 20 1 IIIA, 6 Wada Y, L858R, 5 IIIB, 44 IV, Japan Mixed 73 46 (63.0) 69 (42–85) 56/17 75 AD 36/37 2016 uncommon, 4 22 unknown recurrence 26 Del19, 16 58.1 Mixed 60 30 (50.0) L858R, 18 60 advanced 60/0 60 AD 37/23 (36.3–82.7) Uncommon 19 Del19, 7 Wang S, First-line 57.2 China 39 23 (59.0) L858R, 13 39 advanced 39/0 39 AD NR/NR 2019 only (36.3–82.7) uncommon Second- 7 Del19, 9 59.9 line or 21 7 (33.3) L858R, 5 21 advanced 21/0 21 AD NR/NR (39.7–75.5) more uncommon Yang CJ, First-line 29 Del19, 19 Taiwan 48 30 (62.5) 64.6± 8.9 48 IV 38/10 48 AD 19/29 2017 only L858R NR, not reported; AD, adenocarcinoma; SCC, squamous cell carcinoma; NOS, not otherwise specified; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; IQR, interquartile range. Table 2: Characteristics of 9 studies in qualitative analysis. Female, n Age, years, ECOG-PS, Study Area Afatinib N Mutations Clinical stage Histology (%) median (range) 0–1/≥2 First-line 8 IIIA, 3 IIIB, 16 23 AD, 3 Fujiwara A Japan 28 19 (67.9) 68 (37–82) EGFR mutation NR 2018 only IV, 1 recurrence SCC, 2 other 150 Del19, 53 Hochmair First-line 153/31 (20 Global 204 110 (53.9) 60 (30–86) L858R, 1 197 IV, 7 missing NR MJ, 2018 only missing) uncommon Jung HA, First-line Uncommon EGFR Korea 61 NR NR NR NR NR 2020 only mutation Kanazu M, Uncommon EGFR Japan Mixed 12 NR NR 12 advanced NR NR 2020 mutation Kuan FC, First-line Taiwan 81 42 (51.9) 64 (37–83) 48 Del19, 33 L858R 7 IIIB, 74 IV 70/11 81 AD 2017 only First-line Lim, J 2019 USA 550 355 (64.5) 63.3± 11.4 EGFR mutation NR NR NR only 53 Del19, 31 First-line 96 AD, 3 Su VY, 2020 Taiwan 99 52 (52.5) 64.1± 10.8 L858R, 15 4 IIIB, 95 IV 89/10 only non-AD uncommon Wu SG, 2020 First-line 68.7 32 IV, 4 Taiwan 36 27 (75) 36 uncommon 32/4 36 AD (a) only (43.0–86.1) recurrence 59 Del19, 21 Wu SG, 2020 First-line 83 advanced, 8 Taiwan 91 44 (48.4) 63 (37–83) L858R, 11 NR 91 AD (b) only recurrence uncommon Notes: NR, not reported; AD, adenocarcinoma; SCC, squamous cell carcinoma; ECOG-PS, Eastern Cooperative Oncology Group Performance Status. without metastases group and the brain metastases group 1.0, 95% CI [0.9, 1.1]; P> 0.05) and ORR (RR: 2.0, 95% CI were 74.9% (95% CI [69.1%, 80.2%]) and 61.8% (95% CI [0.5, 7.6]; P> 0.05) (Figures 9(a) and 9(b)) were not [52.2%, 71.0%]), respectively. )e differences in DCR (RR: significant. Journal of Oncology 7 Study Area IR (95% CI) Weight First–line only Chen, YH 2019 Taiwan 0.826 (0.612, 0.950) 4.97 Ho GF, 2019 Malaysia 0.953 (0.884, 0.987) 6.42 Igawa S, 2020 Japan 0.854 (0.722, 0.939) 5.92 Liang SK, 2017 Taiwan 0.936 (0.881, 0.970) 6.71 Liang SK, 2018 Taiwan 0.927 (0.888, 0.955) 6.93 Liu CY, 2017 Taiwan 0.925 (0.869, 0.962) 6.73 Shen YC, 2017 Taiwan 0.625 (0.406, 0.812) 5.03 Sonehara K, 2019 Japan 0.887 (0.781, 0.953) 6.17 Tan WL, 2018 Singapore 0.776 (0.693, 0.846) 6.65 Tanaka H, 2019 (a) Japan 0.855 (0.756, 0.925) 6.34 Wad a Y, 2016 (a) Japan 1.000 (0.692, 1.000) 3.59 Wang S, 2019 (a) China 0.974 (0.865, 0.999) 5.69 Yang CJ, 2017 Taiwan 5.92 1.000 (0.926, 1.000) Subtotal (I = 78.115%, p = 0.000) 0.908 (0.862, 0.946) 77.07 Second–line or more Kan F, 2014 United Kingdom 0.444 (0.319, 0.575) 6.18 Tanaka H, 2019 (b) Japan 0.808 (0.675, 0.904) 6.00 Japan 0.854 (0.722, 0.939) 5.92 Wada Y, 2016 (b) Wang S, 2019 (b) China 0.857 (0.637, 0.970) 4.83 Subtotal (I = 89.561%, p = 0.000) 0.748 (0.525, 0.920) 22.93 Heterogeneity between groups: p = 0.085 Overall (I = 87.168%, p = 0.000) 0.876 (0.815, 0.927) 100.00 0 .2 .4 .6 .8 1 (a) Study Area IR (95% CI) Weight First–line only Taiwan 0.739 (0.516, 0.898) 4.98 Chen, YH 2019 Malaysia 0.765 (0.660, 0.850) 5.85 Ho GF, 2019 Igawa S, 2020 Japan 0.625 (0.474, 0.760) 5.57 Liang SK, 2017 0.671 (0.587, 0.748) 6.00 Taiwan Liang SK, 2018 0.695 (0.635, 0.750) 6.12 Taiwan Liu CY, 2017 Taiwan 0.719 (0.639, 0.790) 6.01 Shen YC, 2017 Taiwan 0.625 (0.406, 0.812) 5.02 0.806 (0.686, 0.896) 5.71 Sonehara K, 2019 Japan Tan WL, 2018 Singapore 0.704 (0.616, 0.782) 5.97 Tanaka H, 2019 (a) Japan 0.645 (0.527, 0.751) 5.80 Japan 0.800 (0.444, 0.975) 3.97 Wada Y, 2016 (a) Wang S. 2019 (a) China 0.564 (0.396, 0.722) 5.43 Yang CJ, 2017 Taiwan 0.833 (0.698, 0.925) 5.57 Subtotal (I = 29.840%, p = 0.146) 0.708 (0.672, 0.743) 71.98 Second–line or more Kan F, 2014 United Kingdom 5.72 0.143 (0.067, 0.254) Tamura K, 2019 Japan 0.401 (0.377, 0.425) 6.24 0.250 (0.140, 0.389) 5.61 Tanaka H, 2019 (b) Japan Japan 5.57 Wada Y, 2016 (b) 0.271 (0.153, 0.418) Wang S, 2019 (b) China 4.88 0.333 (0.146, 0.570) Subtotal (I = 85.532%, p = 0.000) 0.277 (0.168, 0.402) 28.02 Heterogeneity between groups: p = 0.000 Overall (I = 94.936%, p = 0.000) 0.589 (0.488, 0.687) 100.00 0 .2 .4 .6 .8 1 (b) Figure 2: )e meta-analysis results of afatinib efficacy and safety in advanced NSCLC with EGFR mutation: (a) the outcome of disease control rates (DCRs) and (b) the outcome of objective response rates (ORRs). 8 Journal of Oncology Study Area Median (95% CI) Weight First-line only Czech Brat, K 2020 13.10 (11.40, 18.20) 8.15 Chen, YH 2019 Taiwan 10.40 (7.50, 17.20) 6.66 Malaysia 14.20 (11.85, 16.55) 9.18 Ho GF, 2019 Igawa S, 2020 14.10 (7.70, 20.50) 5.26 Japan Korea 19.10 (12.30, 25.90) Kim, Y 2019 4.95 Taiwan 9.72 Liang SK, 2018 12.80 (11.10, 14.50) Lin YT, 2019 Taiwan 12.40 (9.80, 15.00) 8.95 Sonehara K, 2019 Japan 15.70 (11.90, 19.50) 7.73 Tan WL, 2018 Singapore 11.90 (10.30, 19.30) 7.01 Tanaka H, 2019 Japan 7.63 17.80 (13.70, 21.50) Wang S, 2019 (a) China 12.30 (7.60, 17,00) 6.81 Subtotal (I = 20.9%, p = 0.245) 13.61 (12.44, 14.77) 82.06 Second-line or more Tanaka H, 2019 Japan 8.00 (4.90, 9.50) 9.23 Wang S, 2019 (b) 4.10 (1.30, 7.00) 8.71 China 6.14 (2,33, 9.96) Subtotal (I = 77.0%, p = 0.037) 17.94 Overall (I = 80.9%, p = 0.000) 12.45 (10.36, 14.54) 100.00 NOTE: Weights are from random effects analysis 0 10 20 30 (a) Study Area Median (95% CI) Weight First–line only 13 countries 18.70 (15.10, 21.50) Halmos B, 2019 17.82 Hsieh, YY 2019 Taiwan 15.80 (14.50, 17.00) 34.23 28.12 Lin YT, 2019 Taiwan 13.60 (11.70, 15.50) Subtotal (I = 74.7%, p = 0.019) 15.73 (13.45, 18.01) 80.17 Mixed Ito K, 2020 Japan 14.40 (11.40, 17.20) 19.83 Subtotal (I = .%, p = .) 14.40 (11.50, 17.30) 19.83 100.00 Overall (I = 64.2%, p = 0.039) 15.42 (13.62, 17.22) NOTE: Weights are from random effects analysis 010 20 (b) Figure 3: Continued. Journal of Oncology 9 Study Area Afatinib Median (95% CI) Weight Czech First–line only 14.68 Brat, K 2020 29.30 (20.90, 38.60) Chen, YH 2019 Taiwan 23.59 First–line only 29.60 (24.80, 33.00) Ho GF, 2019 28.90 (19.82, 37.99) 14.31 Malaysia First–line only 48.30 (31.40, 65.20) Japan First–line only 6.46 Igawa S, 2020 Lau SC, 2019 39.00 (25.60, 48.80) 10.92 Canada First–line only Li YL, 2019 First–line only 20.70 (16.20, 35.10) 13.76 USA Lin YT, 2019 Taiwan First–line only 16.27 37.00 (25.10, 40.90) Overall (I = 55.2%, p = 0.037) 100.00 31.67 (26.78, 36.56) NOTE: Weights are from random effects analysis 0 20 40 60 (c) Figure 3: )e meta-analysis results of afatinib efficacy and safety in advanced NSCLC with EGFR mutation: (a) the outcome of progression- free survival (PFS); (b) the outcome for overall survival (OS); and (c) the outcome for time to failure (TTF). Study Study Area IR (95% CI) Area IR (95% CI) Weight Weight Halmos B, 2019 Global 0.750 (0.689, 0.805) 8.12 Halmos B, 2019 Global 0.342 (0.281, 0.408) 8.61 Ho GF, 2019 Malaysia 0.541 (0.430, 0.650) 7.73 Ho GF, 2019 Malaysia 0.271 (0.180, 0.378) 7.74 Igawa S, 2020 Japan 0.479 (0.333, 0.628) 7.31 Igawa S, 2020 Japan 0.313 (0.187, 0.463) 6.89 Kan F, 2014 United Kingdom 0.730 (0.603, 0.834) 7.53 Kan F, 2014 United Kingdom 0.143 (0.067, 0.254) 7.33 Kim, Y 2019 Korea 0.230 (0.168, 0.302) 8.03 Kim, Y 2019 Korea 0.303 (0.234, 0.379) 8.40 Liu CY, 2017 Taiwan 0.726 (0.646, 0.797) 7.98 Liu CY, 2017 Taiwan 0.452 (0.370, 0.536) 8.30 Sonehara K, 2019 Japan 0.823 (0.705, 0.908) 7.52 Sonehara K, 2019 Japan 0.548 (0.417, 0.675) 7.31 Tamura K, 2019 Japan 0.785 (0.764, 0.805) 8.33 Tamura K, 2019 Japan 0.320 (0.297, 0.343) 9.14 Tanaka H, 2019 Japan 0.882 (0.787, 0.944) 7.66 Tanaka H, 2019 Japan 0.645 (0.527, 0.751) 7.60 Tanaka H, 2019 Japan 0.423 (0.287, 0.568) Tanaka H, 2019 Japan 0.827 (0.697, 0.918) 7.38 7.03 Wada Y, 2016 Japan 0.164 (0.088, 0.270) 7.54 Wada Y, 2016 Japan 0.767 (0.654, 0.858) 7.64 Wang S, 2019 China 0.707 (0.573, 0.819) 7.21 Wang S, 2019 China 0.862 (0.746, 0.939) 7.47 Yang CJ, 2017 Taiwan 0.208 (0.105, 0.350) 6.89 Yang CJ, 2017 Taiwan 0.646 (0.495, 0.778) 7.31 Overall (I = 89.688%, p = 0.000) 0.365 (0.295, 0.438) 100.00 Overall (I = 95.319%, p = 0.000) 0.704 (0.601, 0.798) 100.00 0.2 .4 .6 .81 0 .2.4.6.8 1 (a) (b) % % Study Area IR (95% CI) Study Area IR (95% CI) Weight Weight Halmos B, 2019 Global 0.557 (0.490, 0.623) 8.60 0.487 (0.420, 0.554) 9.84 Halmos B, 2019 Global Ho GF, 2019 Malaysia 0.706 (0.597, 0.800) 7.74 0.400 (0.295, 0.512) 9.22 Ho GF, 2019 Malaysia Igawa S, 2020 Japan 0.750 (0.604, 0.864) 6.91 0.458 (0.314, 0.608) 8.56 Igawa S, 2020 Japan Kan F, 2014 United Kingdom 0.667 (0.537, 0.780) 7.34 Kim, Y 2019 Korea 0.291 (0.223, 0.367) 9.69 Kim, Y 2019 Korea 0.479 (0.401, 0.558) 8.39 Liu CY, 2017 Taiwan 0.644 (0.560, 0.721) 9.62 Liu CY, 2017 Taiwan 0.753 (0.675, 0.821) 8.29 Sonehara K, 2019 Japan 0.565 (0.433, 0.690) 8.89 Sonehara K, 2019 Japan 0.806 (0.686, 0.896) 7.31 Tanaka H, 2019 Japan 0.711 (0.595, 0.809) 9.11 Tamura K, 2019 Japan 0.586 (0.561, 0.610) 9.11 Tanaka H, 2019 Japan 0.731 (0.590, 0.844) 8.67 Tanaka H, 2019 Japan 0.868 (0.771, 0.935) 7.60 0.247 (0.153, 0.361) 9.07 Wada Y, 2016 Japan Tanaka H, 2019 Japan 0.846 (0.719, 0.931) 7.04 0.724 (0.591, 0.833) 8.80 Wang S, 2019 China Wada Y, 2016 Japan 0.589 (0.468, 0.703) 7.55 Yang CJ, 2017 Taiwan 0.500 (0.352, 0.648) 8.56 Wang S, 2019 China 0.828 (0.706, 0.914) 7.21 Overall (I = 90.529%, p = 0.000) 0.521 (0.419, 0.623) 100.00 Yang CJ, 2017 Taiwan 0.854 (0.722, 0.939) 6.91 0.714 (0.644, 0.779) 100.00 Overall (I = 89.840%, p = 0.000) 0 .2.4.6.8 1 0.2 .4 .6 .81 (c) (d) Figure 4: )e meta-analysis results for various incidence rates after afatinib treatment in advanced NSCLC with EGFR mutation: (a) the incidence rate of diarrhea; (b) the incidence rate of mucositis; (c) the incidence rate of skin rashes; and (d) the incidence rate of paronychia. 