Comparative analysis of first-generation epidermal growth factor receptor inhibitors combined with chemotherapy versus third-generation epidermal growth factor receptor inhibitors in the treatment of advanced non-small cell lung cancer: a systematic review and meta-analysis

Background: In advanced non-small cell lung cancer with EGFR mutations, third-generation EGFR TKIs (3^rd-G TKIs) are currently the preferred first-line treatment. Previous studies have demonstrated that combining first-generation EGFR TKIs with chemotherapy (1^st-G TKIs + chemo) also significantly enhances efficacy compared to 1^st-G TKIs alone. This study aims to compare the effectiveness of 1^st-G TKIs + chemo against 3^rd-G TKIs.

Methods: We conducted an indirect meta-analysis of randomized controlled trials comparing 1^st-G TKIs + chemo to 3^rd-G TKIs. Randomized controlled trials (RCTs) were searched from the PubMed, Embase and Cochrane Library databases. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs). Data were analyzed using inverse variance and Mantel-Haenszel methods.

Results: Ten RCTs with 3,014 patients met the inclusion criteria. Direct comparisons indicated that 1^st-G TKIs + chemo significantly improved PFS (HR 0.54, P < 0.001), OS (HR 0.62, P < 0.001), and ORR (RR 1.21, P < 0.001) compared to 1^st-G TKIs alone. Indirect comparisons between 1^st-G TKIs + chemo and 3^rd-G TKIs revealed no significant differences in PFS (HR 1.17; 95% CI, 0.98 to 1.40; P = 0.075) or OS (HR 0.78; 95% CI, 0.56 to 1.07; P = 0.122). Although 1^st-G TKIs + chemo showed a 16% improvement in ORR compared to 3^rd-G TKIs (RR 1.16; 95% CI, 1.06 to 1.27; P < 0.001), it was also associated with a notable increase in grade ≥3 TRAEs (RR 2.41; 95% CI, 1.63 to 3.57; P < 0.001).

Conclusion: 1^st-G TKIs + chemo demonstrated PFS and OS comparable to 3^rd-G TKIs. Moreover, 1^st-G TKIs + chemo may be a viable option for patients who prioritize a higher response rate.

Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42023461565 identifer, PROSPERO (CRD42023461565).

1 Introduction

Lung cancer is the predominant cause of cancer death worldwide, with approximately 85% of patients presenting with the histological subtypes of non-small cell lung cancer (NSCLC), the most common of which are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) (Herbst et al., 2018). A substantial proportion of patients are unsuitable for surgical intervention, necessitating palliative internal medicine treatments. Epidermal growth factor receptor (EGFR) mutations occur in 40%–60% of Southeast Asian patients and 10%–20% of Caucasian patients with lung adenocarcinomas and reach occurrences of 50%–60% in non-smoking patients with lung cancer. The most common EGFR mutations include exon 19 deletions and missense mutations in exon 21 (Hsu et al., 2018).

Since 2009, the IPASS study (Mok et al., 2009) has validated the effectiveness of 1^st-G TKIs for patients with EGFR-mutant NSCLC. Substantial advancements have been made in the first-line treatment of advanced EGFR-mutant NSCLC, particularly with the development of 3^rd-G TKIs, as demonstrated by studies such as FLAURA (Soria et al., 2018), FLAURA China (Cheng et al., 2021), FURLONG (Shi et al., 2022), AENEAS (Lu et al., 2022) and LASER301 (Cho et al., 2023). These advancements have established 3^rd-G TKIs as the standard of care. However, the resistance mechanisms to 3^rd-G TKIs are complex, and subsequent treatment options remain limited (Fu et al., 2022). Additionally, the adoption of 3^rd-G TKIs as first-line therapy has been constrained in certain regions due to lack of inclusion in insurance coverage, rendering it inaccessible for many patients. Moreover, the APPLE trial (Remon et al., 2024) indicated that sequential treatment with 1^st-G TKIs followed by 3^rd-G TKIs offers comparable overall survival (OS) benefits to upfront 3^rd-G TKIs administration. This suggests a continued role for 1^st-G TKIs and their combinations in clinical practice, highlighting the potential and necessity for combination therapies based on 1^st-G TKIs.

Combination therapy with multiple drugs, particularly the addition of chemotherapy, is a pivotal approach to delaying the onset of drug resistance. Chemotherapy, as a systemic treatment, may eradicate subsets of cancer cells contributing to EGFR-TKIs resistance (Miller and Hanna, 2021). Several clinical studies have demonstrated that 1^st-G TKIs + chemo significantly enhances efficacy compared to 1^st-G TKIs alone. However, a direct comparison between 1^st-G TKIs + chemo and 3^rd-G TKIs has not yet been conducted.

