Efficacy and safety of adjuvant EGFR-TKIs for non-small cell lung cancer with EGFR mutations after surgery: an updated meta-analysis

doi:10.21203/rs.3.rs-1554109/v1

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Research Article

Efficacy and safety of adjuvant EGFR-TKIs for non-small cell lung cancer with EGFR mutations after surgery: an updated meta-analysis

https://doi.org/10.21203/rs.3.rs-1554109/v1

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posted 18 Apr, 2022

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Objectives: This study aims to investigate the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as adjuvant therapy for resected non-small cell lung cancer (NSCLC) patients harboring EGFR mutations compared with adjuvant chemotherapy or placebo, including the latest updated data.

Methods: A comprehensively systematic search for relevant randomized controlled trials (RCTs) was performed. Hazard ratios (HRs) and 95% confidence intervals (CI) were used to analyse disease-free survival (DFS) and overall survival (OS). For dichotomous data, risk ratio (RR) of severe adverse events and relapse patterns was calculated as effect measures.

Results: Nine RCTs involving 1,835 completely resected patients with NSCLC with EGFR mutations were included in the meta-analysis. The use of EGFR-TKIs resulted in a significant improvement in DFS when compared to non-EGFR-TKIs based treatment (HR:0.45; 95% CI=0.29–0.71, P < 0.0005), but no OS benefit was shown (HR:0.79; 95%CI=0.54–1.16, P =0.23). In subgroup analyses, adjuvant EGFR-TKIs elevated DFS significantly compared to single-agent chemotherapy (HR: 0.50; 95%CI = 0.30–0.82, P = 0.006). Adjuvant EGFR-TKIs following chemotherapy also improved DFS significantly compared with single-agent chemotherapy (HR:0.34; 95%CI=0.16–0.69, P=0.003). No differences were found in DFS between adjuvant EGFR-TKIs versus placebo (HR:0.51; 95% CI=0.18 –1.47, P=0.21). Patients with a median treatment time over 12 months (HR:0.42; 95% CI=0.20–0.86; P =0.02) or diagnosed with stage III non-small cell lung cancer NSCLC (HR:0.42;95% CI = 0.20–0.86; P =0.02) induced better DFS. Elevated DFS from adjuvant EGFR-TKIs was still observed regardless of EGFR Mutation Status. Nevertheless, in subgroup analysis, neither subgroup analysis of therapeutic strategies nor median treatment duration observed any benefit from adjuvant EGFR-TKIs in OS. Moreover, adjuvant EGFR-TKIs decreased the risk of lung recurrence (RR: 0.63 ;95%CI=0.44 –0.89). Rash (RR:15.28; 95% CI = 4.71–49.55), Diarrhea (RR:3.08; 95% CI = 1.26–7.52) and ALT or AST increase (RR:8.85; 95% CI = 4.14–18.90) were several common grades 3 or higher adverse events (AEs) of EGFR-TKIs treatment.

Conclusions: EGFR-TKIs treatment exhibited significant improvement in DFS with fewer manageable toxicities for NSCLC patients with EGFR mutations completely resection compared with non-EGFR-TKIs treatment. However, prolonged DFS did not produce any benefits for the OS.