10 Journal of Oncology % % Study Area IR (95% CI) Study Area IR (95% CI) Weight Weight 0.057 (0.031, 0.096) 10.89 Halmos B, 2019 Global Halmos B, 2019 Global 0.092 (0.058, 0.137) 9.62 0.024 (0.003, 0.082) 7.35 Malaysia Ho GF, 2019 Ho GF, 2019 Malaysia 0.047 (0.013, 0.116) 7.66 0.021 (0.001, 0.111) 5.27 Igawa S, 2020 Japan Igawa S, 2020 Japan 0.146 (0.061, 0.278) 6.14 Kan F, 2014 United Kingdom 0.016 (0.000, 0.085) 6.23 Kan F, 2014 United Kingdom 0.143 (0.067, 0.254) 6.89 0.000 (0.000, 0.022) 9.81 Kim, Y 2019 Korea Kim, Y 2019 Korea 0.036 (0.013, 0.077) 9.09 0.048 (0.019, 0.096) 9.38 Liu CY, 2017 Taiwan Sonehara K, 2019 Japan 0.065 (0.018, 0.157) 6.17 Liu CY, 2017 Taiwan 0.082 (0.043, 0.139) 8.86 Japan 0.039 (0.030, 0.049) 14.44 Tamura K, 2019 Sonehara K, 2019 Japan 0.242 (0.142, 0.367) 6.85 Japan 0.026 (0.003, 0.092) 6.93 Tanaka H, 2019 0.151 (0.134, 0.170) 11.06 Tamura K, 2019 Japan Japan 0.000 (0.000, 0.068) 5.54 Tanaka H, 2019 Tanaka H, 2019 Japan 0.079 (0.030, 0.164) 7.38 0.027 (0.003, 0.095) 6.78 Wada Y, 2016 Japan Tanaka H, 2019 Japan 0.135 (0.056, 0.258) 6.37 0.000 (0.000, 0.062) 5.93 Wang S, 2019 China Wada Y, 2016 Japan 0.082 (0.031, 0.170) 728 Yang CJ, 2017 Taiwan 0.000 (0.000, 0.074) 5.27 Wang S, 2019 China 0.103 (0.039, 0.212) 6.67 0.021 (0.010, 0.036) 100.00 Overall (I = 60.806%, p = 0.002) Yang CJ, 2017 Taiwan 0.021 (0.001, 0.111) 6.14 Overall (I = 77.684%, p = 0.000) 0.097 (0.068, 0.131) 100.00 0.2 .4 0 .2 .4 (a) (b) % % Study Area IR (95% CI) Study Area IR (95% CI) Weight Weight Halmos B, 2019 Global 0.035 (0.015, 0.068) 12.48 Halmos B, 2019 Global 0.083 (0.051, 0.127) 12.31 Malaysia Ho GF, 2019 0.035 (0.007, 0.100) 9.33 Ho GF, 2019 Malaysia 0.059 (0.019, 0.132) 5.85 Igawa S, 2020 Japan 0.042 (0.005, 0.143) 7.14 Igawa S, 2020 Japan 0.083 (0.023, 0.200) 3.56 Korea Kim, Y 2019 0.024 (0.007, 0.061) 11.59 Kan F, 2014 United Kingdom 0.079 (0.026, 0.176) 4.53 Liu CY, 2017 Taiwan 0.116 (0.069, 0.180) 11.22 Kim, Y 2019 Korea 0.018 (0.004, 0.052) 9.83 Sonehara K, 2019 Japan 0.097 (0.036, 0.199) 8.13 Liu CY, 2017 Taiwan 0.055 (0.024, 0.105) 8.98 Tanaka H, 2019 Japan 0.013 (0.000, 0.071) 8.91 Sonehara K, 2019 0.081 (0.027, 0.178) Japan 4.47 Tanaka H, 2019 Japan 0.000 (0.000, 0.068) 7.44 Tamura K, 2019 Japan 0.058 (0.047, 0.071) 28.41 Wada Y, 2016 Japan 0.014 (0.000, 0.074) 8.76 Tanaka H, 2019 Japan 0.118 (0.056, 0.213) 5.32 Wang S, 2019 China 0.034 (0.004, 0.119) 7.87 Tanaka H, 2019 Japan 0.038 (0.005, 0,132) 3.83 Yang CJ, 2017 7.14 Taiwan 0.083 (0.023, 0.200) Wada Y, 2016 0.068 (0.023, 0.153) 5.14 Japan Overall (I = 61.354%, p = 0.004) 0.038 (0.020, 0.062) 100.00 Wang S, 2019 China 0.034 (0.004, 0.119) 4.21 Yang CJ, 2017 Taiwan 0.063 (0.013, 0.172) 3.56 Overall (I = 24.285%, p = 0.198) 0.058 (0.045, 0.072) 100.00 0.2 .4 0 .2 .4 (c) (d) Figure 5: )e meta-analysis results for serious adverse reaction incidence rates after afatinib treatment in advanced NSCLC with EGFR mutation: (a) the adverse reaction incidence rate of diarrhea; (b) the adverse reaction incidence rate of mucositis; (c) the adverse reaction incidence rate of skin rashes; and (d) the adverse reaction incidence rate of paronychia. Furthermore, two studies reported differences in DCR/ exon 19 deletion group was undoubtedly higher than that in ORR between mutation types. )e DCRs in the exon 19 the uncommon mutation group (HR: 0.2, 95% CI [0.1, 0.4]; deletion group, exon 21 L858R group, and uncommon group P< 0.05), and PFS in patients without brain metastasis was were 94.0% (95% CI [89.4, 97.4%]), 92.7% (95% CI [80.5%, significantly lower than that in patients with brain metastasis 99.7%]), and 92.8% (95% CI [97.2%, 100.0%]), respectively. (HR: 0.5; 95% CI [0.4, 0.8]; P< 0.05) (Supplementary Figure 3B). No significant difference was observed in ECOG- )e differences in DCR in the exon 19 deletion vs. un- common group (RR: 1.1, 95% CI [0.9, 1.2]; P> 0.05) and PS (0–1) vs. ECOG-PS (≥2) (HR: 0.3, 95% CI [0.1, 1.4]; exon 21 L858R vs. uncommon group (RR: 1.1, 95% CI [0.9, P> 0.05) (Supplementary Figure 3B). However, the het- 1.3]; P> 0.05) were not significant (Figure 9(c)). )e ORRs erogeneity between the two studies was significant in the exon 19 deletion group, exon 21 L858R group, and (I � 59.4%) (Figure 6(c)). uncommon group were 71.9% (95% CI [64.3%, 78.9%]), 69.1% (95% CI [55.2%, 84.0%]), and 59.9% (95% CI [41.3%, 3.6. Sensitivity Analysis and Publication Bias. Publication 77.4%]), respectively. )e differences in ORR in the exon 19 deletion vs. uncommon group (RR: 1.3, 95% CI [0.9, 1.9], bias and sensitivity analyses were performed on the study outcomes. )e sensitivity analysis results revealed that none P> 0.05) and exon 21 L858R vs. uncommon group (RR: 1.3, 95% CI [0.9, 2.0]; P> 0.05) were not significant of the included studies had a noticeable influence on the combined result of PFS between the full-dose and the non- (Figure 9(d)). Moreover, two studies reported PFS in patients with full-dose groups. )e combined results of PFS ranged from brain metastases based on the full-dose and non-full-dose HR: 1.1 (95% CI [0.8, 1.4]) to HR: 1.3 (95% CI [0.9, 1.7]) (P> 0.05) following removal of any single study. Further- groups (Supplementary Figure 3A). For the combined re- sults, the HR was 2.4 (95% CI [0.9, 5.9]; P> 0.05). Fur- more, the Egger test showed that publication bias in the current meta-analysis was not significant (P> 0.05). thermore, the combined results showed that the PFS in the Journal of Oncology 11 % % Study Area WMD (95% CI) Study Area HR (95% CI) Weight Weight 32.12 Liang SK, 2018 Taiwan −0.70 (−4.10, 2.70) Liang SK, 2017 Taiwan 1.19 (0.76, 1.89) 25.58 Liang SK, 2018 Taiwan 1.05 (0.56, 1.96) 13.53 Sonehara K, 2019 Japan −1.50 (−10.28, 7.28) 14.58 Sonehara K, 2019 Japan 0.49 1.11 (0.04, 28.97) Wang S, 2019 (a) China −9.30 (−16.06, −2.54) 19.74 Tan WL, 2018 Singapore 1.59 (0.90, 2.78) 16.69 Wang S, 2019 (b) China 2.00 (−1.04, 5.04) 33.56 Tu CY, 2018 Taiwan 1.02 (0.68, 1.52) 32.82 Overall (I = 67.2%, p =0.028) −1.61 (−5.79, 2.57) 100.00 Wang S, 2019 (a) China 2.78 (0.82, 9.09) 3.67 Wang S, 2019 (b) China 0.60 (0.19, 1.85) 4.10 NOTE: Weights are from random effects analysis Yang CJ, 2017 Taiwan 2.50 (0.67, 9.09) 3.12 −20 −10 0 10 20 Overall (I = 0.0%, p = 0.508) 1.20 (0.95, 1.51) 100.00 .02 .2 1 5 50 (a) (b) Study Area HR (95% CI) Weight In first 6 months <40 vs. 40 mg Liang SK, 2018 Taiwan 1.00 (0.61, 1.64) 64.42 Liu CY, 2017 Taiwan 1.07 (0.55, 2.09) 35.58 Subtotal (I = 0.0%, p = 0.873) 1.03 (0.69, 1.53) 100.00 ECOG PS (0–1 vs. 2-4) Liang SK, 2018 Taiwan 0.67 (0.30, 1.47) 61.84 Yang CJ, 2017 Taiwan 0.17 (0.04, 0.77) 38.16 0.39 (0.10, 1.47) 100.00 Subtotal (I = 59.4%, p = 0.116) .02 .2 1 5 50 (c) Figure 6: )e meta-analysis results for progression-free survival (PFS) among groups after afatinib treatment in advanced NSCLC with EGFR mutation: (a) PFS between non-full-dose group and full-dose group; (b) PFS between the full-dose group and non-full-dose group; and (c) the OS between non-full-dose group and full-dose group in advanced NSCLC patients with epidermal growth factor receptor (EGFR) positive mutations after afatinib treatment. Table 3: Subgroup analysis based on afatinib medication timing and data sources. Heterogeneity test Group No. of studies HR (95%CI) P P I (%) PFS 8 1.20 (0.95, 1.51) 0.124 0.508 0.0 Management of afatinib First-line 7 1.23 (0.98, 1.56) 0.080 0.570 0.0 ≥Second-line 1 0.60 (0.19, 1.87) 0.379 — — Calculated HR (95%CI) Yes 5 1.06 (0.77, 1.44) 0.728 0.483 0.0 No 3 1.39 (0.99, 1.96) 0.057 0.486 0.0 Notes: P : P value for the test of association; P : P value for the test of heterogeneity. A H improved OS (HR: 0.9, 95% CI [0.8–0.9]). In terms of 4. Discussion safety, the incidence of adverse events (Grade ≥3) was as Based on RCT data, a meta-analysis has revealed that in the follows: diarrhea (11.8%) (RR: 8.9, 95% CI [5.3–14.9]), first-line treatment of EGFR-mutated NSCLC, there is no stomatitis (4.8%) (RR: 6.4, 95% CI [1.2–32.7]), and skin conclusive evidence that afatinib is more effective than rash (10.7%) (RR: 7.3, 95% CI [1.5–34.1]) [14]. In this RWE- gefitinib or erlotinib [15]. Meanwhile, Wang et al. have based meta-analysis, the results confirmed that the afatinib performed a meta-analysis of RCTs in advanced NSCLC to was with ORR 58.9% (48.8, 68.7), PFS 12.4 months (10.3, assess the safety and efficacy of afatinib when compared 14.5), TTF 15.4 months (13.6, 17.2), and OS 31.6 months with chemotherapy and first-generation EGFR-TKIs. )eir (26.7, 36.5), which is consistent with RCT results. )e results revealed that compared with control groups, afa- incidences of severe adverse events (Grade ≥3, SAEs) for tinib treatment apparently increased ORR (RR: 1.8, 95% CI diarrhea, skin rashes, paronychia, and mucositis were 9.7% [1.1–2.9]) and improved PFS (HR: 0.5; 95% CI) and (6.8%, 13.1%), 5.8% (4.5%, 7.2%), 3.8% (2.0%, 6.2%), and 12 Journal of Oncology Study Area RR (95% CI) Study Area RR (95% CI) Weight Weight Liang SK, 2017 0.78 (0.60, 1.00) 26.58 Taiwan Liang SK, 2017 Taiwan 0.93 (0.85, 1.03) 48.94 Liu CY, 2017 Taiwan 0.99 (0.81, 1.22) 41.32 Liu CY, 2017 Taiwan 1.03 (0.94, 1.13) 51.06 Yang CI, 2017 Taiwan 0.80 (0.64, 1.01) 32.10 Taiwan Yang CJ, 2017 (Excluded) 0.00 Overall (I = 30.0%, p = 0.240) 0.87 (0.76, 0.99) 100.00 Overall (I = 54.9%, p = 0.136) 0.98 (0.89, 1.08) 100.00 NOTE: Weights are from random effects analysis .604 1 1.66 .8 1 1.2 (a) (b) Figure 7: )e meta-analysis results for disease control rates (DCRs) and objective response rates (ORRs) in different dose groups after afatinib treatment in advanced NSCLC with EGFR mutation: (a) comparison of DCRs in different dose groups and (b) comparison of ORRs in different dose groups. % % Study Area RR (95% CI) Study Area RR (95% CI) Weight Weight Diarrhea Diarrhea Wang S, 2019 China 0.86 (0.66, 1.13) 52.68 Wang S, 2019 China 0.44 (0.06. 3.54) 63.29 Yang CJ, 2017 Taiwan 0.43 (0.28, 0.66) 47.32 2 Taiwan 0.22 (0.01, 5.19) 36.71 0.62 (0.30, 1.28) 100.00 Yang CJ, 2017 Subtotal (I = 87.8%, p = 0.004) . 2 Subtotal (I = 0.0%, p = 0.719) 0.36 (0.07, 2.01) 100.00 Skin rashes Wang S, 2019 China 0.66 (0.45, 0.97) 45.17 Skin rashes Yang CJ, 2017 Taiwan 1.02 (0.80, 1.31) 54.83 2 Wang S, 2019 China 0.43 (0.02, 8.56) 27.38 Subtotal (I = 76.8%, p = 0.038) 0.84 (0.53, 1.34) 100.00 . Yang CJ, 2017 Taiwan 0.10 (0.01, 1.75) 72.62 Mucositis Subtotal (I = 0.0%, p = 0.476) 100.00 0.19 (0.03, 1.32) Wang S, 2019 China 0.92 (0.63, 1.34) 89.36 Yang CJ, 2017 Taiwan 0.66 (0.22, 1.96) 10.64 Paronychia Subtotal (I = 0.0%, p = 0.541) 0.89 (0.62, 1.27) 100.00 Wang S, 2019 China 0.43 (0.02, 8.56) 30.40 Yang CJ, 2017 Taiwan 0.22 (0.02, 1.95) 69.60 Paronychia Wang S, 2019 China 0.61 (0.37, 0.98) 56.83 0.28 (0.05, 1.62) 100.00 Subtotal (I = 0.0%, p = 0.718) Yang CJ, 2017 Taiwan 0.92 (0.52, 1.62) 43.17 Subtotal (I = 15.5%, p = 0.277) 0.72 (0.48, 1.08) 100.00 Dry skin .005 .1 1 10 200 Wang S, 2019 China 0.83 (0.39, 1.77) 18.76 Yang CJ, 2017 Taiwan 0.94 (0.65, 1.35) 81.24 Subtotal (I = 0.0%, p = 0.767) 0.92 (0.66, 1.27) 100.00 Pruritus Wang S, 2019 China 0.63 (0.15, 2.76) 30.45 Yang CJ, 2017 Taiwan 0.66 (0.25, 1.73) 69.55 Subtotal (I = 0.0%, p = 0.972) 0.65 (0.29, 1.46) 100.00 NOTE: Weights are from random effects analysis .1 .5 1 2 10 (a) (b) Figure 8: )e meta-analysis results for total adverse events and severe adverse events in different dose groups after afatinib treatment in advanced NSCLC with EGFR mutation: (a) comparison of total adverse events in different dose groups and (b) comparison of severe adverse events in different dose groups. Table 4: Total AEs (or SAEs) based on different afatinib dose (non-full dose vs. full-dose). Non-full dose Full dose AEs (or SAEs) Total Grade ≥3 Total Grade ≥3 Diarrhea 55.8 (41.1, 70.0)% 1.0 (0.0, 7.4)% 94.7 (86.8, 99.5)% 9.8 (3.0, 19.3) % Skin rashes 77.7 (64.2, 88.9)% 0.0 (0.0, 4.0) % 90.3 (80.9, 97.1)% 7.7 (1.7, 16.5) % Mucositis 34.7 (21.4, 49.2)% 0.0 (0.0, 4.0) % 58.0 (44.9, 70.6)% 0.0 (0.0, 3.0) % Paronychia 48.9 (34.4, 63.5)% 1.5 (0.0, 8.4) % 74.0 (61.7, 84.7) % 7.7 (1.7, 16.5) % Dry skin 55.6 (40.9, 69.8)% 0.0 (0.0, 4.0) % 51.0 (38.0, 64.0) % 0.0 (0.0, 3.0) % Pruritus 16.7 (6.9, 29.3)% 0.0 (0.0, 4.0) % 21.5 (11.6, 33.3) % 0.0 (0.0, 3.0) % AEs, adverse events; SAEs, severe adverse events. 