To address this gap, we devised an indirect comparison using 1^st-G TKIs as a bridge to compare the efficacy and safety of 1^st-G TKIs + chemo versus 3^rd-G TKIs in treating patients with advanced NSCLC harboring EGFR mutations. This study aims to provide additional comparative data to support informed decision-making in first-line therapy. Additionally, we performed subgroup analyses to identify patient populations that might derive greater benefit from 1^st-G TKIs + chemo.

2 Methods

This meta-analysis followed the PRISMA (Page et al., 2021) guidelines and was registered on the PROSPERO website (CRD42023461565).

2.1 Data sources and searches

Relevant studies were comprehensively searched in PubMed, Embase, and Cochrane Library databases prior to 31 December 2023, using the following search terms: “epidermal growth factor receptor,” “non-small cell lung carcinoma,” “Gefitinib,” “Erlotinib,” “Icotinib,” “Chemotherapy,” “Osimertinib,” “Furmonertinib,” “Aumolertinib,” “Lazertinib,” “Olmutinib,” and “randomized clinical trial (RCT).” A detailed description of the retrieval method is provided in Supplementary Material 1. Two investigators (S.P and Z.Y) independently assessed the articles for eligibility, and disagreements between the investigators were resolved through further discussion with a third investigator.

2.2 Study selection

The inclusion criteria for study selection were as follows: 1) patients with advanced, EGFR-mutated NSCLC; 2) interventions: treatment with 1^st-G TKIs + chemo versus a 1^st-G TKIs as the control arm or treatment with a 3^rd-G TKIs versus a 1^st-G TKIs as the control arm; 3) Outcome Measures: inclusion of the hazard ratio (HR) and the corresponding 95% confidence interval (CI) for progression-free survival (PFS); and 4) randomized controlled trials.

2.3 Assessment of study quality

The risk of bias for each eligible study was evaluated using the Cochrane Risk of Bias Tool (Higgins et al., 2011).

2.4 Data extraction and outcomes

Two authors (S.P and Z.Y) independently extracted data and reached a consensus. The primary endpoint was PFS, while the secondary endpoints were OS, objective response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs). PFS and OS were collected as HRs with 95% CIs, while ORR and grade≥3 TRAEs were collected as the dichotomous data.

2.5 Data analyses

In the direct comparison of 1^st-G TKIs + chemo or 3^rd-G TKIs versus 1^st-G TKIs, for continuous variables, which included PFS and OS, HRs with 95% CIs were assessed for each individual study. A meta-analysis of the HRs was performed using the inverse variance technique. Furthermore, for the analysis of ORRs, grade≥3 TRAEs, RRs, and corresponding 95% CIs were calculated for each study by adopting the Mantel-Haenszel method (DerSimonian and Laird, 1986). Heterogeneity was evaluated using Cochran’s Q test; a P value < 0.1 and I² > 50% indicated statistical heterogeneity, thus requiring the use of a random-effects model; otherwise, a fixed-effects model was used (Cumpston et al., 2019).

When conducting an indirect comparison between 1^st-G TKIs + chemo and 3^rd-G TKIs, an adjusted indirect comparison was performed on arm A (1^st-G TKIs + chemo) versus arm B (3^rd-G TKIs), linked by arm C (1^st-G TKIs), using the frequentist methods with the following formula (Bucher et al., 1997): log HR_AB = log HR_AC ˗ log HR_BC, and its standard error (SE) for the log HR was SE (log HRAB) = $\sqrt{{SE\left(\log HR\text{AC}\right)}^2+{SE\left(\log HR\text{BC}\right)}^2}$. RR was evaluated similarly using this formula.

All statistical analyses were conducted using STATA software (version 17.0). Statistical significance was defined as a two-sided P-value < 0.05.

3 Results

3.1 Characteristics of the eligible studies

Ten RCTs (Soria et al., 2018; Cheng et al., 2021; Shi et al., 2022; Lu et al., 2022; Cho et al., 2023; Xu et al., 2019; Cheng et al., 2016; Noronha et al., 2020; Hosomi et al., 2020; Han et al., 2017) were deemed eligible for inclusion in the meta-analysis and included a total of 3014 patients. A brief summary of the included studies is presented in Table 1, and the search process is described in Figure 1. Of the included studies, five investigated the efficacy of 1^st-G TKIs + chemo (n = 600) versus 1^st-G TKIs (n = 543), while the remaining five trials (Soria et al., 2018; Cheng et al., 2021; Shi et al., 2022; Lu et al., 2022; Cho et al., 2023) explored 3^rd-G TKIs (n = 938) versus 1^st-G TKIs (n = 933). There were two randomized phase II Trials (Cheng et al., 2016; Han et al., 2017) and eight randomized phase III studies. The primary endpoint of all studies was PFS, and the PFS of 1^st-G TKIs fluctuated between 8 and 11.9 months. The PFS durations observed for 1^st-G TKIs + chemo spanned from 15.8 to 20.9 months, while the PFS profiles for 3^rd-G TKIs ranged from 17.8 to 20.8 months.