non-small-cell lung cancer

adjuvant treatment

epidermal growth factor receptor tyrosine kinase inhibitors

survival outcomes

Lung cancer accounts for 11.6% of new cancer cases worldwide [1]. In China or all around the world, the incidence of lung cancer is still increasing in recent years and cancer-related deaths caused by lung cancer are far more than any other cancer. About 85% of lung cancers are non-small cell lung cancer (NSCLC) [2]. At present, the gold standard treatment for stage IB-IIIA NSCLC is complete excision[3]. But rates of recurrence are high and 40–60% of patients after surgery die within five years [4]. Adjuvant chemotherapy is approved as standard therapy for NSCLC patients after surgical resection to minimize the chance of postoperative recurrence[5]. Several RCTs[6] have demonstrated that adjuvant cisplatin-based regimen were related to better survival outcomes compared to surgery alone. However, the benefit of adjuvant chemotherapy was only estimated at 5.4% of 5-year OS. Except for high rates of recurrence, the cytotoxic effect of chemotherapy is also the main reason for refusing chemotherapy or incompletion of the treatment[7]. Therefore, alternative therapies which have a better effect on survival improvements are urgently needed. Adjuvant EGFR-TKIs used in patients with advanced disease contributes to better progression-free survival compared to conventional chemotherapy[8]. Approximately 50% of Asian populations have EGFR mutations[9]. The most common mutation status are the exon 19 deletion and exon 21 L858R in NSCLC patients[10]. Patients with advanced NSCLC that has EGFR mutations must receive EGFR-TKI therapy as standard treatment, which could result in better DFS and OS than chemotherapy [11, 12]. Therefore, people started to investigate EGFR-TKIs based adjuvant treatment for NSCLC after completely resection. Several clinical trials comparing adjuvant EGFR-TKIs with chemotherapy or placebo obtained meaningful findings that inform clinical decision making, but there is disagreement over whether adjuvant EGFR-TKIs are effective. Some trials reported that EGFR-TKIs improved DFS or OS for EGFR-mutant NSCLC after surgical resection [13–20], whereas others obtained negative results [21–24]. On December 18, 2020, based on the ADAURA study, adjuvant osimertinib is approved in the United States as an alternative treatment for patients with NSCLC whose tumors have EGFR-mutations. But, whether treatment with EGFR-TKIs improves long-term outcomes compared to adjuvant chemotherapy or placebo remains controversial.

Recently, EVAN [14] and ADJUVANT [13] study updated their latest OS data and exploratory analysis. And another two head-to-head researches, the EVIDENCE [15] study and IMPACT [21] study, presented their findings. We aimed to conduct a comprehensively updated meta-analysis of only RCTs to evaluate the efficacy and safety of adjuvant EGFR-TKIs in completely resected EGFR mutant NSCLC.

2.1 Search Strategy

Trials comparing the survival of adjuvant EGFR-TKIs with chemotherapy or placebo in EGFR mutant NSCLC after radical resection were eligible for inclusion. The Cochrane Library, Embase, and PubMed were searched for eligible studies published up to November 5, 2021, without restriction regarding the start date. The main search terms used included “lung cancer,” “non-small cell lung cancer,” “EGFR,” “gefitinib,” “afatinib,” “erlotinib,” “icotinib,” “dacomitinib,” or “osimertinib,” “epidermal growth factor receptor,” and “randomized control trial”. Detailed search strategies are available in supplementary materials. Abstracts of recent academic conferences were supplemented by manual searches.

2.2 Study Selection

Inclusion criteria are as follows: (1) patients must be pathologically confirmed as stage I–IIIA, completely resected NSCLC harboring EGFR mutations; (2) RCTs comparing adjuvant EGFR-TKIs with chemotherapy or placebo after operation were eligible; (3) the trial reported primary outcome or secondary outcome, such as DFS, OS or Toxicity. The exclusion criteria were as follows: (1) cases, duplicate records, single-arm trials, retrospective studies, reviews, meta-analysis; (2) patients who had previously undergone immunologic therapy, EGFR-TKIs or radiotherapy before resection; (3) trials ended early or had insufficient data for statistical analysis.

2.3 Data Extraction

Two investigators independently extracted the basic data and disagreement was settled through discussion with a third investigator. Following baseline data were collected: the first author, publication time, name of the trial, region, trial phase, sample size, median age, median follow-up time, median EGFR-TKIs treatment time, number of participants in experiment groups and control groups, survival outcomes, EGFR mutation status, number of adverse events(graded ≥ 3) and sites of relapse. The primary outcome was DFS. Secondary outcomes were OS, grade 3/4 AEs and recurrence.

2.4 Statistical Analysis

Two investigators used the Cochrane Collaboration’s Tool for estimating the risk of bias to evaluate the quality of included studies [25]. Publication bias was evaluated by Egger’s and Begg’s tests. Statistical significance was defined as p-value < 0.05. Review Manager 5.4 software and STATA 12.0 software were used to perform all statistical analyses. HRs for primary endpoint DFS and secondary endpoint OS and their 95% CIs were collected from each trial. If the trial didn’t report HRs or 95% Cis, we estimate the HR from Kaplan–Meier curves in accordance with the measures of Tierney et al. [26].and Parmar et al .[27]. For time-event variables, including DFS and OS, we calculated log-transformed hazard ratio [log (HR)] and standard error values from HR and their 95% CIs to summarize HRs via the generic inverse variance method. For dichotomous variables, such as grade 3/4 AEs and relapse sites, we calculated the risk ratios (RRs) via the Mantel–Haenszel method.

