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Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non–small-Cell Lung Cancer Patients

  • Minjiang Chen
    Affiliations
    Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Cheng District, Beijing, China.
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  • Yan Xu
    Affiliations
    Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Cheng District, Beijing, China.
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  • Jing Zhao
    Affiliations
    Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Cheng District, Beijing, China.
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  • Xiaoyan Liu
    Affiliations
    Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Cheng District, Beijing, China.
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  • Xiangning Liu
    Affiliations
    Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Cheng District, Beijing, China.
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  • Dongming Zhang
    Affiliations
    Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Cheng District, Beijing, China.
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  • Yuequan Shi
    Affiliations
    Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Cheng District, Beijing, China.
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  • Li Zhang
    Affiliations
    Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Cheng District, Beijing, China.
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  • Wei Zhong
    Correspondence
    Address for correspondence: Wei Zhong, Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Cheng District, Beijing 100730, China.
    Affiliations
    Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Cheng District, Beijing, China.
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  • Mengzhao Wang
    Affiliations
    Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Cheng District, Beijing, China.
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Open AccessPublished:December 27, 2022DOI:https://doi.org/10.1016/j.cllc.2022.12.003

      Abstract

      Introduction

      Platinum doublet chemotherapy is the standard of care in patients with non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC.

      Materials and Methods

      We retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy.

      Results

      Of the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively).

      Conclusion

      The combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.

      Keywords

      Introduction

      Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are currently the standard of care for non–small-cell lung cancer (NSCLC) with sensitive EGFR mutations. The use of TKIs has been proven to improve the prognosis of NSCLC patients; however, acquired resistance invariably develops to first, second, and third generation TKIs within 1 to 2 years.
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      Understanding and targeting resistance mechanisms in NSCLC.
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      AENEAS: A randomized phase iii trial of aumolertinib versus gefitinib as first-line therapy for locally advanced or metastatic non-small-cell lung cancer with EGFR Exon 19 deletion or L858R mutations.
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      Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicenter, double-blind, randomised phase 3 study.
      One of the main mechanisms of drug resistance of first and second generation EGFR-TKIs is the development of a second point mutation of threonine substitution with methionine at amino acid position 790 at exon 20 (T790M). Third-generation EGFR-TKIs, such as osimertinib, have been developed to overcome TKI resistance in T790M-positive patients.
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      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      ,
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      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      However, the acquired resistance to osimertinib is highly heterogeneous.
      • Cardona AF
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      Mechanisms of resistance to first-line osimertinib in Hispanic patients with EGFR mutant non-small cell lung cancer (FRESTON-CLICaP).
      At present, therapeutic options for advanced NSCLC patients without EGFR T790M mutations and patients progressing after osimertinib are limited to platinum-based doublet chemotherapy.
      In the last decade, immunotherapy has revolutionized the management of thoracic disease but appears to be ineffective in the EGFR-mutated subset of NSCLC. Although some responses have been reported,
      • Gettinger S
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      Five-year follow-up of Nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study.
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      Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
      the long-term benefits of immune checkpoint monotherapy in EGFR-mutated NSCLC are generally lacking. Compared with chemotherapy, both first-line and second-line immune checkpoint inhibitor (ICI) monotherapy did not improve progression-free survival (PFS) and overall survival (OS) in the subgroup of EGFR-mutated patients.
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      Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer.
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      Recently, evidence from the IMpower150 study showed that ICIs and chemotherapy combination therapy regimens were associated with favorable outcomes in the subgroup of patients harboring EGFR mutations after TKI resistance.
      • Reck M
      • Mok TSK
      • Nishio M
      • et al.
      Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.
      However, evidence from large-scale phase III randomized clinical trials on the role of ICI in EGFR-mutant NSCLC patients is lacking. Therefore, more studies are urgently needed to explore the efficacy of ICI and chemotherapy combinations in EGFR-mutant NSCLC patients.
      In the present study, we retrospectively summarized and compared the efficacy of ICI plus chemotherapy in EGFR-mutant NSCLC after the progression of TKI treatment with chemotherapy. The propensity score-matched (PSM) method was used to adjust the clinical characteristics and mutation types, which might have affected the results.

