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Abstract
The IMpower010 and KEYNOTE-091 trials have demonstrated the benefit of adjuvant immunotherapy (IO) after chemotherapy (C+IO) in resected non-small cell lung cancer (NSCLC), including those with epidermal growth factor receptor gene (EGFR) mutation. Meanwhile, several studies have reported that EGFR-tyrosine kinase inhibitor (EGFR-TKI) may prolong disease-free survival (DFS) in these patients. However, there is currently a lack of head-to-head comparison between these two adjuvant therapy strategies. Therefore, we designed a comparative analysis of their efficacy to inform clinical decision-making by assessing DFS as the primary outcome. The results of direct meta-analysis indicated that EGFR-TKI reduced the risk of recurrence and/or death in completely resected NSCLC (HREGFR-TKI/chemo = 0.41, 95% CI: 0.23 to 0.74, p=0.003), while C+IO did not significantly improve DFS compared with chemotherapy alone (HRC+IO/chemo=0.68, 95% CI: 0.31 to 1.50, p=0.338). Indirect comparison suggested that EGFR-TKI has a trend to prolong DFS compared with C+IO (HR EGFR-TKI/C+IO = 0.60, 95% CI: 0.23 to 1.61, p=0.312), while the third-generation TKI (3rd-TKI) osimertinib significantly outperformed C+IO (HR3rd-TKI/C+IO = 0.29, 95% CI: 0.12 to 0.70, p=0.006). In conclusion, osimertinib rather than immunotherapy should be regarded as the preferred adjuvant therapy in completely resected, EGFR-mutant NSCLC.
- Immune Checkpoint Inhibitors
- Non-Small Cell Lung Cancer
- Adjuvant Drug Therapy
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Background
In recent years, significant advancements have been made in the adjuvant treatment landscape for patients with completely resected (R0) non-small cell lung cancer (NSCLC). Notable developments include the approval of atezolizumab and pembrolizumab by the US Food and Drug Administration(FDA) as adjuvant therapies following chemotherapy (C+IO) in R0 NSCLC, which is based on the positive outcomes from the IMpower0101 and KEYNOTE-0912 trials. Interestingly, the indication of adjuvant atezolizumab or pembrolizumab therapy does not exclude patients with epidermal growth factor receptor gene mutation (EGFRm), which has been shown to confer resistance to immune checkpoint blockade (ICB) therapy targeting programmed death-ligand 1 (PD-1) or its ligand, PD-L1, in patients with metastatic disease. Prior to these two adjuvant immunotherapy studies, the landmark ADAURA trial and other clinical trials3–7 have specifically established the role of EGFR-tyrosine kinase inhibitor (TKI) in prolonging disease-free survival (DFS) of NSCLC with EGFRm after radical surgery, despite the fact that some of the EGFR-TKI trials fail to demonstrate an overall survival (OS) benefit. Therefore, with the emergence of adjuvant immunotherapy indicated for R0 NSCLC regardless of EGFR mutational status, a critical question concerning the optimal treatment selection for EGFR-mutant patients after complete resection has been raised.
Considering that randomized controlled trials that directly compare the efficacy of EGFR-TKI with ICB are lacking and are unlikely to be conducted in the near future, we carried out this indirect comparison meta-analysis using chemotherapy as a common comparator to classify the relative efficacy of adjuvant EGFR-TKI versus ICB. The objective of this study is to provide insights into the aforementioned question and inform clinical decision-making for adjuvant treatment selection in EGFR-mutant NSCLC.
Method
PubMed, Embase, and the Cochrane Library databases were thoroughly searched for eligible studies using items including “EGFR”, “adjuvant”, “lung cancer”, and “randomized control trial”. Meeting abstracts from the American Society of Clinical Oncology, European Society of Medical Oncology, American Association for Cancer Research, and World Conference on Lung Cancer were also reviewed (online supplemental figure 1). The primary outcome was DFS. Eligible studies were randomized controlled trials that provided data to compare the efficacy of EGFR-TKI or C+IO with control groups as adjuvant treatment for R0 NSCLC with EGFRm. For the analysis, we extracted data about DFS, including HRs and CIs, for each included study. We first compared the DFS benefit with EGFR-TKI (arm A) or C+IO (arm B) with chemotherapy alone (or control; arm C), respectively. Next, an indirect comparison of EGFR-TKI and C+IO was performed using the following formula8: log HRAB=log HRAC - log HRBC, and the SE (standard error) for the log HR was calculated as: 
.