Q-test and I² statistic test were performed to estimate the heterogeneity among studies. I² > 50% or Q-test p < 0.1 was deemed as significant heterogeneity and the random effects model was conducted to pool outcomes [28]. Otherwise, the fixed-effects model was applied. If the heterogeneity was significant, subgroup analyses and sensitivity studies were performed to investigate the sources of the heterogeneity. Simultaneously, s subgroup analysis was performed to identify factors affecting the efficacy of EGFR-TKIs on excised EGFR-mutated NSCLC Subgroup analyses included therapeutic strategies, EGFR mutation status, median treatment duration and disease stage. And Sensitivity analysis was performed by excluding each study sequentially. We used bilateral P-values and conducted the analysis with a significance level of 0.05.

3.1 Characteristics of Included Studies

A comprehensive literature search yielded a total of 4,604 non-duplicate records. The full texts of 20 articles were reviewed after screening the titles and abstracts of the articles. Finally, nine trials comparing adjuvant EGFR-TKIs group with non-EGFR-TKIs group in NSCLC patients undergoing radical surgery were included in this meta-analysis. In the PRISMA flow diagram, the detailed process of literature search is displayed. (Fig. 1)

From nine clinical trials, 1,835 EGFR mutation-positive, resected NSCLC patients (938 patients in the adjuvant EGFR-TKIs group and 897 patients in the non-EGFR-TKIs group) were involved in the meta-analysis. RADIANT study, BR19 study and ADAURA study compared adjuvant EGFR-TKIs with placebo. The other six trials were head-to-head researches directly comparing adjuvant EGFR-TKIs with chemotherapy. Among nine clinical trials, NSCLC patients with EGFR mutations only accounted for 16.5% and 3.0% in the RADIANT study and BR19 study, respectively. So, we enrolled participants with EGFR mutations separately from the BR19 and RADIANT trials. Moreover, the BR19 study finished early with the smallest sample size. The EVAN study updated the latest OS published as a conference abstract. The characteristics of all the included trials are presented in Table 1.

Table 1

characteristics of included trials
Trial	Patients	Stage	Median age	Median treatment TKI duration(month)	Median follow up(month)	Treatment				HR(95%CI)
Trial	Patients	Stage	Median age	Median treatment TKI duration(month)	Median follow up(month)	Intervention	N	Control	N	DFS	OS
Br19 2013[21]	15	IB-IIIA	66.5	4.8	56.4(range 1.2–75.6)	gefitinib	7	placebo	8	1.84(0.44–7.73)	3.16(0.61–16.45)
Li 2014[13]	60	IIIA	57	6	30(range 3.7–52.7)	chemotherapy-gefitinib	30	chemotherapy	30	0.37(0.16–0.85)	0.37(0.12–1.11)
Feng 2015[22]	39	IB-IIIA	56	NA (range 4–8)	24	chemotherapy-icotinib	21	chemotherapy	18	0.25(0.06–1.09)	NA
RADIANT 2015[23]	161	IB-IIIA	62	11.9	47	erlotinib	102	placebo	59	0.61(0.38–0.98)	1.09(0.55–2.16)
ADAURA 2020[17]	682	IB-IIIA	63	22.5	24	osimertinib	339	placebo	343	0.20(0.15–0.27)	NA
EVAN 2021[19]	102	ⅢA	51	23.9	54.8	erlotinib	51	chemotherapy	51	0.27(0.14–0.53)	0.32(0.15–0.67)
ADJUVANT 2021[20]	222	II–IIIA	59	21.9	80	gefitinib	111	chemotherapy	111	0.56(0.40–0.79)	0.92(0.62–1.36)
EVIDENCE 2021[18]	322	II–IIIA	59	22.2	24.9	icotinib	161	chemotherapy	161	0.37(0.24–0.55)	0.75(0.37–1.51)
IMPACT 2021[24]	232	II–IIIA	64	24	70	gefitinib	116	chemotherapy	116	0.92(0.67–1.28)	1.03(0.65–1.65)

3.2 DFS

All nine trials, comparing the EGFR-TKIs group with the non-EGFR-TKIs group in the adjuvant setting for patients with resected EGFR-mutant NSCLC, reported DFS follow-up data. The data of patients with EGFR mutations in BR19 and RADIANT trials were extracted. The heterogeneity was significant (I² = 86%; P < 0.05; Fig. 2A), and hence a random-effects model was applied to pool the data. The pooled HRs demonstrated that compared with the non-EGFR-TKIs group, treatment with EGFR-TKIs was associated with a significantly prolonged DFS (HR:0.45, 95% CI = 0.29–0.71, P = 0.0005, Fig. 2A). Sensitivity analysis was performed, but excluding any study did not influence the final pooled results, suggesting the stability and reliability of our results.

