Immunotherapy efficacy between exon 19 deletion and exon 21 L858R mutation in advanced EGFR mutant non-small-cell lung cancer: a direct and indirect meta-analysis

Introduction

Lung cancer, mainly non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related death worldwide (1). Epidermal growth factor receptor (EGFR) mutations play an important role in both the development and the progression of lung cancer (2). EGFR mutations occur in 40–55% of Asian patients with NSCLC, with the most common subtypes being exon 19 deletion (19 Del) and exon 21 L858R mutation (21 L858R), together accounting for 80–90% of all EGFR mutations (3-5). Most EGFR-mutant lung cancer patients are sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs) (6). But efficacy of EGFR-TKI on different mutation subtypes is different. Previous studies had confirmed that patients with 19 Del had superior efficacy of EGFR-TKI compared to those with 21 L858R (7-9).

Patients with EGFR mutations have to turn to traditional chemotherapy after resistant to third-generation EGFR-TKI, like other EGFR wild-type patients (10). With the advent of immunotherapy (IO), advanced NSCLC patients without driver mutations are found to benefit from IO alone or in combination with chemotherapy. And anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy or in combination with chemotherapy has been approved as standard treatment for these patients (11). However, the situation for EGFR-mutant patients is less favorable compared to those with wild-type EGFR, as it is widely acknowledged that EGFR-mutant NSCLC patients generally have poorer responses to IO (12).

Nevertheless, some studies have found that EGFR mutant subtypes might influence the efficacy of IO (13-15). Few studies revealed that 21 L858R had more clinical benefit than 19 Del when using IO-involved treatment (11,16-19), while other studies showed different results (17,20-24). It is still controversial whether EGFR mutation subtypes have effects on therapeutic efficacy of IO in advanced EGFR mutant NSCLC patients. Therefore, we performed this meta-analysis by incorporating relevant studies to evaluate whether the IO efficacy differs between 19 Del and 21 L858R. We present this article in accordance with the PRISMA reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-884/rc).

Methods

Literature search and study selection

Two authors (Z.C. and L.P.) independently searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases using the following terms: EGFR/epidermal growth factor receptor, exon, mutation, NSCLC/non-small-cell lung cancer and IO/PD-1/PD-L1 (Appendix 1). Searching terminal date was on June 14^th, 2024. Detailed protocol was created in advance and registered in the Prospective Register of Systematic Reviews (ID: CRD42024558161). No language restrictions were set in the search. Records were imported into Endnote 21 software to eliminate duplications.

Two investigators (Z.C. and L.P.) independently reviewed the titles, abstracts, and keywords of the identified records to select appropriate articles for full review. Any discrepancies were resolved by consensus. Eligible studies should meet the following criteria: (I) original studies which investigated IO treatment in EGFR mutant NSCLC; (II) studies focused on IO treatment with clinical efficacy data; (III) clinical outcomes stratified by EGFR mutation subtypes (19 Del and 21 L858R); (IV) with available data to calculate odds ratios (ORs)/hazard ratios (HRs) and its 95% confidence intervals (CIs) for dichotomous data and survival data. Studies that did not meet the above inclusion criteria were excluded.

Data extraction and quality assessment

The primary outcome for this meta-analysis was progression-free survival (PFS), with secondary outcomes including overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Four reviewers (Z.C., Y.Y., X.H., and J.Z.) independently extracted data from included studies. HRs for survival data (PFS and OS) and ORs for dichotomous data (ORR and DCR) with corresponding 95% CIs were extracted. The following main information was also extracted: lead author, year, details of treatment, the number of participants with either 19 Del or 21 L858R mutations. When updated data for survival were available, the latest data were preferred. Three reviewers (Z.C., Lin Zhang, and K.X.) used the Cochrane Risk of Bias 2 tool to assess the quality of included randomized control trials (RCT) and a modified Newcastle-Ottawa scale to assess other studies independently. Discrepancies were discussed by all investigators to reach a consensus.