2.1% (1.0%, 3.6%), respectively. Furthermore, in the present )e efficacy of tolerability-guided dose adjustment re- study, the efficacy of afatinib in the first-line-only group mains controversial. Previously, it has been suggested that was significantly superior to that in the second-line 40 mg was the recommended afatinib dose for first-line treatment. )erefore, the efficacy and safety of afatinib has therapy [10]. A recent study has revealed that the PFS of the been confirmed by RWE. non-full-dose group was 12.8 months, while the PFS was Journal of Oncology 13 % % Study Area RR (95% CI) Study Area RR (95% CI) Weight Weight Brain metastases (No vs. Yes) Brain metastases (No vs. Yes) Ho GF, 2019 Malaysia 3.00 (0.55, 16.38) 0.25 Ho GF, 2019 Malaysia 4.51 (1.45, 14.00) 41.39 Liang SK, 2018 Taiwan 1.06 (0.97, 1.15) 99.75 Liang SK, 2018 1.14 (0.95, 1.38) 58.61 Taiwan Subtotal (I = 30.6%, p = 0.230) 1.06 (0.98, 1.16) 100.00 Subtotal (I = 81.8%, p = 0.019) 2.01 (0.53, 7.60) 100.00 NOTE: Weights are from random effects analysis .01 .1 1 10 100 .01 .1 1 10 100 (a) (b) Study Area RR (95%, CI) Weight Study Area RR (95% CI) Weight Exon 19 deletion vs. Uncommon mutation Exon 19 deletion vs. Uncommon mutation Ho GF, 2019 Malaysia 2.72 (0.41, 18.24) 0.63 Ho GF, 2019 Malaysia 2.27 (0.47, 11.01) 5.64 Liang SK, 2017 Taiwan 1.06 (0.91, 1.23) 99.37 Liang SK, 2017 Taiwan 1.26 (0.86, 1.86) 94.36 Subtotal (I = 0.0%, p = 0.332) 1.07 (0.92, 1.24) 100.00 2 1.30 (0.90, 1.89) 100.00 Subtotal (I = 0.0%, p = 0.477) Exon 21 L858R vs. Uncommon mutation Exon 21 L858R vs. Uncommon mutation Ho GF, 2019 2.28 (0.31, 16.62) Malaysia 0.65 2.65 Ho GF, 2019 Malaysia 0.40 (0.03, 5.21) Liang SK, 2017 1.08 (0.92, 1.27) 99.35 Taiwan Liang SK, 2017 Taiwan 1.39 (0.91, 2.13) 97.35 1.09 (0.92, 1.27) 100.00 2 Subtotal (I = 0.0%, p = 0.463) Subtotal (I = 0.0%, p = 0.350) 1.34 (0.88, 2.05) 100.00 .01 .1 1 10 100 .01 .1 1 10 100 (c) (d) Figure 9: )e meta-analysis results for disease control rates (DCRs) and objective response rates (ORRs) in subgroups after afatinib treatment in advanced NSCLC with EGFR mutation: (a) comparison of DCRs in different status of brain metastases; (b) comparison of ORRs in different status of brain metastases; (c) comparison of DCRs in different mutation sites; and (d) comparison of ORRs in different mutation sites. 11.0 months for the full-dose group; however, the difference groups of tolerability-guided afatinib dose adjustment were was not significant (HR: 1.3, 95% CI [0.9–2.0]) [42]. Yang not significant. Moreover, compared with the 40 mg/day et al. have reported that afatinib 30 mg daily as an initial dose dose, 57.8% (1917/3319) of patients received a lower afatinib presents a similar response rate and PFS as an initial dose of dose, with only 0.5% (18/3319) of patients receiving a higher 40 mg daily [43]. In the current RWE-based meta-analysis, afatinib dose; this could partly explain the lower tolerability the results revealed that the difference in PFS and OS be- and higher toxicities associated with afatinib 40 mg daily. However, it should be noted that the anticancer efficacy ORR tween the afatinib non-full-dose group (<40 mg) and full- dose group (>40 mg) was not significant (P> 0.05). How- of afatinib 30 mg daily did not surpass that of the 40 mg daily ever, the ORR in the full-dose group was 78.5% (95% CI dose. Besides, the incidence and severity of adverse reactions [66.7%, 88.4%]), which was significantly higher than that in showed a decreased trend in patients receiving non-full dose, the non-full-dose group (67.8%; 95% CI [56.8, 77.9]). )us, which indicated the tolerability-guided dose adjustment the real-world data suggested that decreasing the afatinib alleviated afatinib-related adverse effects. )us, the real- dose does not negatively impact efficacy; the full dose should world data support that dose adjustment can be guided be employed for treating NSCLC patients with EGFR mu- according to tolerance once adverse reactions occur. tations if tolerance permits. In addition to the afatinib dose, clinical factors such as brain metastases can influence the results of patients with Furthermore, moderate-to-severe adverse drug reactions usually result in dose reduction or discontinuation. Nu- advanced EGFR-mutant NSCLC [46]. In the LUX-Lung 6 trial, the median PFS of patients with brain metastases merous clinical trials have reported that afatinib 40 mg daily as the starting dose presented severe adverse drug reactions, treated with afatinib was lower than that of patients without including skin rash, paronychia, and diarrhea [11, 12, 44]. brain metastases [47], which was in accordance with our 40 mg afatinib daily presented a significantly higher inci- results, suggesting that brain metastases is an influence dence of Grade 3 skin rash (16% vs. 0%) and diarrhea (100% factor of patients with advanced EGFR-mutant NSCLC vs. 41%) than 30 mg daily afatinib [45]. In the present study, based on afatinib dose. the frequency and severity of adverse events (including )e current study was the first RWE-based meta-analysis diarrhea, skin rash, mucositis, paronychia, and pruritus) was to explore the efficacy and adverse reactions in patients with higher in patients who administered 40 mg afatinib daily advanced EGFR-mutated NSCLC. However, some limita- tions persist in the current study: (1) the small sample size of than in those who administered 30 mg afatinib daily. However, the differences of adverse reactions in the two some included studies influenced certain outcome indicators 14 Journal of Oncology of meta-analysis; (2) it was not possible to assess the prepared and revised the manuscript. All authors read and methodological quality of included studies and the impact of approved the final manuscript. quality on the results in this RWE study owing to a lack of suitable quality evaluation tools; (3) subgroup analysis was Acknowledgments not performed on first-generation or second-generation )is study was supported by grants from the National EGFR-TKIs for comparing afatinib with erlotinib, daco- Natural Science Foundation of Hunan Province (2020JJ4418 mitinib, and gefitinib. and 2020RC3067), Clinical Medical Technology Innovation In conclusion, afatinib is a safe and effective first-line Guided Project (2020SK51112), Natural Science Foundation treatment in patients with EGFR-mutated NSCLC, and of Hunan Province National Health Commission (B2019091 tolerability-guided afatinib dose adjustment might not affect and 20201286), Natural Science Foundation of Changsha the PFS of these patients. )is study was performed based on Science and Technology Bureau (Kq1901084, Kq1901080, real-world data, reflecting information on curative effects in and Kq2001024), Cancer Foundation of China real-world patients and fully compensates for disadvantages (NCC2018B58), Key Research and Development Project of of RCTs. Hunan Province (2017WK2061), and Hui Lan Public Foundation (HL-HS2020-1). Abbreviations CI: Confidence interval Supplementary Materials DCR: Disease control rate Supplementary Figure 1: the meta-analysis results for var- ECOG- Eastern Cooperative Oncology Group ious incidence rates of adverse events after afatinib treat- PS: Performance Status ment in advanced NSCLC with EGFR mutation: (A) the EGFR: Epidermal growth factor receptor incidence rate of fatigue; (B) the incidence rate of increased HR: Hazard risk alanine aminotransferase (ALT); (C) the incidence rate of IR: Incidence rate increased aspartate aminotransferase (AST) levels; and (D) NSCLC: Non-small-cell lung cancer the incidence rate of interstitial lung disease (ILD). Sup- ORR: Overall response rate plementary Figure 2: the meta-analysis results for incidence OS: Overall survival rates of severe adverse events after afatinib treatment in PFS: Progression-free survival advanced NSCLC with EGFR mutation: (A) the adverse RCT: Randomized clinical trial reaction incidence rate of fatigue; (B) the adverse reaction RR: Relative risk incidence rate of increased alanine aminotransferase (ALT) RWE: Real-world evidence levels; (C) the adverse reaction incidence rate of increased TTF: Time to failure aspartate aminotransferase (AST) levels; and (D) the adverse TKIs: Tyrosine kinase inhibitors reaction incidence rate of interstitial lung disease (ILD). WMD: Weighted mean difference Supplementary Figure 3: the meta-analysis results for risk of AE: Adverse event progression-free survival (PFS) after afatinib treatment in SAE: Severe adverse event. advanced NSCLC with EGFR mutation: (A) PFS between brain metastases group vs. non-brain metastases group and Data Availability (B) PFS between exon 19 deletion vs. uncommon, exon 19 )e raw data supporting the conclusions of this manuscript deletion vs. exon 21 L858R, brain metastases (no vs. yes), and will be made available by the authors, without undue res- ECOG-PS (0–1) vs. ECOG-PS (≥2). (Supplementary ervation, to any qualified researcher. Materials) Disclosure References [1] No authors listed, “Erratum: Global cancer statistics 2018: An earlier version of abstract of this manuscript has been GLOBOCAN estimates of incidence and mortality worldwide presented as meeting abstract in 2021 ASCO. for 36 cancers in 185 countries,” CA: A Cancer Journal for Clinicians, vol. 70, p. 313, 2020. 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Efficacy and Safety of Afatinib in the Treatment of Advanced Non-Small-Cell Lung Cancer with EGFR Mutations: A Meta-Analysis of Real-World Evidence

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Copyright © 2021 Lemeng Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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1687-8469
DOI
10.1155/2021/8736288
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Abstract