3.3 Subgroup analyses of DFS

3.3.1therapeutic strategies

Four trials compared adjuvant EGFR-TKIs with chemotherapy alone. The Br.19, RADIANT and ADAURA trials compared adjuvant EGFR-TKIs with a placebo. Li’s study and Feng’s study compared adjuvant EGFR-TKIs following chemotherapy with adjuvant single-agent chemotherapy. In the subgroup analysis of different therapeutic strategies, adjuvant EGFR-TKIs improved DFS significantly compared with single-agent chemotherapy (HR: 0.50; 95%CI = 0.30 − 0.82, P = 0.006, I² = 83%, Fig. 3A). Adjuvant EGFR-TKIs following chemotherapy also induce longer DFS than adjuvant single-agent chemotherapy (HR: 0.34 ;95%CI = 0.16–0.69, P = 0.003, I² = 0, Fig. 3A). But the HR was 0.51(95%CI = 0.18 − 1.47, P = 0.21, I² = 91%, Fig. 3A), when compared adjuvant EGFR-TKIs with the placebo.

3.3.2EGFR Mutation Status

A total of seven studies reported subgroup data on EGFR mutation types. The exon 19 deletion and exon 21 L858R are two most common mutation subtypes of NSCLC. Results of this subgroup analysis were based on 751 NSCLC patients with exon 19 deletion and 552 patients with L858R mutation from seven RCTs. The HR of DFS in patients with Exon 19 deletion or L858R point mutation was 0.37 (95% CI = 0.20–0.69; P = 0.002; I² = 84%, Fig. 3B) and 0.52 (95% CI = 0.34–0.78; P = 0.002; I² = 68%, Fig. 3B), respectively, with statistical significance.

3.3.3 Disease stage

A total of six studies reported subgroup DFS data on disease stages. Pooled HRs demonstrated that patients with more advanced disease might benefit more from EGFR-TKIs. As shown in Fig. 5, patients diagnosed with stage III NSCLC showed a favorable effect on DFS, with a HR of 0.42 (95% CI = 0.20–0.86; P = 0.02, I² = 92%, Fig. 3C). However, no significant difference was observed in DFS for stage I (HR :0.65; 95% CI = 0.26–1.59, P = 0.35, I² = 83%, Fig. 3C) and II (HR:0.46; 95% CI = 0.20–1.04, P = 0.06, I² = 88%, Fig. 3C) NSCLC patients.

3.3.4 Median treatment duration

In order to explore the effect of treatment duration on DFS benefit of adjuvant EGFR-TKIs treatment, we performed the subgroup analysis of median treatment duration. The treatment duration of eight trials was 2 years. The ADAURA trial was 3 years. Most lung cancers after surgery relapse within 1 year or 2 years [29, 30]. Because the median treatment duration of all the studies was less than two years, we set 12 months as the end time of median treatment duration, and nine studies were divided into two groups. The median duration of treatment was more than 12 months, and the risk of disease recurrence was significantly reduced by 59%. The HR was 0.41 (95% CI = 0.35–0.48, P < 0.00001, Fig. 3D), with significant heterogeneity (I² = 92%, p < 0.00001). However, when median treatment duration was less than 12 months, adjuvant EGFR-TKIs didn’t improve DFS compared with non-EGFR-TKIs, with a HR of 0.55 (95% CI = 0.18–1.51, P = 0.04, I² = 56%, Fig. 3D).

3.4 OS

Data for the OS were available in seven trials. The Feng’s trial and the ADAURA trial did not report OS data. Among the other included studies, the EVAN and ADJUVANT studies updated the latest OS data recently. The HRs of subgroups with EGFR mutations in BR19 trial and RADIANT trial were extracted. The HR of OS calculated from seven trials demonstrated adjuvant EGFR-TKIs in patients with EGFR-mutant NSCLC after radical resection showed a trend of decreasing the risk of all-cause death compared to control groups, although no significant improvement was observed statistically (HR: 0.79; 95%CI = 0.54–1.16, P = 0.23 Fig. 2B). Moderate heterogeneity was detected (I ² = 53.0%, P = 0.05). We conducted a random-effects model and a sensitivity analysis. After sequentially deleting each study, the corresponding summary HRs did not change significantly.