Table 1

Table 1. Characteristics of the included randomized controlled trials.

Figure 1

Figure 1. Flow diagram of trial selection.

A summary of the risk of bias evaluation is provided in Supplementary Material 2. The primary source of bias stemmed from the absence of blinding in clinical studies that compared 1^st-G TKIs + chemo with 1^st-G TKIs. Funnel plots are shown in Supplementary Material 3, with no asymmetry observed in the funnel plots. (PFS Egger test P = 0.107, OS Egger test P = 0.237, ORR Egger test P = 0.105, grade ≥3 TRAEs Egger test P = 0.164).

3.2 Direct comparisons between 1st-G TKIs + chemo or 3rd-G TKIs versus 1st-G TKIs

1^st-G TKIs + chemo presented a significant improvement in PFS (HR, 0.54; 95%CI, 0.47 to 0.61, P < 0.001) (Figure 2A), OS (HR, 0.62; 95%CI, 0.47 to 0.81, P < 0.001) (Figure 2B), and ORR (RR, 1.21; 95%CI, 1.12 to 1.30, P < 0.001) (Figure 2C) compared to use of 1^st-G TKIs as monotherapy. However, the risk of grade ≥3 TRAEs (RR, 2.24; 95%CI, 1.57 to 3.20, P < 0.001) (Figure 2D) of 1^st-G TKIs + chemo was increased compared to 1^st-G TKIs monotherapy.

Figure 2

Figure 2. Direct comparisons between first-generation EGFR-TKIs plus chemotherapy or third-generation EGFR-TKIs versus first-generation EGFR-TKIs Abbreviations: PFS, progression-free survival; OS, overall survival; ORR, objective response rate; grade ≥3 TRAEs, grade ≥3 treatment-related adverse events; HR, hazard ratio; RR: Risk Ratio; TKI, epidermal growth factor receptor tyrosine kinase inhibitors; Chemo, Chemotherapy; 1^st-G TKI, first-generation epidermal growth factor receptor tyrosine kinase inhibitors; 3^rd-G TKI, third-generation epidermal growth factor receptor tyrosine kinase inhibitors.

Compared with 1^st-G TKIs, 3^rd-G TKIs significantly improved PFS (HR, 0.46; 95%CI, 0.42 to 0.52, P < 0.001) (Figure 2A) and showed a significant improvement in OS (HR, 0.80; 95%CI, 0.67 to 0.95, P = 0.010) (Figure 2B), although there was no statistically significant difference in ORR (RR, 1.04; 95%CI, 0.99 to 1.09, P = 0.166) (Figure 2C). The risk of grade ≥3 TRAEs (RR, 0.93; 95%CI, 0.79 to 1.10, P = 0.377) (Figure 2D) was similar between 1^st-G TKIs and 3^rd-G TKIs regimens.

3.3 Indirect comparisons between 1^st-G TKIs + chemo and 3^rd-G TKIs

1^st-G TKIs + chemo presented numerically poorer PFS than 3^rd-G TKIs regimens (HR, 1.17; 95%CI, 0.98 to 1.40, P = 0.075) (Figure 3A), although this difference lacks statistical significance. Across most subgroups, a shorter PFS was observed in 1^st-G TKIs + chemo compared to the 3^rd-G TKIs, particularly in patients younger than 65 years of age (HR, 1.40; 95%CI, 1.07 to 1.85, P = 0.02), patients with no history of smoking (HR, 1.32; 95%CI, 1.02 to 1.71, P = 0.04), patients with a PS score of 0 (HR, 1.49; 95%CI, 1.06 to 2.08, P = 0.02), and patients with EGFR exon 19 deletion mutations (HR, 1.32; 95%CI, 1.03 to 1.68, P = 0.03) (Figure 3B). However, in patients with brain metastases (HR, 0.85; 95%CI, 0.55 to 1.32, P = 0.46) (Figure 3B), the efficacy of 1^st-G TKIs + chemo was numerically longer than that of 3^rd-G TKIs, without statistical significance.

