Background: Non-small cell lung cancer (NSCLC) accounts for about 85% of generally reported lung cancer patients. Objectives: This is a systematic review of the clinical efficacy and safety of osimertinib in treating epidermal growth factor receptor (EGFR) mutation-positive advanced NSCLC. Methods: A network search was completed for clinical research literature (from inception of each database to May 30, 2020) on osimertinib for EGFR mutation-positive advanced NSCLC. Strict inclusion and exclusion criteria were formulated to screen the literature. After data extraction, RevMan 5.3 software was utilized for quality evaluation and meta-analysis. The primary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events of grades 3 and 4. Results: Finally, 6 eligible articles and a total of 1,848 patients containing 1,123 in experimental groups and 725 in control groups were included. Meta-analysis indicated that ORR (odds ratio [OR] = 3.40, 95% CI 1.64∼7.01, p = 0.0009), DCR (OR = 4.36, 95% CI 3.09∼6.15, p < 0.00001), PFS (HR = 0.36, 95% CI 0.27∼0.47, p < 0.00001), and OS (OR = 0.58, 95% CI 0.46∼0.72, p < 0.00001) of the experimental group were prominently better than the control group. Adverse events of grades 3 and 4 mainly incorporated decreased nausea, rash, stomatitis, and vomiting, which were dramatically relieved compared with the control group. Conclusion: Osimertinib is currently an appreciably effective and well-tolerated therapeutic avenue for EGFR mutation-positive advanced NSCLC.

© 2022 S. Karger AG, Basel

Introduction

Non-small cell lung cancer (NSCLC) occupies about 85% of generally reported lung cancer patients. Platinum-based chemotherapy is the cornerstone for patients with advanced NSCLC [1]. The discovery of oncogenic driver genes, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase rearrangements, as well as the development of specific molecular targeted drugs [2], have fundamentally altered treatment prospects for patients with advanced NSCLC.

EGFR-tyrosine kinase inhibitors (TKIs) are suggested to be the first-line treatment for EGFR-mutated advanced NSCLC [3]. Although the clinical response rate of EGFR-TKIs is relatively high (about 50–70%), patients usually develop drug resistance within 1–2 years of treatment [4]. The secondary mutation of T790M EGFR is presented as the prominent factor of resistance cases [5]. T790M mutation reduces the ability of first-generation reversible EGFR-TKIs (gefitinib, erlotinib, icotinib) to bind to the adenosine triphosphate-binding pocket [6, 7]. Although second-generation EGFR-TKIs (afatinib, dacomitinib) can overcome the T790M resistance mutation, their toxicity limits clinical application [8, 9]. Hence, the development of third-generation EGFR TKIs is necessary. The third-generation aims to target EGFR-TKI sensitivity mutations and T790M resistance mutations, thereby repressing EGFR T790M positive tumor growth [10]. We will further investigate the function of osimertinib compared with previous generations of EGFR-TKIs in EGFR mutation-positive advanced NSCLC patients.

Osimertinib (AZD9291), as the third-generation EGFR-TKIs, can selectively alleviate EGFR-TKI sensitivity and EGFR T790M resistance mutations, with low activity against wild-type EGFR [11]. A recent study has elucidated that osimertinib is superior to standard EGFR-TKI treatment with similar safety and a lower incidence of serious adverse events in the first-line treatment of EGFR mutation-positive advanced NSCLC [12]. At present, clinical controlled trials on osimertinib and standard EGFR-TKI treatment have been carried out. However, the results are controversial due to the difference in sample size among individual studies. Thus, it is still not clear about the clinical efficacy of osimertinib for treating EGFR mutation-positive advanced NSCLC. We attempted to systematically analyze clinical efficacy and safety of osimertinib for treating EGFR mutation-positive advanced NSCLC and provide a reference for osimertinib in lung cancer therapy.

Materials and MethodsLiterature Retrieval

A network search of PubMed, Embase, Web of Science, and the Cochrane Library was performed for clinical research literature (from inception of each database to May 30, 2020) on osimertinib for treating EGFR T790M mutation-positive advanced NSCLC. The following retrieval strategies were adopted: (“osimertinib” OR “AZD3759” OR “mereletinib” OR “Tagrisso”) AND (“Non-Small Cell Lung Cancer” OR “Non-Small Cell Lung Carcinoma” OR “Non Small Cell Lung Carcinoma” OR “Non-Small-Cell Lung Carcinoma” OR “Nonsmall Cell Lung Cancer” OR “Non-Small-Cell Lung Carcinomas” OR “Non-Small-Cell Lung Carcinoma” OR “NSCLC”). Furthermore, we manually searched the included references to avoid missing any eligible studies.

Literature ScreeningInclusion Criteria

(1) Research object: EGFR mutation-positive advanced NSCLC patients; (2) research type: randomized controlled trials; (3) interventional measures: the experimental group received osimertinib and control group received platinum-based chemotherapy or other EGFR-TKI drugs or placebo; (4) outcome indicators: the description of hazard ratio (HR) of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and incidence of adverse events of grades 3 and 4, etc.