3.4.1 Subgroup Analyses of OS

In the subgroup analysis of different therapeutic strategies, adjuvant EGFR-TKIs didn’t induce longer OS compared with placebo (HR:1.41; 95% CI = 0.58–1.44; P = 0.45, I² = 27%, Fig. 4A). The OS of adjuvant EGFR-TKIs was also not statistically significant compared with adjuvant chemotherapy (HR:0.74; 95%CI = 0.48–1.15, P = 0.18, I² = 60%, Fig. 4A). Only Li’s study reported OS data comparing adjuvant EGFR-TKIs following chemotherapy with chemotherapy. And adjuvant EGFR-TKIs following chemotherapy also didn’t improve OS compared with chemotherapy (HR:0.37;95% CI = 0.12–1.11; P = 0.08, I² = NA, Fig. 4A).

we performed the OS subgroup analysis of different treatment duration to explore the effect of treatment duration of adjuvant EGFR-TKIs on OS benefit. We set 12 months as the end time of median treatment duration the same as subgroup analyses of DFS. When the median treatment time was over 12 months, adjuvant EGFR-TKI didn’t improve OS compared with non-EGFR-TKIs group, with a HR of 0.74 (95% CI = 0.48–1.15; P = 0.18, Fig. 4B). Significant heterogeneity was detected (I ² = 60%, P = 0.06). When the median treatment time was less than 12 months, the HR was also no statistical significance (HR = 0.96 95% CI = 0.36–2.6, P = 0.94, Fig. 4B), with significant heterogeneity (I² = 60%, p = 0.08). Since the OS data of subgroups with EGFR mutation status and Disease stage were not reported, we did not perform subgroup analyses of EGFR mutation status and disease stage for OS.

3.5 Disease Relapse

The EVAN study and the study by Feng didn’t report data on disease recurrence. Li’s study only reported brain recurrence. Detailed data on disease recurrence from the ADJUVANT study were published in another paper. [31]. A total of seven trials were included. Adjuvant EGFR-TKIs reduced the risk of lung relapse (RR: 0.63; 95%CI = 0.44 − 0.89; Fig. 5D), but didn’t decrease the incidence of local recurrence (RR: 0.49; 95%CI = 0.20 − 1.15, Fig. 5A) and distant relapse (RR:0.44; 95%CI = 0.15 − 1.25, Fig. 5B). EGFR-TKIs therapy also didn’t reduce the risk of bone recurrence (RR:0.69; 95%CI = 0.43 − 1.11, Fig. 5E) and liver recurrence (RR: 0.46; 95%CI = 0.13 − 1.60, Fig. 5F). EGFR-TKIs tended to reduce brain relapse (OR:0.78, 95%CI = 0.37–1.68, Fig. 5C), but the difference was not statistically significant. However, adjuvant osimertinib could significantly decrease the risk of brain relapse (RR:0.12; 95%CI = 0.04–0.34, Fig. 5C).

3.6 Adverse Reactions

Toxicity analysis only included grade 3 or higher adverse events (AEs), which are illustrated in Table 2. Compared with the non-EGFR-TKIs group, adjuvant EGFR-TKIs was related with a higher incidence of rash (RR:15.28; 95% CI = 4.71–49.55), Diarrhea (RR:3.08; 95% CI = 1.26–7.52) and ALT or AST increase (RR:8.85; 95% CI = 4.14–18.90). Neutropenia (RR:0.01; 95% CI = 0.00–0.04), vomiting or nausea (RR:0.04; 95% CI = 0.01–0.18) and Leucopenia (RR:0.08; 95% CI = 0.01–0.87) were the three most common AEs of non-EGFR-TKI therapy.