      Material and Methods

      Patients

      Patient information was retrieved from the real-world electronic medical database.
      • Xu Y
      • Zhang L
      • Fang J
      • et al.
      Establishment of a prospective multicenter cohort for advanced non-small cell lung cancer in China (CAPTRA-Lung study).
      The inclusion criteria for enrollment in the study were as follows: 1) having a pathological diagnosis of NSCLC; 2) with sensitive EGFR mutations (EGFR exon 19 deletion or Leu858Arg mutations) tested by polymerase chain reaction or next-generation sequencing; 3) had stage IV NSCLC or recurrent disease; 4) had received EGFR-TKI (first, second, or third-generation) and progression on targeted therapy; 5) test negative of EGFR exon 20 T790M mutation or had progression on third-generation TKI therapy; and 6) had received at least one cycle of platinum-based doublet chemotherapy with or without pembrolizumab. Patients who had received chemotherapy for an advanced disease before starting TKIs, had used TKIs as neoadjuvant or adjuvant, with unknown EGFR T790M status on the progression of first or second-generation EGFR-TKIs, or had biopsy-proven small cell transformation on the progression of EGFR-TKI were excluded.
      Patient demographics, treatment history, driver genes, and follow-up treatments were retrospectively reviewed. Patients who were started on platinum doublet chemotherapy-based regimens between January 1, 2015, and December 1, 2021, at Peking Union Medical College Hospital were included in this study. All patients received at least one cycle of chemotherapy with or without immunotherapy.

      Outcome Measurements

      Efficacy was determined using the RECIST1.1 criteria. PFS and OS were calculated from the start of the first chemotherapy until radiology confirmed progression or death. Patients who remained progression-free or alive at the last follow-up visit (December 1, 2021) were censored.

      Statistical Analysis

      PSM was performed by R (version 3.4.2; R Foundation for Statistical Computing, Vienna, Austria) to obtain a matched pair in patients who underwent chemotherapy plus immunotherapy and chemotherapy alone. To minimize the differences of clinical characters and EGFR mutation types between the 2 groups, the covariates, including sex, smoking history, performance status, EGFR mutation type (including EGFR T790M mutation status after progression), histology, number of prior systemic therapies, and combination use of bevacizumab. Within matching strategies, a treated individual can be matched to the comparison individual with the most similar propensity score within a certain caliper (0.2 of the standard deviation of the propensity score) (Supplementary Figure 1). If one treated individual can match to more than one comparison group individuals the first match will be chosen.
      Continuous and categorical variables were compared using analysis of variance and chi-squared tests (χ2), respectively. Kaplan-Meier curves were used to display PFS and OS. Hazard ratios (HRs) were estimated using a Cox proportional hazards regression model, and 95% confidence intervals (CIs) were calculated using the Brookmeyer-Crowley method. We performed pairwise comparisons between the groups to determine the association between treatment and outcomes. Statistical analyses were performed using SPSS 25.0 (IBM Corp., Armonk, NY.) and GraphPad Prism 8.0 (GraphPad Software, San Diego, CA).
      All patients in the study had signed written informed consents during their inclusion in the database according to the protocol for analyzing the clinical data
      • Borghaei H
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      • Horn L
      • et al.
      Nivolumab versus docetaxel in Advanced nonsquamous non-small-cell lung cancer.
      . The study was approved by the Institutional Review Board of the Peking Union Medical College Hospital.