Figure 3

Figure 3. Indirect comparisons and subgroup analyses for PFS between first-generation EGFR-TKIs plus chemotherapy and third-generation EGFR-TKIs Abbreviations: PFS, progression-free survival; OS, overall survival; ORR, objective response rate; TRAEs, grade ≥3 treatment-related adverse events; HR, hazard ratio; RR, Risk Ratio; Chemo, Chemotherapy; 1^st -G TKI, first-generation epidermal growth factor receptor tyrosine kinase inhibitors; 3^rd-G TKI, third-generation epidermal growth factor receptor tyrosine kinase inhibitors; ECOG PS, Eastern Cooperative Oncology Group (ECOG) Performance Status; Ex 19 del, del 19 mutation; L858R, ex21 L858R mutation.

Conversely, 1^st-G TKIs combined with chemotherapy produced a numerically lower risk of death than 3^rd-G TKIs (OS: HR 0.78, 95% CI 0.56–1.07; P = 0.122), but this difference did not reach statistical significance (Figure 3A). The combination did, however, yield a significantly higher objective response rate (ORR: RR 1.16, 95% CI 1.06–1.27; P < 0.001) and was associated with a markedly increased incidence of grade ≥3 treatment-related adverse events (RR 2.41, 95% CI 1.63–3.57; P < 0.001) (Figure 3A).

4 Discussion

To the best of our knowledge, this is the first meta-analysis to perform an indirect comparison between 1^st-G TKIs + chemo and 3^rd-G TKIs alone. Our findings indicate that PFS and OS were comparable between these two regimens in patients with EGFR-mutant NSCLC. However, the 1^st-G TKIs + chemo significantly increased the ORR by 16%, at the cost of a marked increase in the risk of grade ≥3 TRAEs (RR, 2.41, P < 0.001).

From the meta-analysis of the direct comparison between 1^st-G TKIs + chemo and the 1^st-G TKIs, 1^st-G TKIs + chemo presented significantly longer PFS and OS than 1^st-G TKIs alone, in agreement with the findings of previous meta-analyses (Wu et al., 2021). A possible reason for this is that some patients treated with 1^st-G TKIs alone did not receive subsequent chemotherapy after disease progression, for various reasons. Moreover, early combination chemotherapy can delay resistance to EGFR-TKIs and improve the survival rate of patients compared to sequential chemotherapy (Chang et al., 2021). The possible mechanism is that tumors with acquired drug resistance may contain a mixed cell population of drug-sensitive and drug-resistant cells with different growth rates, and early combined chemotherapy can better eliminate this heterogeneity (Moore and Wheatley-Price, 2021).

Furthermore, in the indirect comparison, when the 1^st-G TKIs was replaced with the current preferred 3^rd-G TKIs, the PFS and OS benefits of 1^st-G TKIs + chemo compared to 3^rd-G TKIs were comparable, indicating that1^st-G TKIs + chemo has potential as a first-line treatment. However, it is important to note that in studies of 1^st-G TKIs + chemo, only 23.3% of patients subsequently received 3^rd-G TKIs treatment (Hosomi et al., 2020). If more patients were able to receive 3^rd-G TKIs after progression, the results of 1^st-G TKIs + chemo would likely be even more pronounced.

Despite these potential benefits, 1^st-G TKIs + chemo has several notable drawbacks. These include increased adverse reactions and the possibility of rapid disease progression or death in some patients, preventing them from accessing 3^rd-G TKIs. Therefore, careful consideration and patient selection are crucial. Identifying subgroups of patients who are more likely to benefit from 1^st-G TKIs + chemo is essential to optimize treatment outcomes.

From the results of the primary endpoint, 1^st-G TKIs + chemo presented a statistically significant advantage in terms of ORR compared with 3^rd-G TKIs. This indicates that the use of 1^st-G TKIs + chemo can effectively reduce the tumor burden and is suitable for patients requiring rapid tumor shrinkage. Based on the subgroup analysis, it is noteworthy that, among patients with baseline brain metastases, first-generation EGFR-TKI plus chemotherapy yielded numerically longer progression-free survival (HR 0.85, 95% CI 0.55–1.32; P = 0.46); however, this difference was not statistically significant, and no superiority over third-generation EGFR-TKIs can be claimed. Osimertinib and other third-generation TKIs are known to reach higher cerebrospinal-fluid concentrations than first-generation compounds (Popat et al., 2023), and any apparent advantage of adding chemotherapy remains speculative and requires dedicated pharmacokinetic investigation. Furthermore, our meta-analysis lacked individual-patient data on intracranial progression; future studies should report CNS-specific endpoints such as CNS progression-free survival or time-to-brain-progression to determine the relative efficacy of these strategies in patients with brain metastases.