Hindawi Journal of Oncology Volume 2021, Article ID 8736288, 16 pages https://doi.org/10.1155/2021/8736288 Research Article Efficacy and Safety of Afatinib in the Treatment of Advanced Non-Small-Cell Lung Cancer with EGFR Mutations: A Meta-Analysis of Real-World Evidence Lemeng Zhang , Yongzhong Luo , Jianhua Chen, Tianli Cheng, Hua Yang, Changqie Pan, Haitao Li, and Zhou Jiang oracic Medicine Department 1, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China Correspondence should be addressed to Yongzhong Luo; luoyongzhong@hnca.org.cn Received 21 October 2021; Accepted 29 November 2021; Published 18 December 2021 Academic Editor: Ozkan Kanat Copyright © 2021 Lemeng Zhang et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. )e purpose of this study was to explore the efficacy and safety of afatinib in advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations based on real-world evidence. Materials and Methods. Eligible real-world studies were identified from PubMed, Cochrane Library, and Embase. Cochrane guidelines were used to assess the quality of included studies. Cochran’s Q test and I statistics were used for the heterogeneity analysis. Results. Twenty-five studies were included in this meta-analysis; nine studies were included in the qualitative descriptive analysis. )e summarized disease control rate (DCR) was 87.6% (81.5%, 92.7%), and the overall response rate (ORR) was 58.9% (48.8%, 68.7%). )e pooled median progression-free survival (PFS) was 12.4 (10.3, 14.5) months, mean time to failure (TTF) was 15.4 (13.6, 17.2) months, and median overall survival (OS) was 31.6 (26.7, 36.5) months. )e total incidences of adverse events (AEs) for skin rashes, diarrhea, paronychia, and mucositis were 71.4% (64.4%, 77.9%), 70.4% (60.1%, 79.8%), 52.1% (41.9, 62.3%), and 36.5% (29.5%, 43.8%), respectively. )e incidences of severe adverse events (SAEs, Grade ≥3) for diarrhea, skin rashes, paronychia, and mucositis were 9.7% (6.8%, 13.1%), 5.8% (4.5%, 7.2%), 3.8% (2.0%, 6.2%), and 2.1% (1.0%, 3.6%), respectively. Differences in PFS and OS between the afatinib non-full-dose (<40 mg) and full-dose (>40 mg) groups were not significant (P> 0.05). However, the ORR in the full- dose group was 78.5% (66.7%, 88.4%), which was significantly higher than that in the non-full-dose group (67.8% [56.8%, 77.9%]). Conclusion. )e efficacy and safety of afatinib has been confirmed by real-world evidence in advanced NSCLC with EGFR mutation, consistent with randomized controlled trial results. In real-world setting, tolerability-guided dose adjustment might not affect the afatinib efficacy. Afatinib is an irreversible second-generation ErbB family 1. Introduction blocker [6], which has been approved as a first-line treat- Lung cancer is the leading cause of cancer-related deaths and ment for NSCLC patients with EGFR exon 19 deletions or a serious threat to human health [1]. Non-small-cell lung exon 21 L858R substitution mutations [7]. In 2013, afatinib cancer (NSCLC) accounts for more than 80% of lung cancer was approved worldwide as a first-line treatment for patients [2]. Epidermal growth factor receptor (EGFR) mutations with EGFR-mutant NSCLC [5, 8]. )e LUX-Lung 3/6/7 have been identified in approximately 50% of Asian and trials revealed that afatinib had obvious effects in the 10–15% of Caucasian lung adenocarcinoma patients [3, 4]. treatment of advanced EGFR-mutant NSCLC [9–12] and Currently, tyrosine kinase inhibitors (TKIs), including might provide a better curative effect than first-generation erlotinib, gefitinib, dacomitinib, afatinib, and osimertinib, EGFR-TKIs [13]. Moreover, a meta-analysis based on ran- are the standard first-line treatment for advanced NSCLC domized controlled trials (RCTs) has shown that afatinib patients with EGFR mutations [5]. prolonged progression-free survival (PFS), increased overall 2 Journal of Oncology survival (OS), and the overall response rate (ORR) [14]. 2.2. Inclusion and Exclusion Criteria. In the present study, However, whether afatinib is effective in particular sub- the inclusion criteria employed were as follows: (i) the groups remains controversial due to the RCT exclusion subjects were patients with advanced EGFR-mutated criteria [14, 15]. Furthermore, the adverse effects of afatinib NSCLC diagnosed by histology and cytology; (ii) the study limit its clinical application [16]. )us, a dose-adjustment reported the efficacy (ORR, disease control rate (DCR), OS, strategy guided by tolerability can yield clinical benefits PFS, and time to failure (TTF)) or safety (adverse reactions/ based on RCT data [14, 16], which need to be demonstrated serious adverse reactions) of afatinib in the treatment of through real-world evidence (RWE)-based data. NSCLC; (iii) the study reported the difference in efficacy and It is undeniable that the credibility of RCTs can be safety based on different groups, including different afatinib inferred from causality and is thus considered the gold doses (full dose (40 mg/day for 6 months or more) vs. non- standard of clinical research; however, RCTs may not reflect full dose (<40 mg/day for 6 months or 40 mg/day for a real-world practice due to strict inclusion criteria [17]. reduction in the first 6 months)), mutation type (exon 19 Patients in the real-world may differ in numerous charac- deletion vs. uncommon, exon 21 L858R vs. uncommon, exon 19 deletion vs. exon 21 L858R), ECOG-PS (0–1 vs. 2–4), and teristics from those in RCTs. RWE-based studies collect data of patients treated as a whole in clinical practice according to brain metastases; (iv) the research type was RWE. local government regulations, overcoming inherent limita- )e exclusion criteria were as follows: (i) nontreatment tions of RCTs, and can assess the efficacy and safety in- studies, including letters, reviews, and comments; (ii) the formation of patients in the real world [18, 19]. )erefore, it study lacked parameters required for quantitative analysis is crucial to confirm the efficacy and safety of afatinib by (including mean, sample size, standard deviation of the using RWE data. Additionally, a previous study based on experimental group and the control group required for real-world data proved that afatinib dose adjustment de- continuous variable meta-analysis) and could not be ob- creases the intensity and frequency of adverse drug reactions tained through the conversion of other data in the study without affecting the efficacy [20]. Although RWE con- (enrolled as the qualitative description study); (iii) the study tributes to the evaluation of certain clinical influential fac- lacked baseline information such as gender, age, tumor classification, and ECOG-PS, reporting only the efficacy tors, the impact of dose adjustment, brain metastasis, mutation type, and Eastern Cooperative Oncology Group (PFS and TTF) of afatinib (enrolled as the qualitative de- Performance Status (ECOG-PS) on the efficacy and safety of scription study); (iv) the research type was RCT. Further- afatinib remains elusive. more, only one study (containing complete information) Accordingly, we performed a meta-analysis based on was extracted if more than one study was published using the real-world afatinib data in advanced NSCLC with EGFR same data. mutations. To the best of our knowledge, this is the first meta-analysis based on RWE to explore the efficacy and 2.3. Data Extraction and Quality Assessment. In the present safety of afatinib in advanced NSCLC with EGFR mu- study, two independent researchers participated in data tations. In this study, related RWE from Embase, extraction. )e available data included first author name, PubMed, and Cochrane Library databases were analyzed. year of publication, gender, sample size, history, country, Herein, we aimed to comprehensively analyze the efficacy age, stage, ORR, DCR, OS, PFS, TTF, and adverse reactions. and safety of afatinib in NSCLC patients with advanced )e extraction tables were exchanged after both researchers EGFR mutations based on real-world evidence. Fur- had completed the above data extraction work. Any in- thermore, we explored the impact of tolerability-guided consistencies in extracted results were resolved through dose adjustment, brain metastasis, mutation type, and discussion. ECOG-PS. 2.4. Statistical Analysis. STATA software (version 11.0) was 2. Materials and Methods used for statistical analysis. )e incidence rate (IR) and 95% confidence interval (CI) were used as the effect size to )is meta-analysis was performed following the guidelines evaluate the incidence of ORR, DCR, AEs, and SAEs in of the meta-analyses (PRISMA) statement [21]. patients with NSCLC administering afatinib. )e median (95% CI) was used to assess the months of PFS, OS, and TTF, while weighted mean difference (WMD) and 95% CI were 2.1. Data Sources. Relevant studies were searched and identified in electronic databases, including Embase, utilized as combined indices of effect quantity. )e relative risk (RR) and 95% CI were used as the combined indices of PubMed, and Cochrane Library (updated to December 31, 2020). )e main search keywords included “afatinib,” “non- effect quantity to comprehensively evaluate differences in small cell lung cancer,” NSCLC, “lung adenocarcinoma,” ORR, DCR, and incidence of adverse reactions between the and “adenosquamous carcinoma” )e search was performed two groups. Moreover, the risk of OS/PFS was analyzed based on a combination of subject and free words. Addi- using hazard risk (HR) and 95% CI. If the study did not tionally, a manual search of references in identified literature directly report the HR (95% CI) of OS and PFS but reported was performed to obtain additional information regarding the median survival and log-rank P-value in non-full dose vs. full dose of afatinib, the HR (95% CI) could be converted the procedure. No language restrictions were applied to the current meta-analysis. using the method described before [22]. Journal of Oncology 3 Cochran’s Q test and I statistics were used to perform (95% CI [13.6–17.2]). )e difference in TTF between the the heterogeneity analysis [23]. A random-effects model was first-line-only group (15.7 months, 95% CI [13.4, 18.0]) and used if heterogeneity was obtained (P< 0.05, I > 50%); the mixed group (14.4 months, 95% CI [11.5, 17.3]) was not conversely, a fixed-effects model was employed. Moreover, significant (P> 0.05). Seven studies reported the OS out- to assess the effect of the above factors on the combined comes in patients treated with afatinib (Figure 3(c)). )e results of PFS, a subgroup analysis was conducted on PFS heterogeneity test among these seven studies was statistically based on the timing of afatinib administration and data significant (I > 50%, P< 0.05). )e combined median OS sources (direct reports in study or obtained by conversion). was 31.6 months (95% CI [26.7–36.5]). Furthermore, a sensitivity analysis was undertaken to assess In total, 12 studies reported the incidence of diarrhea, the effect of combined results by analyzing the relevant mucositis, and skin rashes and 10 studies reported the total studies individually. Finally, the Egger test [24] was used to incidence of paronychia, including any grade (Figures 4(a)– analyze publication bias between the two groups. 