Statistical analysis

The random-effects model was used in case of potential heterogeneity and to avoid underestimation of standard errors of pooled estimates in our meta-analyses. All calculations were performed by stata/MP 17.0 (StataA Corp., College Station, TX, USA). The trial-specific HRs for indirect comparison between 19 Del and 21 L858R were calculated according to a previously reported method (25). The logHR of the adjusted indirect comparison for arm A vs. arm B was estimated by logHR_AB = logHR_AC − logHR_BC, and its standard error for the log HR was SE(logHRAB)=SE(logHRAC)2+SE(logHRBC)2. Subgroup analysis was also performed on patients receiving IO monotherapy and IO combination therapy. Heterogeneity was evaluated using the Cochrane Q statistic and I² statistic. Sensitivity analyses assessed robustness of the synthesized results with leave-one-out method. Publication bias was evaluated through the regression asymmetry test of Egger. All statistical tests were two-sided, with P value less than 0.05 considered as significant. The results were presented in forest plots.

Results

Eligible studies

A total of 1,067 records were identified and 19 potentially relevant studies were read in detail. Four studies lacking available data to calculate OR/HR and its 95% CI were discarded and we ultimately included 15 studies that involved 1,209 EGFR-mutant advanced NSCLC patients with IO treatment (19 Del, n=676; 21 L858R, n=533) (Figure 1, Tables 1,2). Eleven studies (11,16-24,26) which exhibited direct comparison of 19 Del (n=379) and 21 L858R (n=313) for clinical efficacy were included for direct meta-analysis. Four phase III RCTs (12-15), involving 517 EGFR-mutated advanced NSCLC patients (19 Del, n=297; 21 L858R, n=220), which investigated the efficacy of IO combination treatment vs. chemotherapy, were included in the indirect meta-analysis using the subgroup data of EGFR mutation subtypes. Figure 1 summarizes the flow chart. Tables 1,2 summarize the characteristics of patients in the involved studies for direct meta-analysis and indirect meta-analysis, respectively. The results of the quality assessment were listed in Figure S1.

Figure 1 Profile summarizing the trial flow. OR, odds ratio; HR, hazard ratio; CI, confidence interval; ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival.

Direct and indirect comparisons of IO efficacy between 19 Del and 21 L858R

Direct meta-analysis revealed that patients with 19 Del had shorter PFS (HR =1.55; 95% CI: 1.21–1.98; P=0.001) and OS (HR =1.36; 95% CI: 1.04–1.78; P=0.02) and poorer DCR (OR =0.51; 95% CI: 0.29–0.87; P=0.02) than those with 21 L858R significantly (Figure 2A,2B). There was no significant difference in ORR between 19 Del and 21 L858R, though patients with 19 Del still tend to have inferior ORR (OR =0.69; 95%CI: 0.44–1.07; P=0.09; Figure 2B). Figure 3A shows the relationship of the indirect comparisons based on the assumption that no significant difference of chemotherapy efficacy existed between 19 Del and 21 L858R. Based on the subgroup data from IMpower151 (12), ORIENT 31 (13), ATTLAS (14), and HARMONi-A (15), patients with 19 Del still had significantly shorter PFS compared to those with 21 L858R (HR=1.50, 95% CI: 1.09–2.07; P=0.01) (Figure 3B). Sensitivity analysis using leave-one-out method was done to reflect the influence of the individual data set to the pooled HRs/ORs, and the corresponding pooled HRs/ORs were not materially altered. There was no publication bias for outcome measures, as all P values were greater than 0.05 in Egger’s test.

Figure 2 Direct meta-analysis of 19 Del vs. 21 L858R in IO-involved treatment. (A) Direct comparison of PFS and OS between 19 Del and 21 L858R in IO-involved treatment. (B) Direct comparison of ORR and DCR between 19 Del and 21 L858R in IO-involved. 19 Del, exon 19 deletion; 21 L858R, exon 21 L858R mutation; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; OS, overall survival; ORR, objective response rate; OR, odds ratio; DCR, disease control rate; IO, immunotherapy.

Figure 3 Indirect meta-analysis of 19 Del vs. 21 L858R in IO-involved treatment. (A) Geometric distribution of indirect comparisons. Solid lines between regimens represented the existence of direct comparisons. This indirect comparison was based on the assumption that no significant difference of chemotherapy efficacy existed between 19 Del and 21 L858R. (B) Indirect comparison of PFS between 19 Del and 21 L858R in IO combination treatment. IO: including anti-PD-1/PD-L1 antibody; IO combination: including IO plus chemo or IO plus chemo and antiangiogenic therapy. IO, immunotherapy; 19 Del, exon 19 deletion; 21 L858R, exon 21 L858R mutation; chemo, chemotherapy; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; PD-1, programmed death-1; PD-L1, programmed death-ligand 1.