In other subgroups, including patients younger than 65 years, non-smokers, those with an ECOG PS of 0, and those with EGFR exon 19 deletion mutations, 3^rd-G TKIs were the preferred treatment. EGFR mutation type is a crucial biomarker for treating NSCLC with EGFR-TKIs. Compared to 1^st-G TKIs + chemo, patients with EGFR exon 19 deletion achieved a superior PFS (HR, 1.32; 95% CI, 1.03–1.68) when treated with 3^rd-G TKIs as monotherapy, while patients with exon 21 mutation showed comparable PFS (HR, 1.06; 95% CI, 0.77–1.39) when treated with 1^st-G TKIs + chemo and 3^rd-G TKIs. This finding could be attributed to the higher incidence of the T790M mutation and the lower incidence of concomitant mutations in patients with EGFR exon 19 deletions than in those with EGFR exon 21 mutations, therefore, the selection of a 3^rd-G TKIs could directly overcome the T790M mutation, thereby extending PFS (Hong et al., 2018). Moreover, In patients aged <65 years, never-smokers, and ECOG 0, several biological and clinical factors may underlie the observed superiority of third-generation EGFR-TKIs. First, never-smokers harbour markedly fewer tobacco-related passenger mutations and a lower prevalence of resistance-associated co-mutations such as TP53, STK11 and RB1, which are enriched in smoking-related tumours and accelerate escape from EGFR blockade (Moorthi et al., 2024; Labbe et al., 2017). Second, the absence of heavy mutagenic exposure yields a comparatively low tumour-mutational burden, reinforcing ‘oncogene addiction’ to mutant EGFR and prolonging sensitivity to potent third-generation inhibitors (Rudin et al., 2009). Third, patients with ECOG 0 generally tolerate therapy without dose reduction, preserving full osimertinib exposure; dose-intensity analyses from AURA3 and real-world series confirm that optimal pharmacokinetics translate into deeper and more durable responses (Papadimitrakopoulou et al., 2020; Ramalingam et al., 2020). Although compelling, these subgroup findings remain exploratory and should be validated prospectively, ideally in trials stratified by co-mutation status and performance score.

The recent study FLAURA2 (Planchard et al., 2023) that compared osimertinib combined with chemotherapy to 1^st-G TKIs monotherapy revealed that the osimertinib regimen presented a significant improvement in progression-free survival (PFS) (25.5 months vs. 16.7 months) among patients with advanced NSCLC and EGFR mutations. This suggests that combining 3^rd-G TKIs and chemotherapy may offer a new treatment option for these patients. However, subsequent OS data must be considered to determine this regimen’s clinical significance. The combination of EGFR-TKI with other drugs will be a focus of future research and may impact the current standard of using 3^rd-G TKIs as a first-line therapy.

Based on the results of our current study, considering both efficacy and safety data, 1^st-G TKIs + chemo did not present superior performance over 3^rd-G TKIs. However, 1^st-G TKIs + chemo is a potential choice for patients with brain metastases or those who require high response rates.

Our study has some limitations that should be noted when interpreting our findings. First, the number of included studies was relatively small, and only two phase II studies were present in our dataset, which reduced the level of evidence. Second, no direct comparative study was available. In addition, OS and ORR were not the primary endpoints; thus, the data may be considered immature. Finally, we were unable to further compare 1^st-G TKIs + chemo and 3^rd-G TKIs + chemo groups.

In this meta-analysis, 1^st-G TKIs + chemo regimens presented PFS and OS comparable to those of 3^rd-G TKIs, with a statistically significant improvement in ORR. However, the risk of grade ≥3 TRAEs significantly increased. This suggests that in clinical practice, for patients with EGFR mutations, if we intend to use 1^st-G TKIs + chemo as a first-line treatment, further population screening is imperative to determine the optimal medication.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Author contributions

SP: Data curation, Formal Analysis, Investigation, Visualization, Writing – original draft, Writing – review and editing. ZY: Investigation, Methodology, Software, Supervision, Writing – review and editing. HZ: Formal Analysis, Investigation, Validation, Writing – original draft. CL: Methodology, Software, Validation, Writing – review and editing. HQ: Resources, Supervision, Writing – original draft. SH: Conceptualization, Project administration, Visualization, Writing – review and editing. YZ: Funding acquisition, Software, Visualization, Writing – original draft.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. This study was funded by grants 2022A1515010386 from Guangdong Basic and Applied Basic Research Foundation, 82272837 from the National Natural Science Funds of China; and 2023A04J2130 from Guangzhou Basic and Applied Basic Research project. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2025.1586332/full#supplementary-material

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