4(d)) and Grade ≥3 (Figures 5(a)–5(d)), respectively. )e results revealed that the most common AEs were diarrhea, mucositis, skin rashes, and paronychia, with an incidence of 3. Results 70.4% (95% CI [60.1%, 79.8%]) (Figure 4(a)), 36.5% (95% CI 3.1. Literature Review and Characteristics of Included Studies. [29.5%, 43.8%]) (Figure 4(b)), 71.4% (95% CI [64.4%, In total, 994, 990, and 281 studies were explored in the 77.9%]) (Figure 4(c)), and 52.1% (95% CI [41.9%, 62.3%]) Embase, PubMed, and Cochrane Library databases, re- (Figure 4(d)), respectively. Meanwhile, the incidences of spectively (Figure 1). After eliminating duplicate studies, a common SAEs (Grade ≥3) for diarrhea, mucositis, skin total of 1525 studies were obtained, with 1479 studies further rashes, and paronychia were 9.7% (95% CI [6.8%, 13.1%]) excluded as these failed to meet the inclusion criteria after (Figure 5(a)), 2.1% (95% CI [1.0%, 3.6%]) (Figure 5(b)), 5.8% assessing the abstract and title. Among the remaining 46 (95% CI [4.5%, 7.2%]) (Figure 5(c)), and 3.8% (95% CI studies, 12 relevant studies were identified after reading the [2.0%, 6.2%]) (Figure 5(d)), respectively. full text. Manual retrieval did not detect any study that could Additionally, the total incidence of fatigue was 15.1% be included in the current analysis. Finally, a total of 25 (95% CI [4.1, 30.9], Supplementary Figure 1A) and the studies [20, 25–33] with sufficient data were included (Ta- incidence of severe fatigue was 0.8% (95% CI [0.0, 2.2], ble 1). A total of nine studies [34–41] were included in the Supplementary Figure 2A). )e total and severe alanine current qualitative descriptive analysis (Table 2). aminotransferase (ALT) levels elevated were 8.3% (95% CI [0.0%, 31.0%]) (Supplementary Figure 1B) and 0.7% (95% CI [0.0%, 2.3%]) (Supplementary Figure 2B), respectively. )e 3.2. Study Characteristics. )e 25 enrolled studies were incidence of total and severe aspartate aminotransferase published between 2014 and 2020. )e study areas were (AST) levels elevated was 6.2% (95% CI [0.0%, 34.3%]) primarily in Asia. Moreover, 19, 1, and 5 studies were en- (Supplementary Figure 1C) and 0.3% (95% CI [0.0%, 1.5%]) rolled in first-line, second-line, and mixed population (Supplementary Figure 2C), respectively. )e incidence of groups, respectively. total and severe interstitial lung disease (ILD) was 1.1% (95% CI [0.1%, 2.9%]) (Supplementary Figure 1D) and 0.7% (95% 3.3.Meta-AnalysisforEfficacyandSafetyofAfatinibBasedon CI [0.0%, 2.3%]) (Supplementary Figure 2D), respectively. RWE. A total of 15 studies presented the outcomes of DCR Finally, except for skin rashes and fatigue, significant het- (Figure 2(a)) and ORR (Figure 2(b)). Among these 15 erogeneity was observed among all studies that contained 2 2 studies, the heterogeneity was statistically significant (I other indicators (I > 50%, P< 0.05). 50%, P< 0.001), and the combined result of DCR was 87.6% (95% CI [81.5%, 92.7%]), and the difference between the 3.4. Effect of Tolerability-Guided Afatinib Dose Adjustment. first-line-only group (90.8%; 95% CI [86.2%, 94.6%]) and second-line group (74.8%; 95% CI [52.5%, 92.0%]) was not Compared with the full dose of 40 mg/day, 57.8% (1917/ 3319) patients administered non-full dose of afatinib (Ta- significant (P> 0.05). )e combined ORR was 58.9% (95% CI [48.8%, 68.7%]). )e difference in ORR between the first- ble 1). Seven studies (8 sets of research data) reported PFS between the non-full-dose and full-dose groups line-only group (70.8%; 95% CI [67.2%, 74.3%]) and second- line group (22.7%; 95% CI [16.8%, 40.2%]) was significant (Figure 6(a)). Among them, HRs (95% CI) in four studies (five sets of data) were obtained by conversion. )e het- (P< 0.05). Moreover, a total of 12 studies indicated the PFS out- erogeneity for these data was not significant (I < 0.0%, P> 0.05). For the combined results, the HR was 1.2 (95% CI comes of afatinib (Figure 3(a)), and the heterogeneity was [0.9, 1.5]; P> 0.05) (Table 3, Figure 6(a)), which indicated statistically significant (I > 50%, P< 0.05). )e combined median PFS was 12.4 months (95% CI [10.3, 14.5]). For PFS, that dose reduction does not impact the therapeutic efficacy in terms of PFS. )e PFS of the non-full-dose group was the difference between the first-line-only group (13.6 months; 95% CI [12.4, 14.7]) and second-line group (6.1 5.0–14.2 months, while the PFS in the full-dose group was 3.0–15.7 months. For the combined results, the WMD was months; 95% CI [2.3, 9.9]) was significant (P< 0.05). Fur- thermore, four studies reported TTF outcomes (Figure 3(b)). −1.6 months (95% CI [−5.7, 2.5]) (Figure 6(b)). Two studies reported the difference in OS risk between the non-full-dose )e heterogeneity was statistically significant (I > 50%, P< 0.05), and the combined median TTF was 15.4 months and full-dose groups (Figure 6(c)). )e result of the 4 Journal of Oncology Records identified through database (n=2215) PubMed (n=990), Embase (n=944), The Cochrane library (n=281) Records after duplicates removed (n = 1525) Records screened Records excluded (n = 1479) title/abstract (n = 1525) Full-text articles excluded with Full-text articles assessed reasons (n = 12) 6 without interested outcomes; for eligibility (n = 46) 5 RCTs; 1 Review. Studies included in Articles excluded with reasons quantitative synthesis (n = 9) (meta-analysis) 9 without available data for (n = 34) meta-analyses. Studies included in quantitative synthesis (meta-analysis) (n = 25) Figure 1: Flow diagram of the screening process for eligible studies. heterogeneity test indicated that the heterogeneity between Two studies reported differences in total AEs based on the two groups was not significant (I < 0.0%, P> 0.05); thus, the full-dose and non-full-dose groups. Significant het- for the combined result, the HR was 1.03 (95% CI [0.69, 1.5]; erogeneity in the total AEs was observed in diarrhea and P> 0.05), which indicated that dose reduction did not affect skin rashes (I > 50.0%; P< 0.05) but was not observed in the therapeutic efficacy in terms of OS. mucositis and paronychia (I > 50.0%, P< 0.05) )ree studies reported the difference between DCR and (Figure 8(a)). )e heterogeneity of diarrhea, skin rashes, ORR based on different afatinib doses. )e heterogeneity of and paronychia (Grade ≥3) was not significant (I > 50.0%, DCR in these studies was significant (I > 50%, P> 0.05). )e P< 0.05) (Figure 8(b)). )e incidence of total AEs and non-full-dose group (95.1% [88.0%, 99.4%]) presented a SAEs, including diarrhea, skin rash, mucositis, paronychia, DCR similar to the full-dose group [95.6% (90.3, 99.1%)]. dry skin, and pruritus, showed a decreased trend in the For the combined results, the RR was 0.9 (95% CI [0.8, 1.0]; non-full-dose group (Table 4), which indicated the toler- P> 0.05) (Figure 7(a)). Moreover, the results of the het- ability-guided dose adjustment alleviated afatinib-related erogeneity test for ORR were I < 50% and P> 0.05. )e adverse effects. non-full-dose group (67.8 [56.8%, 77.9%]) presented a significantly lower ORR than the full-dose group (78.5 3.5. Effect of Subgroup on Efficacy and Safety of Afatinib. [66.7%, 88.4%]). For the combined results, the RR was 0.8 (95% CI [0.7, 0.9]; P> 0.05) (Figure 7(b)). Although the Two studies reported differences in the DCR and ORR in brain metastases. )e DCRs in the without metastases group difference in PFS and OS was not significant, the ORR was and the brain metastases group were 94.6% (91.3%, 97.3%) significantly higher in the full-dose group compared with the non-full-dose group. and 89.1% (82.2%, 94.6%), respectively. )e ORRs in the Included Eligibility Screening Identification Journal of Oncology 5 Table 1: Characteristics of 25 included studies in this meta-analysis. Age, years, ECOG- Dose Female, Clinical Study Area Afatinib N median Mutations PS, 0–1/ Histology reduce, n (%) stage (range) ≧2 no/yes Brat, K First-line 12 IIIB, 135 Czech 147 96 (65.3) 62.8± 11.1 EGFR mutation 147/0 145 AD, 2 other NR/NR 2020 only IV 17 Del19, 4 Chen YH, First-line Taiwan 23 15 (65.2) 42–81 L858R, 2 23 advanced NR NR NR/NR 2019 only uncommon del Re M, First-line 34 Del19, 7 Italy 41 20 (48.8) 70.5± 11.3 2 IIIB, 39 IV NR NR 26/15 2019 only L858R Halmos B, First-line 138 67.0 178 Del19, 49 12 IIIB, 216 192/27 (9 226 AD, 1 SCC, Global 228 51/173 2019 only (60.5) (32.0–90.0) L858R IV missing) 1 NOS 68 Del19, 11 Ho GF, First-line Malaysia 85 47 (55.3) 59.1± 10.8 L858R, 6 4 IIIB, 81 IV 69/16 82 AD, 3 SCC 49/26 2019 only uncommon Hsieh YY, First-line 424 43 IIIB, 708 735 AD, 16 Taiwan 751 62.5± 11.2 EGFR mutation 678/73 NR/NR 2019 only (56.5) IV other Igawa S, First-line 29 Del19, 19 36 IV, 12 Japan 48 27 (56) 67 (35–85) 24/24 NR 21/27 2020 only L858R recurrence 141 Del19, 47 39 IA-IIIA, Ito K, 102 203/12 (3 208 AD, 10 Japan Mixed 218 64.3 (34–87) L858R, 30 11 IIIB, 168 NR/NR 2020 (46.8) missing) non-AD uncommon IV Second- 15 Del19, 13 58 AD, 1 SCC, 2 Kan F, United 50/12 (1 line or 63 37 (58.7) 64 (29–83) L858R, 4 63 IV NOS, 1 large 33/31 2014 Kingdom missing) more uncommon cell, 1 unknown 114 Del19, 37 Kim, Y First-line Korea 165 80 (48.5) 57 (30–79) L858R, 14 165 IV 156/9 NR 53/112 2019 only uncommon 41 Del19, 20 Lau SC, First-line Canada 70 44 (63) 62 (34–84) L858R, 9 70 advanced 68/2 66 AD, 4 other NR/NR 2019 only uncommon Li YL, First-line 52 Del19, 35 31/10 (46 USA 87 62 (71.3) 69 (62–81) 2 IIIB, 85 IV 86 AD, 1 SCC NR/NR 2019 only L858R missing) 81 Del19, 24 Liang SK, First-line 4 IIIB, 136 Taiwan 140 87 (62.1) 61 (28–87) L858R, 35 129/11 140 AD 81/59 2017 only IV uncommon 151 Del19, 53 Liang SK, First-line 157 259 Taiwan 259 62 (28–87) L858R, 55 240/19 259 AD 139/120 2018 only (60.6) advanced uncommon 59 Del19, 23 Lin YT, First-line 60 (53–71) 95 AD, 4 non- Taiwan 99 61 (61.6) L858R, 13 99 advanced 92/7 NR/NR only IQR AD uncommon 73 Del19, 61 Liu CY, First-line 16 IIIB, 130 Taiwan 146 78 (53.4) 63.2± 11.3 L858R, 12 123/23 146 AD 79/67 2017 only IV uncommon Shen YC, First-line Taiwan 24 15 (62.5) 59 (33–86) 24 uncommon 1 IIIB, 23 IV 19/5 24 AD 24/NR 2017 only 5 I-IIIA, 5 42 Del19, 15 Sonehara First-line IIIB, 40 IV, 61 AD, 1 Japan 62 36 (58.1) 67 (46–85) L858R, 3 57/5 23/39 K, 2019 only 13 unclassified uncommon recurrence 1554 AD, 14 94 IIIB, 1206 1020 Del19, 421 SCC, 2 NOS, 1 Tamura K, 947 IV, other 580/ Japan Mixed 1602 67 (34–90) L858R, 137 1381/221 large cell, 32 2019 (59.1) 301, 1 1008 uncommon others, 1 missing unknown 87 Del19, 27 Tan WL, First-line 121 AD, 1 SCC, Singapore 125 61 (48.8) 62 (26–86) L858R, 