Table 2

Severe Adverse events comparing EGFR-TKIs-based therapy vs EGFR-TKIs -based therapy
Toxicity	Number of trials	EGFR-TKI-based therapy		Non-EGFR-TKI-based therapy		RR (95%CI)	P	Heterogeneity
Toxicity	Number of trials	Events	Total	Events	Total	RR (95%CI)	P	I²(%)	P
Neutropenia	4	1	439	194	439	0.01(0.00-0.04)	< 0.00001	0	0.69
Leucopenia	5	2	469	109	469	0.08(0.01–0.87)	0.04	73	0.006
Hypokalaemia	3	0	388	7	388	0.18(0.03-1.00)	0.05	0	0.88
Anorexia	5	5	748	20	709	0.28(0.12–0.69)	0.006	44	0.13
Diarrhea	7	19	910	4	871	3.08(1.26–7.52)	0.01	0	0.69
ALT/AST increased	3	53	388	7	388	8.85(4.14–18.90)	< 0.00001	73	0.02
Paronychia	2	7	455	0	459	8.04(1.01–63.98)	0.05	0	0.91
Rash	6	50	571	0	528	15.28(4.71–49.55)	< 0.00001	0	0.93
Anaemia	3	1	616	25	620	0.08(0.02–0.32)	0.0005	0	0.6
Vomiting/Nausea	4	0	353	44	353	0.04(0.01–0.18)	< 0.0001	17	0.31
Myelosuppression	3	0	323	12	323	0.11(0.02–0.58)	0.01	0	0.98
Fatigue	5	1	455	7	412	0.32(0.09–1.13)	0.08	0	0.83

3.7 Study Quality and Publication Bias

As seen in risk of bias graphs (Figure S1), six studies were not double-blinded trials and were assessed as high risk for performance bias or detective bias. The other three trials were at a low risk of Bias. Based on data of DFS and OS, funnel plots of Egger’s tests that assessed the publication bias between adjuvant EGFR-TKIs and non-EGFR-TKIs were drawn. (Fig.S2) These plots are visually symmetric. Likewise, no publication bias was found for DFS (p = 0.602 [> 0.05] for Begg’s test, p = 0.089 [> 0.05] for Egger's test) and OS (p = 0.368 [> 0.05] for Begg’s test, p = 0.315 [> 0.05] for Egger's test).

In stage IB-IIIA NSCLC patients undergoing radical surgery, adjuvant therapy is required due to the presence of micro-metastases or residual tumor cells after surgery. Previous meta-analyses have demonstrated that adjuvant EGFR-TKIs could prolong DFS with fewer adverse reactions [32–36]. Nevertheless, those meta-analyses included fewer RCTs or retrospective studies. they were lower in quality and reliability. Our study included all RCTs to date, which is the largest meta-analysis of adjuvant EGFR-TKIs for stage IB-IIIA NSCLC patients undergoing radical surgery. The latest OS data and exploratory analysis of EVEN and ADJUVANT studies were included. Moreover, two recently published head-to-head research studies, EVIDENCE study and IMPACT study, were added, with an increase of 43% in the sample size of patients with EGFR mutations.

Our analysis revealed that adjuvant EGFR-TKIs significantly improved DFS and reduced the risk of recurrence by 62% compared with non-EGFR-TKIS treatment in NSCLC patients with EGFR-positive mutations after radical resection. Therefore, these studies strengthened the current evidence of a DFS benefit of EGFR-TKIs treatment, suggesting that they can provide an alternative to adjuvant chemotherapy for patients with EGFR-mutated NSCLC. However, DFS benefit did not transformed into an OS advantage in our study.

With respect to reasons why adjuvant EGFR-TKIs did not induce longer OS. The Br 19 study and Li’s study did not obtain significantly improved OS benefit, which may be due to the short treatment time and small sample size in EGFR mutations. In addition, the OS data of the RADIANT, ADAURA and EVIDENCE study were immature because of short follow-up times. Though the updated OS in EVAN was encouraging, it was challenging to determine whether adjuvant EGFR-TKIs has OS benefit since this was a statistically weak phase II trial. Treatment considerations after relapse will be of great importance. Another possible reason is that the control group may have received follow-up therapy after the disease relapsed, which would have improved OS the control group. But this makes it difficult to achieve statistically significant differences in OS between the experiment group and the control group. In ADJUVANT study, patients treated with follow-up EGFR-TKIs had longer OS compared with patients in the VP group who received other follow-up treatments. (Median OS, 62.8 months; 95% CI, 40.5 to NC and median OS, 49.5 months; 95% CI, 34.7 to NC, respectively). Therefore, the proposal of using DFS as an alternative for OS in the adjuvant setting should be also taken into consideration [37, 38]. The OS data of ongoing trial ADAURA regarding osimertinib is eagerly awaited.