Subgroup analysis

We divided IO-involved treatment into IO monotherapy and IO combination therapy (IO combined with chemotherapy and/or anti-angiogenic agents) for subgroup analysis. Although there was no statistical difference in terms of PFS, OS, ORR, and DCR, patients with 21 L858R still tend to have more clinical benefit compared to 19 Del no matter whether treated by IO monotherapy or IO combination therapy. Figure S2 shows more detailed data.

Discussion

For advanced NSCLC patients with sensitive EGFR mutations, whether the efficacy or prognosis of IO in 19 Del or 21 L858R is the same remains unclear. A meta-analysis incorporating all available data from correlative studies is a good way to address this question. We conducted this study with direct and in-direct meta-analysis and found that patients with 21 L858R had more IO benefit than those with 19 Del. Patients with 19 Del had 49% reduction in disease control, 55% increasement in the risk of progression and 36% increasement in the risk of death when compared to those with 21 L858R. Although the difference in ORR was not statistically significant, the ORR of 21 L858R also tended to be superior than that of 19 Del. Subgroup analysis showed similar tendency that 21 L858R had more clinical benefit than that of 19 Del, regardless of IO monotherapy or IO combination.

Studies have indicated that PD-L1 levels are significantly lower in EGFR-mutant populations, which may partially account for the poor response to IO observed in these patients (27-29). Moreover, further studies have found that patients with the 21 L858R mutation are significantly more likely to exhibit high PD-L1 expression compared to those with the 19 Del (30). The proportion of dual positive of tumor-infiltrating lymphocyte (TIL) and PD-L1 samples was remarkably higher in the 21 L858R group than the 19 Del group (31). While the TIL⁺/PD-L1⁺ population was found to benefit from chemotherapy plus IO (32). This may be an important reason why the efficacy of IO is better in the 21 L858R group compared to the 19 Del group.

Furthermore, although most of the current studies suggest that the efficacy of IO is poor in the EGFR-mutant population, this may be due to the much poorer clinical outcomes of the 19 Del group compared to the 21 L858R group, resulting in underestimation of the efficacy of IO in patients with EGFR mutations. It is necessary to re-examine the effect of EGFR mutant subtypes on IO treatment and re-evaluate the efficacy of IO in different EGFR mutant subtypes, especially in 21 L858R. On the other hand, EGFR mutant subtypes (19 Del/21 L858R) should be considered as a stratification factor in designing or reviewing clinical trials regarding IO in addition to EGFR-TKI.

This is the first study to comprehensively investigate the impact of EGFR mutation subtypes on IO efficacy. However, there were still several limitations. Firstly, most of the enrolled studies included in the direct comparisons were retrospective. The indirect comparisons were based on subgroup data of prospective trials. These might compromise the evidence level. In addition, some efficacy data of ORR, DCR, PFS or OS could not be extracted, which might influence statistical significance in pooled analysis as well as in subgroup analysis. What’s more, the literature search for this study was completed on June 14, 2024. Since then, additional relevant studies have been published, but they were not included in the analysis (33,34). These studies may potentially influence the results of the meta-analysis. Future research should incorporate these newly published studies and further explore their implications for our field of study. Finally, the indirect meta-analysis was conducted on the assumption that no significant difference of chemotherapy efficacy existed between EGFR 19 Del and 21 L858R. This is also one of the limitations of this article, as there are currently no direct studies exploring the differences in chemotherapy efficacy between EGFR 19 Del and 21 L858R.

For advanced EGFR-mutant NSCLC patients, 21 L858R had superior IO efficacy compared with 19 Del. It suggests that the IO efficacy in EGFR mutant NSCLC is previously underestimated which needs to be re-evaluated with the stratification by EGFR mutation subtypes, especially for those with 21 L858R. Moreover, EGFR mutation subtype should be considered as an essential stratification factor in future studies regarding IO treatment.

Conclusions

For advanced EGFR mutant NSCLC patients, 21 L858R had superior IO efficacy compared with 19 Del.

Acknowledgments

We thank the patients for their participation in clinical trial and the investigators for releasing the clinical data.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-884/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-884/prf

Funding: This work was supported by the Chinese National Natural Science Foundation Project (No. 82102872).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-884/coif). All authors report that this work was supported by the Chinese National Natural Science Foundation Project (No. 82102872). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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