11 125 IV NR 62/62 2018 only 3 NOS uncommon 6 Journal of Oncology Table 1: Continued. Age, years, ECOG- Dose Female, Clinical Study Area Afatinib N median Mutations PS, 0–1/ Histology reduce, n (%) stage (range) ≧2 no/yes 46 Del19, 28 9 IIIB, 45 IV, First-line 74 AD, 1 SCC, 1 76 52 (68.4) 68 (42–88) L858R, 2 22 67/9 18/58 only NOS Tanaka H, uncommon recurrence Japan 2019 Second- 29 Del19, 21 line or 52 41 (78.9) 65 (39–90) L858R, 2 46/6 51 AD, 1 SCC NR/NR recurrence more uncommon 58< 65 58 Del19, 23 Tu CY, First-line years/ 3 IIIB, 101 Taiwan 104 65 (62.5) L858R, 23 93/11 104 AD 67/31 2018 only 46> 65 IV uncommon years 44 Del19, 20 1 IIIA, 6 Wada Y, L858R, 5 IIIB, 44 IV, Japan Mixed 73 46 (63.0) 69 (42–85) 56/17 75 AD 36/37 2016 uncommon, 4 22 unknown recurrence 26 Del19, 16 58.1 Mixed 60 30 (50.0) L858R, 18 60 advanced 60/0 60 AD 37/23 (36.3–82.7) Uncommon 19 Del19, 7 Wang S, First-line 57.2 China 39 23 (59.0) L858R, 13 39 advanced 39/0 39 AD NR/NR 2019 only (36.3–82.7) uncommon Second- 7 Del19, 9 59.9 line or 21 7 (33.3) L858R, 5 21 advanced 21/0 21 AD NR/NR (39.7–75.5) more uncommon Yang CJ, First-line 29 Del19, 19 Taiwan 48 30 (62.5) 64.6± 8.9 48 IV 38/10 48 AD 19/29 2017 only L858R NR, not reported; AD, adenocarcinoma; SCC, squamous cell carcinoma; NOS, not otherwise specified; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; IQR, interquartile range. Table 2: Characteristics of 9 studies in qualitative analysis. Female, n Age, years, ECOG-PS, Study Area Afatinib N Mutations Clinical stage Histology (%) median (range) 0–1/≥2 First-line 8 IIIA, 3 IIIB, 16 23 AD, 3 Fujiwara A Japan 28 19 (67.9) 68 (37–82) EGFR mutation NR 2018 only IV, 1 recurrence SCC, 2 other 150 Del19, 53 Hochmair First-line 153/31 (20 Global 204 110 (53.9) 60 (30–86) L858R, 1 197 IV, 7 missing NR MJ, 2018 only missing) uncommon Jung HA, First-line Uncommon EGFR Korea 61 NR NR NR NR NR 2020 only mutation Kanazu M, Uncommon EGFR Japan Mixed 12 NR NR 12 advanced NR NR 2020 mutation Kuan FC, First-line Taiwan 81 42 (51.9) 64 (37–83) 48 Del19, 33 L858R 7 IIIB, 74 IV 70/11 81 AD 2017 only First-line Lim, J 2019 USA 550 355 (64.5) 63.3± 11.4 EGFR mutation NR NR NR only 53 Del19, 31 First-line 96 AD, 3 Su VY, 2020 Taiwan 99 52 (52.5) 64.1± 10.8 L858R, 15 4 IIIB, 95 IV 89/10 only non-AD uncommon Wu SG, 2020 First-line 68.7 32 IV, 4 Taiwan 36 27 (75) 36 uncommon 32/4 36 AD (a) only (43.0–86.1) recurrence 59 Del19, 21 Wu SG, 2020 First-line 83 advanced, 8 Taiwan 91 44 (48.4) 63 (37–83) L858R, 11 NR 91 AD (b) only recurrence uncommon Notes: NR, not reported; AD, adenocarcinoma; SCC, squamous cell carcinoma; ECOG-PS, Eastern Cooperative Oncology Group Performance Status. without metastases group and the brain metastases group 1.0, 95% CI [0.9, 1.1]; P> 0.05) and ORR (RR: 2.0, 95% CI were 74.9% (95% CI [69.1%, 80.2%]) and 61.8% (95% CI [0.5, 7.6]; P> 0.05) (Figures 9(a) and 9(b)) were not [52.2%, 71.0%]), respectively. )e differences in DCR (RR: significant. Journal of Oncology 7 Study Area IR (95% CI) Weight First–line only Chen, YH 2019 Taiwan 0.826 (0.612, 0.950) 4.97 Ho GF, 2019 Malaysia 0.953 (0.884, 0.987) 6.42 Igawa S, 2020 Japan 0.854 (0.722, 0.939) 5.92 Liang SK, 2017 Taiwan 0.936 (0.881, 0.970) 6.71 Liang SK, 2018 Taiwan 0.927 (0.888, 0.955) 6.93 Liu CY, 2017 Taiwan 0.925 (0.869, 0.962) 6.73 Shen YC, 2017 Taiwan 0.625 (0.406, 0.812) 5.03 Sonehara K, 2019 Japan 0.887 (0.781, 0.953) 6.17 Tan WL, 2018 Singapore 0.776 (0.693, 0.846) 6.65 Tanaka H, 2019 (a) Japan 0.855 (0.756, 0.925) 6.34 Wad a Y, 2016 (a) Japan 1.000 (0.692, 1.000) 3.59 Wang S, 2019 (a) China 0.974 (0.865, 0.999) 5.69 Yang CJ, 2017 Taiwan 5.92 1.000 (0.926, 1.000) Subtotal (I = 78.115%, p = 0.000) 0.908 (0.862, 0.946) 77.07 Second–line or more Kan F, 2014 United Kingdom 0.444 (0.319, 0.575) 6.18 Tanaka H, 2019 (b) Japan 0.808 (0.675, 0.904) 6.00 Japan 0.854 (0.722, 0.939) 5.92 Wada Y, 2016 (b) Wang S, 2019 (b) China 0.857 (0.637, 0.970) 4.83 Subtotal (I = 89.561%, p = 0.000) 0.748 (0.525, 0.920) 22.93 Heterogeneity between groups: p = 0.085 Overall (I = 87.168%, p = 0.000) 0.876 (0.815, 0.927) 100.00 0 .2 .4 .6 .8 1 (a) Study Area IR (95% CI) Weight First–line only Taiwan 0.739 (0.516, 0.898) 4.98 Chen, YH 2019 Malaysia 0.765 (0.660, 0.850) 5.85 Ho GF, 2019 Igawa S, 2020 Japan 0.625 (0.474, 0.760) 5.57 Liang SK, 2017 0.671 (0.587, 0.748) 6.00 Taiwan Liang SK, 2018 0.695 (0.635, 0.750) 6.12 Taiwan Liu CY, 2017 Taiwan 0.719 (0.639, 0.790) 6.01 Shen YC, 2017 Taiwan 0.625 (0.406, 0.812) 5.02 0.806 (0.686, 0.896) 5.71 Sonehara K, 2019 Japan Tan WL, 2018 Singapore 0.704 (0.616, 0.782) 5.97 Tanaka H, 2019 (a) Japan 0.645 (0.527, 0.751) 5.80 Japan 0.800 (0.444, 0.975) 3.97 Wada Y, 2016 (a) Wang S. 2019 (a) China 0.564 (0.396, 0.722) 5.43 Yang CJ, 2017 Taiwan 0.833 (0.698, 0.925) 5.57 Subtotal (I = 29.840%, p = 0.146) 0.708 (0.672, 0.743) 71.98 Second–line or more Kan F, 2014 United Kingdom 5.72 0.143 (0.067, 0.254) Tamura K, 2019 Japan 0.401 (0.377, 0.425) 6.24 0.250 (0.140, 0.389) 5.61 Tanaka H, 2019 (b) Japan Japan 5.57 Wada Y, 2016 (b) 0.271 (0.153, 0.418) Wang S, 2019 (b) China 4.88 0.333 (0.146, 0.570) Subtotal (I = 85.532%, p = 0.000) 0.277 (0.168, 0.402) 28.02 Heterogeneity between groups: p = 0.000 Overall (I = 94.936%, p = 0.000) 0.589 (0.488, 0.687) 100.00 0 .2 .4 .6 .8 1 (b) Figure 2: )e meta-analysis results of afatinib efficacy and safety in advanced NSCLC with EGFR mutation: (a) the outcome of disease control rates (DCRs) and (b) the outcome of objective response rates (ORRs). 8 Journal of Oncology Study Area Median (95% CI) Weight First-line only Czech Brat, K 2020 13.10 (11.40, 18.20) 8.15 Chen, YH 2019 Taiwan 10.40 (7.50, 17.20) 6.66 Malaysia 14.20 (11.85, 16.55) 9.18 Ho GF, 2019 Igawa S, 2020 14.10 (7.70, 20.50) 5.26 Japan Korea 19.10 (12.30, 25.90) Kim, Y 2019 4.95 Taiwan 9.72 Liang SK, 2018 12.80 (11.10, 14.50) Lin YT, 2019 Taiwan 12.40 (9.80, 15.00) 8.95 Sonehara K, 2019 Japan 15.70 (11.90, 19.50) 7.73 Tan WL, 2018 Singapore 11.90 (10.30, 19.30) 7.01 Tanaka H, 2019 Japan 7.63 17.80 (13.70, 21.50) Wang S, 2019 (a) China 12.30 (7.60, 17,00) 6.81 Subtotal (I = 20.9%, p = 0.245) 13.61 (12.44, 14.77) 82.06 Second-line or more Tanaka H, 2019 Japan 8.00 (4.90, 9.50) 9.23 Wang S, 2019 (b) 4.10 (1.30, 7.00) 8.71 China 6.14 (2,33, 9.96) Subtotal (I = 77.0%, p = 0.037) 17.94 Overall (I = 80.9%, p = 0.000) 12.45 (10.36, 14.54) 100.00 NOTE: Weights are from random effects analysis 0 10 20 30 (a) Study Area Median (95% CI) Weight First–line only 13 countries 18.70 (15.10, 21.50) Halmos B, 2019 17.82 Hsieh, YY 2019 Taiwan 15.80 (14.50, 17.00) 34.23 28.12 Lin YT, 2019 Taiwan 13.60 (11.70, 15.50) Subtotal (I = 74.7%, p = 0.019) 15.73 (13.45, 18.01) 80.17 Mixed Ito K, 2020 Japan 14.40 (11.40, 17.20) 19.83 Subtotal (I = .%, p = .) 14.40 (11.50, 17.30) 19.83 100.00 Overall (I = 64.2%, p = 0.039) 15.42 (13.62, 17.22) NOTE: Weights are from random effects analysis 010 20 (b) Figure 3: Continued. Journal of Oncology 9 Study Area Afatinib Median (95% CI) Weight Czech First–line only 14.68 Brat, K 2020 29.30 (20.90, 38.60) Chen, YH 2019 Taiwan 23.59 First–line only 29.60 (24.80, 33.00) Ho GF, 2019 28.90 (19.82, 37.99) 14.31 Malaysia First–line only 48.30 (31.40, 65.20) Japan First–line only 6.46 Igawa S, 2020 Lau SC, 2019 39.00 (25.60, 48.80) 10.92 Canada First–line only Li YL, 2019 First–line only 20.70 (16.20, 35.10) 13.76 USA Lin YT, 2019 Taiwan First–line only 16.27 37.00 (25.10, 40.90) Overall (I = 55.2%, p = 0.037) 100.00 31.67 (26.78, 36.56) NOTE: Weights are from random effects analysis 0 20 40 60 (c) Figure 3: )e meta-analysis results of afatinib efficacy and safety in advanced NSCLC with EGFR mutation: (a) the outcome of progression- free survival (PFS); (b) the outcome for overall survival (OS); and (c) the outcome for time to failure (TTF). Study Study Area IR (95% CI) Area IR (95% CI) Weight Weight Halmos B, 2019 Global 0.750 (0.689, 0.805) 8.12 Halmos B, 2019 Global 0.342 (0.281, 0.408) 8.61 Ho GF, 2019 Malaysia 0.541 (0.430, 0.650) 7.73 Ho GF, 2019 Malaysia 0.271 (0.180, 0.378) 7.74 Igawa S, 2020 Japan 0.479 (0.333, 0.628) 7.31 Igawa S, 2020 Japan 0.313 (0.187, 0.463) 6.89 Kan F, 2014 United Kingdom 0.730 (0.603, 0.834) 7.53 Kan F, 2014 United Kingdom 0.143 (0.067, 0.254) 7.33 Kim, Y 2019 Korea 0.230 (0.168, 0.302) 8.03 Kim, Y 2019 Korea 0.303 (0.234, 0.379) 8.40 Liu CY, 2017 Taiwan 0.726 (0.646, 0.797) 7.98 Liu CY, 2017 Taiwan 0.452 (0.370, 0.536) 8.30 Sonehara K, 2019 Japan 0.823 (0.705, 0.908) 7.52 Sonehara K, 2019 Japan 0.548 (0.417, 0.675) 7.31 Tamura K, 2019 Japan 0.785 (0.764, 0.805) 8.33 Tamura K, 2019 Japan 0.320 (0.297, 0.343) 9.14 Tanaka H, 2019 Japan 0.882 (0.787, 0.944) 7.66 Tanaka H, 2019 Japan 0.645 (0.527, 0.751) 7.60 Tanaka H, 2019 Japan 0.423 (0.287, 0.568) Tanaka H, 2019 Japan 0.827 (0.697, 0.918) 7.38 7.03 Wada Y, 2016 Japan 0.164 (0.088, 0.270) 7.54 Wada Y, 2016 Japan 0.767 (0.654, 0.858) 7.64 Wang S, 2019 China 0.707 (0.573, 0.819) 7.21 Wang S, 2019 China 0.862 (0.746, 0.939) 7.47 Yang CJ, 2017 Taiwan 0.208 (0.105, 0.350) 6.89 Yang CJ, 2017 Taiwan 0.646 (0.495, 0.778) 7.31 Overall (I = 89.688%, p = 0.000) 0.365 (0.295, 0.438) 100.00 Overall (I = 95.319%, p = 0.000) 0.704 (0.601, 0.798) 100.00 0.2 .4 .6 .81 0 .2.4.6.8 1 (a) (b) % % Study Area IR (95% CI) Study Area IR (95% CI) Weight Weight Halmos B, 2019 Global 0.557 (0.490, 0.623) 8.60 0.487 (0.420, 0.554) 9.84 Halmos B, 2019 Global Ho GF, 2019 Malaysia 0.706 (0.597, 0.800) 7.74 0.400 (0.295, 0.512) 9.22 Ho GF, 2019 Malaysia Igawa S, 2020 Japan 0.750 (0.604, 0.864) 6.91 0.458 (0.314, 0.608) 8.56 Igawa S, 2020 Japan Kan F, 2014 United Kingdom 0.667 (0.537, 0.780) 7.34 Kim, Y 2019 Korea 0.291 (0.223, 0.367) 9.69 Kim, Y 2019 Korea 0.479 (0.401, 0.558) 8.39 Liu CY, 2017 Taiwan 0.644 (0.560, 0.721) 9.62 Liu CY, 2017 Taiwan 0.753 (0.675, 0.821) 8.29 Sonehara K, 2019 Japan 0.565 (0.433, 0.690) 8.89 Sonehara K, 2019 Japan 0.806 (0.686, 0.896) 7.31 Tanaka H, 2019 Japan 0.711 (0.595, 0.809) 9.11 Tamura K, 2019 Japan 0.586 (0.561, 0.610) 9.11 Tanaka H, 2019 Japan 0.731 (0.590, 0.844) 8.67 Tanaka H, 2019 Japan 0.868 (0.771, 0.935) 7.60 0.247 (0.153, 0.361) 9.07 Wada Y, 2016 Japan Tanaka H, 2019 Japan 0.846 (0.719, 0.931) 7.04 0.724 (0.591, 0.833) 8.80 Wang S, 2019 China Wada Y, 2016 Japan 0.589 (0.468, 0.703) 7.55 Yang CJ, 2017 Taiwan 0.500 (0.352, 0.648) 8.56 Wang S, 2019 China 0.828 (0.706, 0.914) 7.21 Overall (I = 90.529%, p = 0.000) 0.521 (0.419, 0.623) 100.00 Yang CJ, 2017 Taiwan 0.854 (0.722, 0.939) 6.91 0.714 (0.644, 0.779) 100.00 Overall (I = 89.840%, p = 0.000) 0 .2.4.6.8 1 0.2 .4 .6 .81 (c) (d) Figure 4: )e meta-analysis results for various incidence rates after afatinib treatment in advanced NSCLC with EGFR mutation: (a) the incidence rate of diarrhea; (b) the incidence rate of mucositis; (c) the incidence rate of skin rashes; and (d) the incidence rate of paronychia. 