      Results

      Patient Characteristics

      In total, 869 metastatic NSCLC patients with EGFR mutation who had progressed after TKI and had been treated with platinum-based doublet chemotherapy were identified from the real-world database
      • Xu Y
      • Zhang L
      • Fang J
      • et al.
      Establishment of a prospective multicenter cohort for advanced non-small cell lung cancer in China (CAPTRA-Lung study).
      , and 336 were included in the final study cohort after applying the exclusion criteria (Figure 1). Patients treated with chemotherapy plus pembrolizumab were selected as the Chemo + IO (Immuno-Oncology) group. Patients treated with platinum doublet chemotherapy alone were selected and defined as the Chemo group. A total of 82 eligible patients were finally included in the Chemo + IO group. Compared to EGFR-positive patients, the baseline characteristics of eligible patients with and without pembrolizumab immunotherapy were not proportional. After 1:1 matching of patients based on clinical factors, 82 patients were included in the Chemo group. There were no significant intergroup differences in any clinical variable.
      In the Chemo + IO group, the median age was 65.5 years (32-82 years). Most (75.6%) of the patients were never-smokers, and 59.8% were women. Majority of the patients had adenocarcinoma histology (80/82, 97.6%). EGFR mutation subtypes comprised 45.1% (n = 37) EGFR exon 19 deletion (19Del) and 54.9% (n =4 5) EGFR exon 21 L858R mutation (EGFR 21 L858R). Twenty-nine patients carried the acquired EGFR T790M mutation after first-or second-generation TKI treatment. Forty patients were treated with osimertinib as the first- or secondline therapy. Further details of patient characteristics in the 2 groups are shown in Table 1.
      Table 1Characteristics of Patients With Non–Small-Cell Lung Cancer Having EGFR Mutation Treated With Chemotherapy Plus Immunotherapy vs. Chemotherapy After PSM
      Clinical CharacteristicAfter PSM all EGFR Mutated Patients (n = 164)
      Chemo + IO (n=82)Chemo (n=82)P value
      Age, median (range)65.5 (32-82)59 (36-80)
      Age.083
       >654048.83036.6
       ≦654251.25263.4
      Gender1.000
       Male3340.23239.0
       Female4959.85061.0
      Smoking status.572
       Current/Former2024.41619.5
       Never6275.66680.5
      ECOG.385
       0-17389.07287.8
       ≧2911.01012.2
      Histology
       Adeno8097.67996.31.000
      Squamous22.433.7
      Baseline EGFR mutation type.875
       19Del3745.13542.7
       L858R4554.94757.3
      EGFR T790M mutation.504
       Positive2935.42429.3
       Negative5364.65870.7
      Previous TKI lines.745
       One5162.25465.9
       Two3137.82834.1
      Pretreated with Osimertinib.081
       Yes4048.82834.1
       No4251.25465.9
      Liver metastasis.070
       Yes1619.578.5
       No6680.57591.5
      Brain metastasis.597
       Yes2429.32024.4
       No5870.76275.6
      Chemotherapy drugs.826
       Pemetrexed6984.17186.6
       Paclitaxel1315.91113.4
      Bevacizumab.414
       Yes2631.73239.0
       No5668.35061.0
      Abbreviations: ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; PSM = propensity score-matched; THI = tyrosine kinase inhibitor

      Treatment Outcomes With Chemotherapy Plus Immunotherapy vs. Chemotherapy Alone

      At the time of data cutoff (December 1, 2021), the median duration of follow-up in the Chemo+P group and Chemo group were 12.5 months and 13.1 months, respectively. Prolonged median PFS were observed in the Chemo + IO group vs. the Chemo group (6.7 months [95% CI 5.0-8.5] vs. 4.2 months [95% CI 3.3-5.0], HR 0.64 [95% CI 0.46-0.89], P=.0076; Figure 2A). The median OS was immature, with Chemo + IO being 26.7 (95% CI 22.6-30.8; 21 of 82 patients) and 13.4 months (95% CI 10.4-16.4; 63 of 82 patients) with Chemo (HR,0.49 [95% CI 0.31-0.75], P = .0052; Figure 2B). None of the patients had achieved a complete response in both groups. The objective response rates in the Chemo + IO and Chemo groups were 34.1% and 20.7%, respectively. The disease control rates were 91.2% and 76.8%, respectively.
      Figure 2
      Figure 2Kaplan–Meier estimates of progression-free survival and overall survival in the Chemo + IO and Chemo groups
      (A) Kaplan–Meier estimates of progression-free survival and (B) Kaplan–Meier estimates of overall survival.

      Hazard Ratios for Progression Free Survival in Subgroups

      We further investigated whether immunotherapy plus chemotherapy was associated with better PFS in different population subtypes. The outcomes of subgroups with different clinical and genetic features are presented in Figure 3. In the subgroup with women, < 65 years, ECOG (Eastern Cooperative Oncology Group) 0–1, nonsmoker, EGFR 21 mutation, and positive EGFR T790M mutation, PFS was significantly longer in the Chemo + IO group. Prolonged PFS was also observed in patients without brain and liver metastasis.
      Figures 3
      Figure 3Hazard ratios for progression-free survival in subgroups
      Figure shows the hazard ratios (with 95% confidence intervals) for investigator-assessed progression-free survival in biomarker subgroups. The date of data cutoff was December 1, 2021.