We detected that adjuvant EGFR-TKIs did not improve DFS compared with placebo. In this subgroup, among three RCTs enrolled, the Br.19 and RADIANT trials included unselected NSCLC patients. The Br.19 trial terminated prematurely obtained negative results. And only 15 patients harboring EGFR-mutations were recruited. As for RADIANT study, the proportion of NSCLC patients with EGFR mutations after surgery was only 16.5%(161/973). Therefore, any conclusions drawn from the results including above two studies should be interpreted with caution. No improvement of OS was detected in the subgroup analysis of different therapeutic strategies. The results showed that adjuvant EGFR-TKIs following chemotherapy improved DFS significantly compared with chemotherapy alone in postoperative patients. But in this subgroup, only Feng’s study and Li’s study were included with a small sample size. Hence, whether the optimal treatment regimen for resected NSCLC patients with EGFR-mutations is adjuvant EGFR-TKIs alone or EGFR-TKIs after chemotherapy still needs better-designed researches are needed to confirm.

Over the last decade, status of EGFR mutation has been the most useful predictors of the response to EGFR-TKIs treatment in lung adenocarcinoma [39]. Previous studies have shown that in advanced NSCLC, patients with exon 19 deletion mutations have longer progression-free survival and higher objective response rates than patients with exon 21 L858R point mutations [40]. The reason may be that the tyrosine kinase domain of the exon 19 deletion has a more powerful binding force to EGFR-TKIs than that of the L858R mutant [41]. How about the results when EGFR-TKIs administrated in EGFR-mutant NSCLC after surgery? In our exploratory study, DFS benefits were observed regardless of mutation subtypes. The pooled HR showed that adjuvant EGFR-TKIs treatment seems to be also more effective for exon 19 deletion subgroup. But the hypothesis needs additionally specific experimental designs to confirm.

Patients with different stages may have differential effects on survival outcomes. Br 19 study, Feng’s study, RADIANT study and ADAURA study enrolled stage IB–IIIA NSCLC patients while EVAN and Li’s studies only recruited stage IIIA patients. ADJUVANT, EVIDENCE and IMPACT trials mainly centered on stage II and IIIA disease. Included patients with different stages may be an important reason leading to significant heterogeneity among these trials. Previous literature reported that patients with stage II–IIIA disease could benefit from chemotherapy, but for those people with stage IB disease, chemotherapy is not recommended for standard treatment [42]. Whether IB patients after radical operation can benefit from adjuvant EGFR-TKIs remained controversial. Our study detected that adjuvant EGFR-TKIs significantly improved DFS in patients with stage III NSCLC. DFS of stage I and II NSCLC patients were not statistically significant. We hypothesized that stage IIIA NSCLC patients might be related to higher levels of tumor residues or circulating tumor DNA (ctDNA) than stage I and II [43], which cannot be removed by surgery and may be sensitive to systemic treatment. The mechanism remains to be further studied.

Our study manifested that longer treatment duration may be related with better DFS benefits. But the optimal duration of adjuvant EGFR-TKIs treatment needs more specialized trials to confirm. The treatment duration of eight study that we included was 2 years, which was based on the previous studies such as the SELECT [44]and that the highest peak for metastases post-surgery occurred within 1 year or 2 years with chemotherapy. Since many of the studies did not reach the required two-year treatment duration, our analysis observes a better DFS with median treatment duration more than 12 months. But no significant improvement of DFS was observed when median treatment duration less than 12 months. Our results manifested that treatment duration may be associated with difference DFS benefits. A RCT of three months or two years of adjuvant afatinib in resected stage I-III EGFR-mutant NSCLC by Joel W. Neal [45]detected that the median Relapse Free Survival (RFS) was 42.8 months in the three-month group and 58.6 months in the two-year group. Relapses at 2 years were 11% less than with 3 months of adjuvant afatinib. Postoperative patients might obtain better DFS from adjuvant EGFR-TKIs with longer treatment duration. However, for patients considering long-term adjuvant EGFR-TKIs therapy, early drug withdrawal may also affect the study results. Therefore, taking tolerance of therapy into consideration will be essential. The ICOMPARE study is an ongoing trial comparing one year of adjuvant icotinib with two years of that in patients with resected stage II-IIIA NSCLC with EGFR mutations and may produce more important data regarding survival outcomes and toxic effects.

Osimertinib has been shown to cause longer DFS and OS than first generation EGFR-TKIs in advanced NSCLC [46]. In addition, osimertinib has been proved to have higher blood concentrations in the brain than other generations EGFR-TKIs in advanced NSCLC [47]. Osimertinib induced longer DFS than placebo dramatically according to ADAURA study and significantly decrease the risk of brain metastases. However, no direct comparisons between different generations of EGFR-TKIs were designed. And ADAURA study is not a head-to-head research study comparing EGFR-TKIs with chemotherapy. Hence more head-to-head RCTs of adjuvant osimertinib are needed. Only EVAN study provided an OS benefit with erlotinib to date. We are looking forward to the updated OS data of ADAURA.