10 Journal of Oncology % % Study Area IR (95% CI) Study Area IR (95% CI) Weight Weight 0.057 (0.031, 0.096) 10.89 Halmos B, 2019 Global Halmos B, 2019 Global 0.092 (0.058, 0.137) 9.62 0.024 (0.003, 0.082) 7.35 Malaysia Ho GF, 2019 Ho GF, 2019 Malaysia 0.047 (0.013, 0.116) 7.66 0.021 (0.001, 0.111) 5.27 Igawa S, 2020 Japan Igawa S, 2020 Japan 0.146 (0.061, 0.278) 6.14 Kan F, 2014 United Kingdom 0.016 (0.000, 0.085) 6.23 Kan F, 2014 United Kingdom 0.143 (0.067, 0.254) 6.89 0.000 (0.000, 0.022) 9.81 Kim, Y 2019 Korea Kim, Y 2019 Korea 0.036 (0.013, 0.077) 9.09 0.048 (0.019, 0.096) 9.38 Liu CY, 2017 Taiwan Sonehara K, 2019 Japan 0.065 (0.018, 0.157) 6.17 Liu CY, 2017 Taiwan 0.082 (0.043, 0.139) 8.86 Japan 0.039 (0.030, 0.049) 14.44 Tamura K, 2019 Sonehara K, 2019 Japan 0.242 (0.142, 0.367) 6.85 Japan 0.026 (0.003, 0.092) 6.93 Tanaka H, 2019 0.151 (0.134, 0.170) 11.06 Tamura K, 2019 Japan Japan 0.000 (0.000, 0.068) 5.54 Tanaka H, 2019 Tanaka H, 2019 Japan 0.079 (0.030, 0.164) 7.38 0.027 (0.003, 0.095) 6.78 Wada Y, 2016 Japan Tanaka H, 2019 Japan 0.135 (0.056, 0.258) 6.37 0.000 (0.000, 0.062) 5.93 Wang S, 2019 China Wada Y, 2016 Japan 0.082 (0.031, 0.170) 728 Yang CJ, 2017 Taiwan 0.000 (0.000, 0.074) 5.27 Wang S, 2019 China 0.103 (0.039, 0.212) 6.67 0.021 (0.010, 0.036) 100.00 Overall (I = 60.806%, p = 0.002) Yang CJ, 2017 Taiwan 0.021 (0.001, 0.111) 6.14 Overall (I = 77.684%, p = 0.000) 0.097 (0.068, 0.131) 100.00 0.2 .4 0 .2 .4 (a) (b) % % Study Area IR (95% CI) Study Area IR (95% CI) Weight Weight Halmos B, 2019 Global 0.035 (0.015, 0.068) 12.48 Halmos B, 2019 Global 0.083 (0.051, 0.127) 12.31 Malaysia Ho GF, 2019 0.035 (0.007, 0.100) 9.33 Ho GF, 2019 Malaysia 0.059 (0.019, 0.132) 5.85 Igawa S, 2020 Japan 0.042 (0.005, 0.143) 7.14 Igawa S, 2020 Japan 0.083 (0.023, 0.200) 3.56 Korea Kim, Y 2019 0.024 (0.007, 0.061) 11.59 Kan F, 2014 United Kingdom 0.079 (0.026, 0.176) 4.53 Liu CY, 2017 Taiwan 0.116 (0.069, 0.180) 11.22 Kim, Y 2019 Korea 0.018 (0.004, 0.052) 9.83 Sonehara K, 2019 Japan 0.097 (0.036, 0.199) 8.13 Liu CY, 2017 Taiwan 0.055 (0.024, 0.105) 8.98 Tanaka H, 2019 Japan 0.013 (0.000, 0.071) 8.91 Sonehara K, 2019 0.081 (0.027, 0.178) Japan 4.47 Tanaka H, 2019 Japan 0.000 (0.000, 0.068) 7.44 Tamura K, 2019 Japan 0.058 (0.047, 0.071) 28.41 Wada Y, 2016 Japan 0.014 (0.000, 0.074) 8.76 Tanaka H, 2019 Japan 0.118 (0.056, 0.213) 5.32 Wang S, 2019 China 0.034 (0.004, 0.119) 7.87 Tanaka H, 2019 Japan 0.038 (0.005, 0,132) 3.83 Yang CJ, 2017 7.14 Taiwan 0.083 (0.023, 0.200) Wada Y, 2016 0.068 (0.023, 0.153) 5.14 Japan Overall (I = 61.354%, p = 0.004) 0.038 (0.020, 0.062) 100.00 Wang S, 2019 China 0.034 (0.004, 0.119) 4.21 Yang CJ, 2017 Taiwan 0.063 (0.013, 0.172) 3.56 Overall (I = 24.285%, p = 0.198) 0.058 (0.045, 0.072) 100.00 0.2 .4 0 .2 .4 (c) (d) Figure 5: )e meta-analysis results for serious adverse reaction incidence rates after afatinib treatment in advanced NSCLC with EGFR mutation: (a) the adverse reaction incidence rate of diarrhea; (b) the adverse reaction incidence rate of mucositis; (c) the adverse reaction incidence rate of skin rashes; and (d) the adverse reaction incidence rate of paronychia. Furthermore, two studies reported differences in DCR/ exon 19 deletion group was undoubtedly higher than that in ORR between mutation types. )e DCRs in the exon 19 the uncommon mutation group (HR: 0.2, 95% CI [0.1, 0.4]; deletion group, exon 21 L858R group, and uncommon group P< 0.05), and PFS in patients without brain metastasis was were 94.0% (95% CI [89.4, 97.4%]), 92.7% (95% CI [80.5%, significantly lower than that in patients with brain metastasis 99.7%]), and 92.8% (95% CI [97.2%, 100.0%]), respectively. (HR: 0.5; 95% CI [0.4, 0.8]; P< 0.05) (Supplementary Figure 3B). No significant difference was observed in ECOG- )e differences in DCR in the exon 19 deletion vs. un- common group (RR: 1.1, 95% CI [0.9, 1.2]; P> 0.05) and PS (0–1) vs. ECOG-PS (≥2) (HR: 0.3, 95% CI [0.1, 1.4]; exon 21 L858R vs. uncommon group (RR: 1.1, 95% CI [0.9, P> 0.05) (Supplementary Figure 3B). However, the het- 1.3]; P> 0.05) were not significant (Figure 9(c)). )e ORRs erogeneity between the two studies was significant in the exon 19 deletion group, exon 21 L858R group, and (I � 59.4%) (Figure 6(c)). uncommon group were 71.9% (95% CI [64.3%, 78.9%]), 69.1% (95% CI [55.2%, 84.0%]), and 59.9% (95% CI [41.3%, 3.6. Sensitivity Analysis and Publication Bias. Publication 77.4%]), respectively. )e differences in ORR in the exon 19 deletion vs. uncommon group (RR: 1.3, 95% CI [0.9, 1.9], bias and sensitivity analyses were performed on the study outcomes. )e sensitivity analysis results revealed that none P> 0.05) and exon 21 L858R vs. uncommon group (RR: 1.3, 95% CI [0.9, 2.0]; P> 0.05) were not significant of the included studies had a noticeable influence on the combined result of PFS between the full-dose and the non- (Figure 9(d)). Moreover, two studies reported PFS in patients with full-dose groups. )e combined results of PFS ranged from brain metastases based on the full-dose and non-full-dose HR: 1.1 (95% CI [0.8, 1.4]) to HR: 1.3 (95% CI [0.9, 1.7]) (P> 0.05) following removal of any single study. Further- groups (Supplementary Figure 3A). For the combined re- sults, the HR was 2.4 (95% CI [0.9, 5.9]; P> 0.05). Fur- more, the Egger test showed that publication bias in the current meta-analysis was not significant (P> 0.05). thermore, the combined results showed that the PFS in the Journal of Oncology 11 % % Study Area WMD (95% CI) Study Area HR (95% CI) Weight Weight 32.12 Liang SK, 2018 Taiwan −0.70 (−4.10, 2.70) Liang SK, 2017 Taiwan 1.19 (0.76, 1.89) 25.58 Liang SK, 2018 Taiwan 1.05 (0.56, 1.96) 13.53 Sonehara K, 2019 Japan −1.50 (−10.28, 7.28) 14.58 Sonehara K, 2019 Japan 0.49 1.11 (0.04, 28.97) Wang S, 2019 (a) China −9.30 (−16.06, −2.54) 19.74 Tan WL, 2018 Singapore 1.59 (0.90, 2.78) 16.69 Wang S, 2019 (b) China 2.00 (−1.04, 5.04) 33.56 Tu CY, 2018 Taiwan 1.02 (0.68, 1.52) 32.82 Overall (I = 67.2%, p =0.028) −1.61 (−5.79, 2.57) 100.00 Wang S, 2019 (a) China 2.78 (0.82, 9.09) 3.67 Wang S, 2019 (b) China 0.60 (0.19, 1.85) 4.10 NOTE: Weights are from random effects analysis Yang CJ, 2017 Taiwan 2.50 (0.67, 9.09) 3.12 −20 −10 0 10 20 Overall (I = 0.0%, p = 0.508) 1.20 (0.95, 1.51) 100.00 .02 .2 1 5 50 (a) (b) Study Area HR (95% CI) Weight In first 6 months <40 vs. 40 mg Liang SK, 2018 Taiwan 1.00 (0.61, 1.64) 64.42 Liu CY, 2017 Taiwan 1.07 (0.55, 2.09) 35.58 Subtotal (I = 0.0%, p = 0.873) 1.03 (0.69, 1.53) 100.00 ECOG PS (0–1 vs. 2-4) Liang SK, 2018 Taiwan 0.67 (0.30, 1.47) 61.84 Yang CJ, 2017 Taiwan 0.17 (0.04, 0.77) 38.16 0.39 (0.10, 1.47) 100.00 Subtotal (I = 59.4%, p = 0.116) .02 .2 1 5 50 (c) Figure 6: )e meta-analysis results for progression-free survival (PFS) among groups after afatinib treatment in advanced NSCLC with EGFR mutation: (a) PFS between non-full-dose group and full-dose group; (b) PFS between the full-dose group and non-full-dose group; and (c) the OS between non-full-dose group and full-dose group in advanced NSCLC patients with epidermal growth factor receptor (EGFR) positive mutations after afatinib treatment. Table 3: Subgroup analysis based on afatinib medication timing and data sources. Heterogeneity test Group No. of studies HR (95%CI) P P I (%) PFS 8 1.20 (0.95, 1.51) 0.124 0.508 0.0 Management of afatinib First-line 7 1.23 (0.98, 1.56) 0.080 0.570 0.0 ≥Second-line 1 0.60 (0.19, 1.87) 0.379 — — Calculated HR (95%CI) Yes 5 1.06 (0.77, 1.44) 0.728 0.483 0.0 No 3 1.39 (0.99, 1.96) 0.057 0.486 0.0 Notes: P : P value for the test of association; P : P value for the test of heterogeneity. A H improved OS (HR: 0.9, 95% CI [0.8–0.9]). In terms of 4. Discussion safety, the incidence of adverse events (Grade ≥3) was as Based on RCT data, a meta-analysis has revealed that in the follows: diarrhea (11.8%) (RR: 8.9, 95% CI [5.3–14.9]), first-line treatment of EGFR-mutated NSCLC, there is no stomatitis (4.8%) (RR: 6.4, 95% CI [1.2–32.7]), and skin conclusive evidence that afatinib is more effective than rash (10.7%) (RR: 7.3, 95% CI [1.5–34.1]) [14]. In this RWE- gefitinib or erlotinib [15]. Meanwhile, Wang et al. have based meta-analysis, the results confirmed that the afatinib performed a meta-analysis of RCTs in advanced NSCLC to was with ORR 58.9% (48.8, 68.7), PFS 12.4 months (10.3, assess the safety and efficacy of afatinib when compared 14.5), TTF 15.4 months (13.6, 17.2), and OS 31.6 months with chemotherapy and first-generation EGFR-TKIs. )eir (26.7, 36.5), which is consistent with RCT results. )e results revealed that compared with control groups, afa- incidences of severe adverse events (Grade ≥3, SAEs) for tinib treatment apparently increased ORR (RR: 1.8, 95% CI diarrhea, skin rashes, paronychia, and mucositis were 9.7% [1.1–2.9]) and improved PFS (HR: 0.5; 95% CI) and (6.8%, 13.1%), 5.8% (4.5%, 7.2%), 3.8% (2.0%, 6.2%), and 12 Journal of Oncology Study Area RR (95% CI) Study Area RR (95% CI) Weight Weight Liang SK, 2017 0.78 (0.60, 1.00) 26.58 Taiwan Liang SK, 2017 Taiwan 0.93 (0.85, 1.03) 48.94 Liu CY, 2017 Taiwan 0.99 (0.81, 1.22) 41.32 Liu CY, 2017 Taiwan 1.03 (0.94, 1.13) 51.06 Yang CI, 2017 Taiwan 0.80 (0.64, 1.01) 32.10 Taiwan Yang CJ, 2017 (Excluded) 0.00 Overall (I = 30.0%, p = 0.240) 0.87 (0.76, 0.99) 100.00 Overall (I = 54.9%, p = 0.136) 0.98 (0.89, 1.08) 100.00 NOTE: Weights are from random effects analysis .604 1 1.66 .8 1 1.2 (a) (b) Figure 7: )e meta-analysis results for disease control rates (DCRs) and objective response rates (ORRs) in different dose groups after afatinib treatment in advanced NSCLC with EGFR mutation: (a) comparison of DCRs in different dose groups and (b) comparison of ORRs in different dose groups. % % Study Area RR (95% CI) Study Area RR (95% CI) Weight Weight Diarrhea Diarrhea Wang S, 2019 China 0.86 (0.66, 1.13) 52.68 Wang S, 2019 China 0.44 (0.06. 3.54) 63.29 Yang CJ, 2017 Taiwan 0.43 (0.28, 0.66) 47.32 2 Taiwan 0.22 (0.01, 5.19) 36.71 0.62 (0.30, 1.28) 100.00 Yang CJ, 2017 Subtotal (I = 87.8%, p = 0.004) . 