      Clinical Features Associated With Outcomes in the 2 Groups of Patients

      We then analyzed the clinical characteristics, EGFR mutation status, and treatment response to immunotherapy for patients in the Chemo + IO group. Among the clinical factors, PFS of first-line TKI therapy was associated with the efficacy of combined chemotherapy with pembrolizumab. In univariate analysis, patients with long PFS during TKI treatment were also the patients with significantly prolonged PFS in the Chemo + IO group (7.7 vs. 5.9 months, P = .021). Multivariate analysis also revealed that short first-line TKI therapy patients had a greater risk of disease progression (HR, 2.048; 95% CI,1.134-3.699; P = .017) (Supplementary Table 1). We also analyzed the impact of aforementioned clinical factors in the Chemo group. The multivariate analysis revealed that the combination use of bevacizumab was associated with significantly prolonged PFS (HR, 0.608; 95% CI, 0.372, 0.993; P = .047) (Supplementary Table 2).

      Recurrence Pattern and Follow-up Treatment

      The most common sites of disease progression were the lung (88/143, 53.7%), followed by the lymph node (39.2/143, 39.2 %), and the brain (26/143, 18.2 %). Compared to the Chemo group, patients in the Chemo + IO group had a lower incidence of lung recurrence (51.6% vs. 69.1%, P = .038). The distribution of recurrence sites is presented in Figure 4.
      Figure 4
      Figure 4Donut plot showing sites of recurrence in the two groups
      (A) Recurrent site of patients in Chemo + IO group and (B) recurrent site of patients in Chemo group.
      Most patients (130/143, 90.9%) in the 2 groups received subsequent therapies. Among the 62 patients with acquired resistance to Chemo + IO, 35 (56.5%) received subsequent chemotherapy, and 20 (32.3%) received targeted therapy after progression. Further, 3 (4.8%) patients received local treatment, including radiotherapy and radiofrequency ablation, during continued pembrolizumab immunotherapy. Additionally, 7 other patients changed chemotherapy regimens while continuing to use pembrolizumab. In the Chemo group, the most frequent systemic therapy after progression also included second-line chemotherapy (25, 48.1%) and target therapy (16, 30.8%). Five patients received ICIs after progression (Table 2).
      Table 2Follow-up Treatment in the 2 Groups of Patients
      Chemo + IO GroupChemo Group
      Local therapy34.8%56.2%
      Systemic therapy5893.5%7288.9%
       Target therapy2032.3%3340.7%
       Chemotherapy3556.5%2935.8%
       Immunotherapy1016.1%56.2%
      Best supportive care46.5%911.1%

      Safety

      No grade 5 treatment-related adverse events were observed in either the Chemo +IO or Chemo groups. Grade 3 to 4 adverse events were observed in 37 (45.1%) of 82 patients in the Chemo + IO group and 35 (42.7%) of 82 patients in the chemotherapy group. Grade 3 to 4 immune-related adverse events (irAE) were observed in 6 (7.3%) of 82 patients with Chemo + IO, including 2 cases of pneumonia, 2 cases of transaminase elevation, one case of rash, and one case of diarrhea (Supplementary Table 3). All the grade 3 to 4 irAEs resolved either to grade 1 or totally after discontinuing immunotherapy and corticosteroids treatment.