Supplemental material
Result
After rigorous screening, seven studies1–7 involving 1471 patients were finally included. The characteristics of the included studies are summarized in table 1. Five of the studies3–7 compared EGFR-TKI with chemotherapy (control). The remaining two studies,1 2 including IMpowere010 and KEYNOTE-091, compared C+IO with chemotherapy.
Characteristics of patients in included trials
Direct meta-analysis
Compared with chemotherapy alone, EGFR-TKI reduced the risk of recurrence and/or death in completely resected patients with NSCLC with EGFRm (DFS: HREGFR-TKI/chemo = 0.41, 95% CI: 0.23 to 0.74, p=0.003, figure 1A). The third-generation EGFR-TKI (3rd-TKI), osimertinib, led to significantly more DFS improvement than the first-generation EGFR-TKI (1st-TKI) did when compared with chemotherapy (HR for DFS: 0.20 vs 0.51, p=0.004, online supplemental figure 2). The comparison of C+IO with chemotherapy showed that atezolizumab could not, while pembrolizumab could significantly prolong DFS (DFS: HRC+atezolizumab/chemo=0.99, 95% CI: 0.60 to 1.62; HRC+pembrolizumab/chemo=0.44, 95% CI: 0.23 to 0.84, figure 1B). The pooled result revealed that C+IO did not significantly improve DFS compared with chemotherapy alone (HRC+IO/chemo=0.68, 95% CI: 0.31 to 1.50, p=0.338, figure 1B).
Direct and indirect comparisons among EGFR-TKI, IO and control, and subgroup analyses for DFS between EGFR-TKI and IO. (A–B) Forest plot of HR directly comparing DFS between EGFR-TKI or IO with control. (C) Solid lines represent the direct comparison and dotted line represents the indirect comparison between EGFR-TKI versus IO. (D) Forest plot of HR indirectly comparing DFS between EGFR-TKI versus IO in different subgroups. DFS, disease-free survival; EGFR, epidermal growth factor receptor; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1; TKI, tyrosine kinase inhibitor; vs, versus.
Indirect meta-analysis
Indirect comparison showed that EGFR-TKI had a trend to outperform C+IO in reducing the risk of disease recurrence and/or death, either in the context where PD-L1 tumor proportion score (TPS) is unselected (DFS: HREGFR-TKI/C+IO = 0.60, 95% CI: 0.23 to 1.61, p=0.312, figure 1C) or where PD-L1 TPS was restricted to be ≥1% (DFS: HREGFR-TKI/C+IO = 0.72, 95% CI: 0.25 to 2.08, p=0.544, figure 1D). Subgroup analyses showed that 3rd-TKI, but not 1st-TKI, significantly outperformed C+IO in prolonging DFS (HR3rd-TKI/C+IO = 0.29, 95% CI: 0.12 to 0.70, p=0.006; HR1st-TKI/C+IO = 0.75, 95% CI: 0.30 to 1.90, p=0.544). Moreover, EGFR-TKI revealed greater advantages over atezolizumab than over pembrolizumab in terms of DFS (HREGFR-TKI/C+atezolizumab = 0.41, 95% CI: 0.19 to 0.89, p=0.024; HREGFR-TKI/C+pembrlizumab = 0.93, 95% CI: 0.40 to 2.23, p=0.874).
Discussion
The current study presents a timely comparison of adjuvant therapies in the context of completely resected NSCLC with EGFRm, namely EGFR-TKI versus anti-PD-1/PD-L1 immunotherapy following chemotherapy (C+IO). Our results suggest that EGFR-TKI has a trend to prolong DFS compared with C+IO. Specifically, the third-generation EGFR-TKI, osimertinib, significantly outperformed C+IO in reducing the risk of recurrence and/or death. These findings provide valuable insights into the optimal treatment choices for this patient population.