Our previous published meta-analysis [37] showed that adjuvant EGFR-TKIs was associated with more grade 3 or higher AEs compared with the placebo but fewer grade 3 or higher AEs compared with adjuvant chemotherapy. In this meta-analysis, we specifically analyzed the respective adverse reactions of EGFR-TKIs and non-EGFR-TKIs group. It has been reported that adjuvant EGFR-TKIs increased the risk of rash, liver dysfunction, and diarrhea [48], and the most common adverse reactions of adjuvant chemotherapy were hematologic toxicity and inappetence [49], which were consistent with our results for toxicity of EGFR-TKIs. For the EGFR-TKIs group, all grade 3 or higher AEs were manageable, demonstrating that the tolerability of EGFR-TKIs is acceptable for postoperative patients.

Limitations

The meta-analysis has several limitations. First, portion of the data used to synthesize the final results of our meta-analysis were extracted from subgroup analyses of published RCTs, rather than individual patient data. subgroup analyses could tend to overestimate treatment effects. Secondly, some pooled results of our meta-analysis had significant heterogeneity, although we took random-effects models, subgroup analyses and sensitivity analyses to reduce heterogeneity. Diversity and inadequacy of data, such as difference in characters of patients, Types of medicine, experimental designs and follow-up time, may lead to clinical heterogeneity. Moreover, Subsequent treatments and quality of life need to be taken into consideration.

In conclusion, adjuvant EGFR-TKIs significantly decreased the risk of relapse with fewer manageable toxicity in completely resected, stage IB– IIIA, NSCLC patients harboring EGFR mutations compared with non-EGFR-TKIs treatment. However, prolonged DFS did not yield the OS benefits. Adjuvant EGFR-TKIs or EGFR-TKIs following chemotherapy induced longer DFS compared with single-agent chemotherapy. Advanced disease stages and longer treatment duration had significant clinical implications for DFS. EGFR-TKIs therapy could reduce the risk of lung relapse. Therefore, we recommend adjuvant EGFR-TKIs for resected NSCLC patients with EGFR mutations in terms of improving DFS. More studies are needed to confirm our conclusions and explore the optimal TKIs treatment duration and sensitive regimen for specific people.

EGFR-TKIs, epidermal growth factor receptor tyrosine kinase inhibitors; NSCLC, non-small cell lung cancer; RCTs, randomized controlled trials; DFS, disease free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval.

Acknowledgements

None.

Availability of data and materials

The datasets supporting the conclusions of this article are included within

the article.

Consent for publication

Not applicable.

Statement of Ethics

No ethical approval was required as this was a meta-analysis and all data were previously published.

Declaration Competing of Interest

None.

Funding

None.

Author Contributions

Conception and design: Qian Yuan, Hua Chen. Data collection: Jun-Wen Gan, Xiao-jin Wang. Statistical analysis: Qian Yuan, Xiang-wen Wu, Hong-cheng Zhong. Manuscript writing and revising: Qian Yuan, Hua Chen, Qing-dong Cao. All authors have read and approved the manuscript.

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No competing interests reported.

FigureS1.png
Figure S1 Assessment of risk of bias. (A) Risk of bias summary. (B) Risk of bias graph.
FigureS2.png
Figure S2 Egger’s funnel plots of publication bias A Publication bias for DFS between EGFR-TKIs and non-EGFR-TKIs B Publication bias for OS between EGFR-TKIs and non-EGFR-TKIs

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Efficacy and safety of adjuvant EGFR-TKIs for non-small cell lung cancer with EGFR mutations after surgery: an updated meta-analysis

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Abstract

Figures

1. Introduction

2. Materials And Methods

2.1 Search Strategy

2.2 Study Selection

2.3 Data Extraction

2.4 Statistical Analysis

3. Results

3.1 Characteristics of Included Studies

3.2 DFS

3.3 Subgroup analyses of DFS

3.3.3 Disease stage

3.3.4 Median treatment duration

3.4 OS

3.4.1 Subgroup Analyses of OS

3.5 Disease Relapse

3.6 Adverse Reactions

3.7 Study Quality and Publication Bias

4. Discussion

5. Conclusions

Abbreviations

Declarations

References

Competing Interests

Supplementary Files

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