      Discussion

      Since clinical trials have not proven the superiority of immunotherapy over chemotherapy in EGFR-mutated patients, platinum-based chemotherapy remained the most common subsequent treatment regimen after the discontinuation of EGFR-TKI therapy. However, the benefits of chemotherapy for these patients are limited.
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      In this study, we retrospectively assessed the efficacy of pembrolizumab plus chemotherapy in NSCLC patients harboring EGFR mutations and compared them with those of patients receiving chemotherapy alone. By conducting a PSM analysis, we attempted to balance the confounding covariates between the 2 groups. The results showed that pembrolizumab in combination with chemotherapy had significantly superior efficacy along with acceptable treatment-related adverse effects compared with chemotherapy alone. Patients who received chemotherapy plus pembrolizumab achieved a prolonged PFS of 2.6 months (P = .0076) than patients who received chemotherapy alone. These results are consistent with those reported in previous studies.
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      • Hayashi H
      • et al.
      Impact of EGFR-TKI treatment on the tumor immune microenvironment in EGFR mutation-positive non-small cell lung cancer.
      • Sugiyama E
      • Togashi Y
      • Takeuchi Y
      • et al.
      Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer.
      • Gurule NJ
      • McCoach CE
      • Hinz TK
      • et al.
      A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer.
      However, the mechanism underlying the divergent TME responses to TKI therapy remains unclear. Future clinical studies and analysis of re-biopsy tissue from EGFR-mutated NSCLC patients are required to identify subpopulations of patients who are more likely to respond to ICI therapy after progression to TKIs.
      In this study, the frequency of treatment-related serious adverse events was similar to that reported in previous studies.
      • Socinski MA
      • Jotte RM
      • Cappuzzo F
      • et al.
      Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.
      ,
      • Gandhi L
      • Rodríguez-Abreu D
      • Gadgeel S
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      However, most of the adverse effects were related to chemotherapy, and the incidence of serious adverse effects due to pembrolizumab was low.
      Notably, concomitant immunotherapy seemed to have changed the recurrence pattern of patients. In our study, a significantly higher portion of patients in the Chemo + IO group had extra-thoracic progression than those in the Chemo group. Previous studies have also found that patients receiving ICIs may have new lesions as recurrence sites, while previous target lesions remain in good control.
      • Heo JY
      • Yoo SH
      • Suh KJ
      • et al.
      Clinical pattern of failure after a durable response to immune check inhibitors in non-small cell lung cancer patients.
      Since the mechanisms of acquired resistance to ICIs are poorly understood, the resistance type may be more difficult to understand in driver-mutated patients undergoing ICI therapy. Therefore, special consideration is required for these patients. Non-target lesions and lesions outside the thoracic region should be given particular attention during follow-up.
      This study has several limitations. First, the OS in the pembrolizumab plus chemotherapy group was not mature and needed further follow-up. Second, programmed death ligand-1 expression status and tumor mutational burden were not available in most of the patients; therefore, we did not analyze their impact on efficacy. Third, because of the limited number of patients and the retrospective design, the metastasis site of patients were not matched in PSM and we only collected severe side effects (Grade 3-4) in the toxicity profiles. Considering the limitations of the study, the results should be carefully interpreted. Evidence from randomized prospective multicenter trials is still required to provide more evidence for the optimal choice in EGFR-mutated patients.

      Conclusions

      Pembrolizumab combined with chemotherapy may improve PFS and survival compared to platinum-based chemotherapy alone in pretreated EGFR-mutant NSCLC patients after EGFR-TKI therapy discontinuation. Further randomized phase III clinical studies and real-world data are needed to verify this conclusion and provide more evidence for the optimal therapeutic choice in patients with EGFR-mutant lung cancer.

      Clinical Practice Points

      • Platinum-based chemotherapy has remained the most common subsequent treatment regimen for non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation after the discontinuation of EGFR-tyrosine kinase inhibitors (EGFR-TKI) therapy. There are reports that combination therapies of chemotherapy and immune checkpoint inhibitors (ICIs) could be effective in treating EGFR-mutant NSCLC, but the evidence is unconvincing.
      • Pembrolizumab plus chemotherapy showed superior efficacy for EGFR-mutant NSCLC compared with platinum-based chemotherapy alone. Patients who received pembrolizumab plus chemotherapy achieved a prolonged progression-free survival (PFS). Also, the duration of first-line TKI therapy can predict prolonged PFS for patients treated with pembrolizumab plus chemotherapy.
      • Although further evidence-based research from clinical trials is required to confirm the validity of these findings, these findings show that pembrolizumab plus chemotherapy can improve the clinical outcomes of patients with EGFR-mutant NSCLC.

      Disclosure

      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.

      Funding

      This work is suported by the National High Level Hospital Clinical Research Funding (to MW) (grant number: 2022-PUMCH-B-106).

      Acknowledgments

      We thank the patients for providing their information for the study. We would also like to acknowledge Fanghua Pan and Yi Wen (Medbanks Network Technology Co. Ltd.) for providing assistance with data management and performing the PSM. We thank Medbanks Network Technology Co. Ltd. for providing IT support. This work was supported by the National High Level Hospital Clinical Research Funding (to MW) (grant number: 2022-PUMCH-B-106) and the Youth Program of the National Natural Science Foundation (Grant No. 81702292) for the fee of publication and language polishing.

      Appendix. Supplementary materials

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