Exclusion Criteria

(1) The patients did not meet the diagnostic criteria for EGFR mutation-positive advanced NSCLC; (2) studies only used pre- and posttreatment controls or multiple controls; (3) animals experiments were carried out; (4) inconsistent literature data; (5) republished literature, reviews, case reports, meeting records, and expert experience documents.

Data Extraction and Quality Assessment

The literature review protocol was developed in accordance with the PRISMA checklist. Two investigators independently conducted a literature study, screened the literature in strict accordance with the established inclusion and exclusion criteria, and recorded the reasons and number of the excluded literature, respectively. Any discrepancies on whether to include the same literature were resolved by a third investigator after discussion and reasons statement by the previous two investigators. Data extraction was performed after selection, which comprised authors, the year of publication, sample size, interventional measures, and outcome indicators. In terms of the Cochrane Handbook for Systematic Reviews 5.3, study quality was measured from five domains: allocation method, allocation concealment, blinding, loss to follow-up and withdrawal, and intention analysis. The eligible pieces of literature were divided into 3 classes: A, B, and C according to the evaluation results.

Statistical Methods

Cochrane Systematic Reviews Software RevMan 5.3 was utilized for meta-analysis. A heterogeneity test with the χ2 test was used to assess whether there was heterogeneity among the studies. p ≥ 0.1 and I2<50% suggested that there was statistical homogeneity among studies and fixed-effects models were adopted. p < 0.1 and I2 ≥ 50% indicated that there was statistical heterogeneity among studies and random-effects models were adopted. Binary categorical variables adopted odds ratio (OR) as the effect size for combined statistics, and 95% CI was calculated for meta-analysis. OR was set as the ordinate in a funnel chart to determine whether there was any bias among the studies. The measurement data adopted mean difference as the effect size, and the 95% CI was calculated to estimate whether there were statistical differences in effects of varying interventions on different outcome indicators. p < 0.05 was considered as the difference was statistically significant.

ResultsLiterature Screening Results

1,364 documents were retrieved in network, and 332 studies were duplicated. 1,020 reviews, meeting records, other diseases, animal experiments, and case reports were excluded by reading the initial titles and abstracts. Six articles were excluded in which the treatment methods failed to reach inclusion criteria, data were inconsistent, and outcome indicators were unclear by reading the full text. Finally, 6 trials were deemed eligible with 1,848 samples. The study selection was illustrated in Figure 1.

Fig. 1.

Flowchart of literature selection.

Basic Characteristics and Quality Assessment

Six eligible studies [12-17] were included with a total of 1,848 patients assigned to the experimental group (1,123 cases) and the control group (725 cases). The experimental group received osimertinib treatment, while the control group used standard EGFR-TKI treatment. The basic characteristics and quality assessment were reported in Table 1.

Table 1.

Basic characteristics and quality assessment

Results of Meta-AnalysisObjective Response Rate

Six studies analyzed the ORR. There was great heterogeneity among the studies (p < 0.00001, I2 = 89%); therefore, a random-effects model was used for combining effect sizes. The results in Figure 2 presented that the ORR of the experimental group was significantly better versus the control group (OR = 3.40, 95% CI 1.64–7.01, p = 0.0009).

Fig. 2.

Forest plot of ORR of the experimental group and the control group.

Disease Control Rate

Six studies evaluated the DCR. There was no heterogeneity among the studies (p = 0.41, I2 = 2%); therefore, a fixed-effects model was used for combining the effect sizes. The results showed that the DCR of the experimental group was significantly better versus the control group (OR = 4.36, 95% CI 3.09–6.15, p < 0.00001; Fig. 3).

Fig. 3.

Forest plot of DCR of the experimental group and the control group.

Progression-Free Survival

PFS was evaluated by the 6 studies, and there was sizeable heterogeneity in PFS among the studies (p = 0.01, I2 = 67%), so random-effects models were utilized to combine effect size. Results in Figure 4 displayed that PFS of the experimental group was outstandingly better versus the control group (HR = 0.36, 95% CI 0.27∼0.47, p < 0.00001).

Fig. 4.

Forest plot of PFS of the experimental group and the control group.

Overall Survival

OS was evaluated by the 4 studies, and there was no heterogeneity among studies (p = 0.30, I2 = 18%). The fixed-effects models were utilized to combine effect size. Results in Figure 5 demonstrated that OS of experimental group was better than the control group (OR = 0.58, 95% CI 0.460.72, p < 0.00001).

Fig. 5.

Forest plot of OS of the experimental group and the control group.