Subgroup analysis from the IMpower010 study showed that adjuvant atezolizumab failed to elicit DFS benefit (HR=0.99) in patients with EGFRm when including all the PD-L1 expression categories. This result serves as a key explanation for the lack of DFS benefit when comparing C+IO with chemotherapy in our direct meta-analysis. However, within the subgroup of patients with PD-L1 TPS≥1%, atezolizumab exhibits similar and clinically relevant magnitudes of DFS benefit in EGFR-mutant and EGFR wild type NSCLC (HR=0.57 and 0.67, respectively). This observation suggests that PD-L1 expression might serve as a potential biomarker for predicting the efficacy of adjuvant ICB in EGFR-mutant NSCLC. Nevertheless, the strength of this finding is limited by the absence of subgroup data for EGFR-mutant patients based on PD-L1 expression in the KEYNOTE-091 trial. Future studies are warranted to investigate the interplay between PD-L1 level and DFS benefit with ICB adjuvant treatment in EGFR-mutant NSCLC. Another issue required further investigation is the difference between PD-L1 inhibitors (atezolizumab) and PD-1 inhibitors (pembrolizumab) in modulating DFS benefit in EGFR-mutant NSCLC, which has been previously discussed.9
DFS benefits of EGFR-TKI over chemotherapy have been established in a previous study by pooling data from pivotal clinical trials of EGFR-TKI adjuvant therapy10 and were further validated in our study. Herein, we took a step forward by comparing the benefit of EGFR-TKI and IO+C as adjuvant treatment. Our results showed that the magnitude of DFS benefit with EGFR-TKI reduced when the control group was changed from chemotherapy to IO+C (HR increase from 0.41 to 0.60). Although EGFR-TKI did not attain significant advantage over IO+C (HR=0.60, 95% CI: 0.23 to 1.61, p=0.312), it is worth noting that the efficacy attributed to 1st-TKIs might have been underestimated. This underestimation may be due to the fact that the ADAURA trial permitted adjuvant chemotherapy to be administered both in the osimertinib and control groups (hence there exist chemotherapy followed by osimertinib in the experiment arm, as well as placebo only in the control arm), while patients from other EGFR-TKI adjuvant studies received TKI monotherapy only and without adjuvant chemotherapy in TKI arms. This difference in trial design may at least partially explain the finding that 3rd-TKI (HR=0.29, p=0.006) but not 1st-TKI (HR=0.75, p=0.544) significantly improved DFS compared with C+IO. In addition, confirmed OS benefit was demonstrated in the ADUARA trial11 but not in most of the 1st-TKI trials. Collectively, our results from direct and indirect meta-analyses reinforce the role of osimertinib as the preferred adjuvant treatment for R0 EGFR-mutant NSCLC, which is in line with current guidelines and practice patterns. Another point that should be noted is that anti-PD-1/PD-L1 therapy plus EGFR-TKI may lead to increased toxicities, especially those involving the lung, and liver.12 Therefore, while EGFR-TKIs and anti-PD-1/PD-L1 immunotherapy are both regulatorily approved as adjuvant treatment for EGFR-mutant NSCLC, the combination or sequential treatment of both regimens is strongly discouraged.
Despite the relevance of our studies, the conclusions should be considered as temporary for various reasons. First, it remains unclear whether immunotherapy would have significant and clinically relevant benefit in NSCLC with high PD-L1 expression and hence become another adjuvant treatment option besides osimertinib. Second, data for immunotherapy arm is mostly from subgroup analysis of the original trials and the results must be interpreted with caution. Future prospective trials that compare EGFR-TKI and C+IO are required to verify these findings. However, since such a study has not been conducted recently, the present analysis still meets the current clinical needs and may inform future investigations. Third, the small sample size of EGFR-mutant patients in IMpower010 and KEYNOTE-091 also limits the strength of this study, and additional prospective, randomized clinical trials specifically investigating adjuvant IO in completely resected, EGFR mutant NSCLC is needed to validate our conclusions.
In conclusion, this study serves as the first comparative study of anti-PD-1/PD-L1 immunotherapy and EGFR-TKI as adjuvant treatment for completely resected, EGFR-mutant NSCLC. Our findings support that 3rd-TKI, osimertinib, should be the preferred option for adjuvant therapy in NSCLC with EGFRm. Our results also emphasize the need for further exploration to validate the conclusions drawn herein, including the mechanisms of potential DFS benefit from immunotherapy, predictors for adjuvant treatment, novel combination strategies to further improve patients’ clinical outcomes, and so on.
Supplementary materials
Supplementary Data
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Footnotes
ZL, XZ and YW contributed equally.
Contributors The study’s conception and design were formulated by YZ and SH. Data analyses were executed by ZL, XZ, and YW, who were also responsible for manuscript preparation. ZY and CY contributed to the data extraction. All authors have reviewed and approved the manuscript.
Funding This study was funded by grants 82272837, 81972898, 82172713 from the National Natural Science Funds of China; 2022A1515010386, 2023B1515020008 from Guangdong Basic and Applied Basic Research Foundation, 22ykqb15 from the Fundamental Research Funds for the Central Universities, Sun Yat-sen University, A2021055 from the Science and Technology Program of Guangdong Province 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.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.