2 Subtotal (I = 0.0%, p = 0.719) 0.36 (0.07, 2.01) 100.00 Skin rashes Wang S, 2019 China 0.66 (0.45, 0.97) 45.17 Skin rashes Yang CJ, 2017 Taiwan 1.02 (0.80, 1.31) 54.83 2 Wang S, 2019 China 0.43 (0.02, 8.56) 27.38 Subtotal (I = 76.8%, p = 0.038) 0.84 (0.53, 1.34) 100.00 . Yang CJ, 2017 Taiwan 0.10 (0.01, 1.75) 72.62 Mucositis Subtotal (I = 0.0%, p = 0.476) 100.00 0.19 (0.03, 1.32) Wang S, 2019 China 0.92 (0.63, 1.34) 89.36 Yang CJ, 2017 Taiwan 0.66 (0.22, 1.96) 10.64 Paronychia Subtotal (I = 0.0%, p = 0.541) 0.89 (0.62, 1.27) 100.00 Wang S, 2019 China 0.43 (0.02, 8.56) 30.40 Yang CJ, 2017 Taiwan 0.22 (0.02, 1.95) 69.60 Paronychia Wang S, 2019 China 0.61 (0.37, 0.98) 56.83 0.28 (0.05, 1.62) 100.00 Subtotal (I = 0.0%, p = 0.718) Yang CJ, 2017 Taiwan 0.92 (0.52, 1.62) 43.17 Subtotal (I = 15.5%, p = 0.277) 0.72 (0.48, 1.08) 100.00 Dry skin .005 .1 1 10 200 Wang S, 2019 China 0.83 (0.39, 1.77) 18.76 Yang CJ, 2017 Taiwan 0.94 (0.65, 1.35) 81.24 Subtotal (I = 0.0%, p = 0.767) 0.92 (0.66, 1.27) 100.00 Pruritus Wang S, 2019 China 0.63 (0.15, 2.76) 30.45 Yang CJ, 2017 Taiwan 0.66 (0.25, 1.73) 69.55 Subtotal (I = 0.0%, p = 0.972) 0.65 (0.29, 1.46) 100.00 NOTE: Weights are from random effects analysis .1 .5 1 2 10 (a) (b) Figure 8: )e meta-analysis results for total adverse events and severe adverse events in different dose groups after afatinib treatment in advanced NSCLC with EGFR mutation: (a) comparison of total adverse events in different dose groups and (b) comparison of severe adverse events in different dose groups. Table 4: Total AEs (or SAEs) based on different afatinib dose (non-full dose vs. full-dose). Non-full dose Full dose AEs (or SAEs) Total Grade ≥3 Total Grade ≥3 Diarrhea 55.8 (41.1, 70.0)% 1.0 (0.0, 7.4)% 94.7 (86.8, 99.5)% 9.8 (3.0, 19.3) % Skin rashes 77.7 (64.2, 88.9)% 0.0 (0.0, 4.0) % 90.3 (80.9, 97.1)% 7.7 (1.7, 16.5) % Mucositis 34.7 (21.4, 49.2)% 0.0 (0.0, 4.0) % 58.0 (44.9, 70.6)% 0.0 (0.0, 3.0) % Paronychia 48.9 (34.4, 63.5)% 1.5 (0.0, 8.4) % 74.0 (61.7, 84.7) % 7.7 (1.7, 16.5) % Dry skin 55.6 (40.9, 69.8)% 0.0 (0.0, 4.0) % 51.0 (38.0, 64.0) % 0.0 (0.0, 3.0) % Pruritus 16.7 (6.9, 29.3)% 0.0 (0.0, 4.0) % 21.5 (11.6, 33.3) % 0.0 (0.0, 3.0) % AEs, adverse events; SAEs, severe adverse events. 2.1% (1.0%, 3.6%), respectively. Furthermore, in the present )e efficacy of tolerability-guided dose adjustment re- study, the efficacy of afatinib in the first-line-only group mains controversial. Previously, it has been suggested that was significantly superior to that in the second-line 40 mg was the recommended afatinib dose for first-line treatment. )erefore, the efficacy and safety of afatinib has therapy [10]. A recent study has revealed that the PFS of the been confirmed by RWE. non-full-dose group was 12.8 months, while the PFS was Journal of Oncology 13 % % Study Area RR (95% CI) Study Area RR (95% CI) Weight Weight Brain metastases (No vs. Yes) Brain metastases (No vs. Yes) Ho GF, 2019 Malaysia 3.00 (0.55, 16.38) 0.25 Ho GF, 2019 Malaysia 4.51 (1.45, 14.00) 41.39 Liang SK, 2018 Taiwan 1.06 (0.97, 1.15) 99.75 Liang SK, 2018 1.14 (0.95, 1.38) 58.61 Taiwan Subtotal (I = 30.6%, p = 0.230) 1.06 (0.98, 1.16) 100.00 Subtotal (I = 81.8%, p = 0.019) 2.01 (0.53, 7.60) 100.00 NOTE: Weights are from random effects analysis .01 .1 1 10 100 .01 .1 1 10 100 (a) (b) Study Area RR (95%, CI) Weight Study Area RR (95% CI) Weight Exon 19 deletion vs. Uncommon mutation Exon 19 deletion vs. Uncommon mutation Ho GF, 2019 Malaysia 2.72 (0.41, 18.24) 0.63 Ho GF, 2019 Malaysia 2.27 (0.47, 11.01) 5.64 Liang SK, 2017 Taiwan 1.06 (0.91, 1.23) 99.37 Liang SK, 2017 Taiwan 1.26 (0.86, 1.86) 94.36 Subtotal (I = 0.0%, p = 0.332) 1.07 (0.92, 1.24) 100.00 2 1.30 (0.90, 1.89) 100.00 Subtotal (I = 0.0%, p = 0.477) Exon 21 L858R vs. Uncommon mutation Exon 21 L858R vs. Uncommon mutation Ho GF, 2019 2.28 (0.31, 16.62) Malaysia 0.65 2.65 Ho GF, 2019 Malaysia 0.40 (0.03, 5.21) Liang SK, 2017 1.08 (0.92, 1.27) 99.35 Taiwan Liang SK, 2017 Taiwan 1.39 (0.91, 2.13) 97.35 1.09 (0.92, 1.27) 100.00 2 Subtotal (I = 0.0%, p = 0.463) Subtotal (I = 0.0%, p = 0.350) 1.34 (0.88, 2.05) 100.00 .01 .1 1 10 100 .01 .1 1 10 100 (c) (d) Figure 9: )e meta-analysis results for disease control rates (DCRs) and objective response rates (ORRs) in subgroups after afatinib treatment in advanced NSCLC with EGFR mutation: (a) comparison of DCRs in different status of brain metastases; (b) comparison of ORRs in different status of brain metastases; (c) comparison of DCRs in different mutation sites; and (d) comparison of ORRs in different mutation sites. 11.0 months for the full-dose group; however, the difference groups of tolerability-guided afatinib dose adjustment were was not significant (HR: 1.3, 95% CI [0.9–2.0]) [42]. Yang not significant. Moreover, compared with the 40 mg/day et al. have reported that afatinib 30 mg daily as an initial dose dose, 57.8% (1917/3319) of patients received a lower afatinib presents a similar response rate and PFS as an initial dose of dose, with only 0.5% (18/3319) of patients receiving a higher 40 mg daily [43]. In the current RWE-based meta-analysis, afatinib dose; this could partly explain the lower tolerability the results revealed that the difference in PFS and OS be- and higher toxicities associated with afatinib 40 mg daily. However, it should be noted that the anticancer efficacy ORR tween the afatinib non-full-dose group (<40 mg) and full- dose group (>40 mg) was not significant (P> 0.05). How- of afatinib 30 mg daily did not surpass that of the 40 mg daily ever, the ORR in the full-dose group was 78.5% (95% CI dose. Besides, the incidence and severity of adverse reactions [66.7%, 88.4%]), which was significantly higher than that in showed a decreased trend in patients receiving non-full dose, the non-full-dose group (67.8%; 95% CI [56.8, 77.9]). )us, which indicated the tolerability-guided dose adjustment the real-world data suggested that decreasing the afatinib alleviated afatinib-related adverse effects. )us, the real- dose does not negatively impact efficacy; the full dose should world data support that dose adjustment can be guided be employed for treating NSCLC patients with EGFR mu- according to tolerance once adverse reactions occur. tations if tolerance permits. In addition to the afatinib dose, clinical factors such as brain metastases can influence the results of patients with Furthermore, moderate-to-severe adverse drug reactions usually result in dose reduction or discontinuation. Nu- advanced EGFR-mutant NSCLC [46]. In the LUX-Lung 6 trial, the median PFS of patients with brain metastases merous clinical trials have reported that afatinib 40 mg daily as the starting dose presented severe adverse drug reactions, treated with afatinib was lower than that of patients without including skin rash, paronychia, and diarrhea [11, 12, 44]. brain metastases [47], which was in accordance with our 40 mg afatinib daily presented a significantly higher inci- results, suggesting that brain metastases is an influence dence of Grade 3 skin rash (16% vs. 0%) and diarrhea (100% factor of patients with advanced EGFR-mutant NSCLC vs. 41%) than 30 mg daily afatinib [45]. In the present study, based on afatinib dose. the frequency and severity of adverse events (including )e current study was the first RWE-based meta-analysis diarrhea, skin rash, mucositis, paronychia, and pruritus) was to explore the efficacy and adverse reactions in patients with higher in patients who administered 40 mg afatinib daily advanced EGFR-mutated NSCLC. However, some limita- tions persist in the current study: (1) the small sample size of than in those who administered 30 mg afatinib daily. However, the differences of adverse reactions in the two some included studies influenced certain outcome indicators 14 Journal of Oncology of meta-analysis; (2) it was not possible to assess the prepared and revised the manuscript. All authors read and methodological quality of included studies and the impact of approved the final manuscript. quality on the results in this RWE study owing to a lack of suitable quality evaluation tools; (3) subgroup analysis was Acknowledgments not performed on first-generation or second-generation )is study was supported by grants from the National EGFR-TKIs for comparing afatinib with erlotinib, daco- Natural Science Foundation of Hunan Province (2020JJ4418 mitinib, and gefitinib. and 2020RC3067), Clinical Medical Technology Innovation In conclusion, afatinib is a safe and effective first-line Guided Project (2020SK51112), Natural Science Foundation treatment in patients with EGFR-mutated NSCLC, and of Hunan Province National Health Commission (B2019091 tolerability-guided afatinib dose adjustment might not affect and 20201286), Natural Science Foundation of Changsha the PFS of these patients. )is study was performed based on Science and Technology Bureau (Kq1901084, Kq1901080, real-world data, reflecting information on curative effects in and Kq2001024), Cancer Foundation of China real-world patients and fully compensates for disadvantages (NCC2018B58), Key Research and Development Project of of RCTs. Hunan Province (2017WK2061), and Hui Lan Public Foundation (HL-HS2020-1). Abbreviations CI: Confidence interval Supplementary Materials DCR: Disease control rate Supplementary Figure 1: the meta-analysis results for var- ECOG- Eastern Cooperative Oncology Group ious incidence rates of adverse events after afatinib treat- PS: Performance Status ment in advanced NSCLC with EGFR mutation: (A) the EGFR: Epidermal growth factor receptor incidence rate of fatigue; (B) the incidence rate of increased HR: Hazard risk alanine aminotransferase (ALT); (C) the incidence rate of IR: Incidence rate increased aspartate aminotransferase (AST) levels; and (D) NSCLC: Non-small-cell lung cancer the incidence rate of interstitial lung disease (ILD). Sup- ORR: Overall response rate plementary Figure 2: the meta-analysis results for incidence OS: Overall survival rates of severe adverse events after afatinib treatment in PFS: Progression-free survival advanced NSCLC with EGFR mutation: (A) the adverse RCT: Randomized clinical trial reaction incidence rate of fatigue; (B) the adverse reaction RR: Relative risk incidence rate of increased alanine aminotransferase (ALT) RWE: Real-world evidence levels; (C) the adverse reaction incidence rate of increased TTF: Time to failure aspartate aminotransferase (AST) levels; and (D) the adverse TKIs: Tyrosine kinase inhibitors reaction incidence rate of interstitial lung disease (ILD). WMD: Weighted mean difference Supplementary Figure 3: the meta-analysis results for risk of AE: Adverse event progression-free survival (PFS) after afatinib treatment in SAE: Severe adverse event. advanced NSCLC with EGFR mutation: (A) PFS between brain metastases group vs. non-brain metastases group and Data Availability (B) PFS between exon 19 deletion vs. uncommon, exon 19 )e raw data supporting the conclusions of this manuscript deletion vs. exon 21 L858R, brain metastases (no vs. yes), and will be made available by the authors, without undue res- ECOG-PS (0–1) vs. ECOG-PS (≥2). (Supplementary ervation, to any qualified researcher. Materials) Disclosure References [1] No authors listed, “Erratum: Global cancer statistics 2018: An earlier version of abstract of this manuscript has been GLOBOCAN estimates of incidence and mortality worldwide presented as meeting abstract in 2021 ASCO. for 36 cancers in 185 countries,” CA: A Cancer Journal for Clinicians, vol. 70, p. 313, 2020. 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