Adverse Events of Grades 3 and 4

The adverse events of grades 3 and 4 were compared between the two groups, including loss of appetite, diarrhea, fatigue, nausea, rash, stomatitis, and vomiting. No heterogeneity was seen among studies, and fixed-effects models were utilized to combine the effect size. Differences in loss of appetite (OR = 0.70, 95% CI 0.36∼1.38, p = 0.31; Fig. 6), diarrhea (OR = 0.98, 95% CI 0.46∼2.05, p = 0.95; Fig. 7), fatigue (OR = 1.20, 95% CI 0.28∼ 5.21, p = 0.81; Fig. 8), and nausea (OR = 0.79, 95% CI 0.21∼3.00, p = 0.73; Fig. 9) were not statistically significant, while differences in rash (OR = 0.13, 95% CI 0.03∼0.55, p = 0.005; Fig. 10), stomatitis (OR = 0.16, 95% CI 0.07∼0.40, p < 0.0001; Fig. 11), and vomiting (OR = 0.15, 95% CI 0.03∼0.70, p = 0.02; Fig. 12) were statistically significant. The above results manifested that the experimental group treatment program could dramatically ameliorate the occurrence of adverse events of grades 3 and 4.

Fig. 6.Fig. 7.Fig. 8.Fig. 9.Fig. 10.Fig. 11.Fig. 12.Discussion

How to effectively deal with the drug resistance of lung cancer patients after EGFR-TKI targeted drug treatment has become the main direction of personalized diagnosis and treatment of advanced NSCLC. At present, osimertinib is ratified for clinical utilize as third-generation EGFR-TKI. Measured with the early EGFR-TKIs, osimertinib denotes stronger selectivity for mutant EGFR receptors and pharmacokinetics in vitro [18]. Bearing a resemblance to early EGFR-TKIs, diarrhea (44%), and rash (42%) are the most common osimertinib-induced adverse events [19]. In this study, we substantiated that osimertinib could significantly improve the ORR and DCR as well as extend the PFS and OS of patients with EGFR T790M mutation-positive advanced NSCLC versus standard first-line treatment. Additionally, common adverse events of grades 3 and 4 contained loss of appetite, diarrhea, fatigue, nausea, rash, stomatitis, and vomiting in the 6 enrolled studies. Thus, we assumed that osimertinib could notably diminish the occurrence of adverse events of grades 3 and 4.

A clinical study exhibits that the PFS (10.1 months) and ORR (71%) of osimertinib are superior to pemetrexed combined with platinum drugs for patients with advanced lung cancers, and adverse events are remarkably lessened [20]. FLAURA illustrated that in positive advanced NSCLC patients, PFS time of osimertinib treatment was conspicuously longer with a median PFS of 18.9 months, and disease progression or death risk was decreased by 54% compared with standard EGFR-TKI treatment. Osimertinib safety was similar to standard EGFR-TKI, while adverse events of grades 3 and 4 decreased. These data indicate that osimertinib is superior to the current standard EGFR-TKI treatment [21]. Besides, several previous meta-analyses on efficacy and safety of osimertinib for EGFR-mutated NSCLC clarify the weighty curative effect of osimertinib [8, 22]. Our results further supported the aforementioned conclusions. Based on the preceding evidence, it could be presumed that osimertinib was the first choice for advanced NSCLC during early EGFR-TKI treatment or after T790M mutations. Moreover, previous clinical data point out that osimertinib has better blood-brain barrier penetration than gefitinib, rositinib, or afatinib, and it also benefits advanced lung cancer patients with brain metastases [23]. The preplanned subgroup analysis in the AURA3 study also reveals that osimertinib has an increased central nervous system (CNS) response rate (70% vs. 31%) and a longer PFS of CNS (11.7 vs. 5.6 months) versus chemotherapy [24]. We did not perform a comprehensive analysis of CNS metastasis due to sufficient data. Thus, it is necessary to conduct more relevant clinical trials for further analysis.

The present study had several limitations. First of all, inevitable confounding factors remained in this study on the basis of entirely clinical trials-derived data. Second, conceivable publication as well as selection bias existed. Funnel plots were not generated to evaluate publication bias and slight sample study effects with few test samples enclosed in each comparison. Third, as an endpoint for evaluating the factual effect of each treatment, data on OS might lead to heterogeneity. Moreover, patients were not stratified regarding smoking status or gender, which may sway final consequences. In further studies, meta-analysis can be carried out in groups to explore the relative treatment effects based on these clinical characteristics, which is a problem required to be solved in the future.

In conclusion, our research clarified that osimertinib was significantly better than the standard EGFR-TKI treatment in dealing with EGFR mutation-positive advanced NSCLC, which had superior safety and could be taken for the first-line therapy of advanced NSCLC. To boot, incidence of adverse events like nausea, rash, and vomiting of osimertinib was lower than previous generation of EGFR-TKI. Nevertheless, it is compelling to do further clinical trials to compare first-line osimertinib treatment with order of taking EGFR-TKI and osimertinib to update the data and furnish a reference for optimizing clinical application of osimertinib.

Conflict of Interest Statement

The authors deny that they have conflicts of interest.

Funding Sources

This study has not received any funding.

Author Contributions

Jie Pan: conceptualization, methodology, writing–original draft, and funding acquisition Xiaoping Cai: conceptualization, writing–review and editing, supervision, and project administration. Zhuo Cao: validation, formal analysis, and data curation. Jiongwei Pan: investigation and resources. Hao Zheng: visualization and writing–review and editing.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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