Efficacy analysis of immunotherapy‑based combinations for patients with EGFR‑mutant advanced non‑small cell lung cancer after TKI failure
- Authors:
- Published online on: August 20, 2024 https://doi.org/10.3892/ol.2024.14637
- Article Number: 504
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Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Lung cancer is one of the most common causes of cancer-related deaths worldwide, and was estimated to account for 21% of cancer-related deaths in the United States in 2023 (1). Patients with metastatic lung cancer who are eligible for targeted therapy survive longer than those who are ineligible (2,3). Most patients with advanced non-small cell lung cancer (NSCLC) with an oncogenic mutation of epidermal growth factor receptor (EGFR) benefit significantly from EGFR tyrosine kinase inhibitors (TKIs); however, patients typically progress after 9–13 months of treatment with first- or second-generation EGFR-TKIs (4–8). Among these patients, the resistant EGFR T790M mutation (p.-Thr790Met) is found in 50–60% of tumors (9–12). The third-generation EGFR-TKI osimertinib is effective for treating the T790M mutation, but disease progression occurs after a median time of 10.1 months (13,14).
When osimertinib is used as a first-line therapy or treatment for NSCLC with the resistant T790M mutation in EGFR, the acquired resistance mechanisms are complex, including EGFR-mediated T790M C797S mutation, MET amplification, HER2 amplification and histological transformation; however, the resistance mechanisms in approximately half of cases remain unclear (15–17). The treatment options are limited, and platinum-based chemotherapy is the main treatment option for these patients.
Immunotherapy-based combination therapies are the standard treatment for EGFR/ALK-negative advanced NSCLC. However, clinical trials have indicated that patients with EGFR-mutant NSCLC have a poor response to anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) single-agent therapy (18–23), and immunotherapy-based combinations may be a potentially effective strategy. Therefore, the present study evaluated the efficacy of immune checkpoint inhibitors (ICIs) combined with chemotherapy with or without bevacizumab in patients with advanced EGFR-mutant NSCLC after TKI failure to inform clinical practice regarding treatment strategies for these patients.
Materials and methods
Patients
The medical records of all patients with lung cancer at Fujian Cancer Hospital (Fuzhou, China) from March 1, 2019 to July 15, 2023 were reviewed. The eligible patients had EGFR-mutant advanced lung adenocarcinoma, with an Eastern Cooperative Oncology Group (ECOG) performance-status score (24) of 0–2 and at least one measurable tumor. Only patients who: i) experienced treatment failure with first-/second-generation EGFR-TKIs who were T790M mutation negative or who experienced treatment failure with a third-generation EGFR-TKI, ii) received ICIs plus chemotherapy with or without bevacizumab therapy, and iii) were stages IVA or IVB according to the 8th TNM classification (25). were included in the study. The study was approved by the Ethics Committee of Fujian Cancer Hospital (approval no. SQ2021-176-01).
Molecular diagnostics
Analysis of EGFR mutations in biopsy specimens or circulating tumor DNA (ctDNA) from all patients was performed by amplification-refractory mutation system (ARMS) PCR using an ADx-ARMS EGFR kit (Amoy Diagnostics Co., Ltd.) or by next-generation sequencing (NGS) at diagnosis. The EGFR T790M mutation was detected in biopsy specimens or ctDNA using the ADx-ARMS EGFR kit or NGS, or by droplet digital PCR (ddPCR) using an EGFR T790M (S-ddPCR) kit (CB240008; Shanghai Yuanqi Biomedical Technology Co., Ltd.) when patients failed first-/second-generation EGFR-TKI treatment. The primer sequences used for ARMS-PCR were as follows: EGFR 19E746_A750del-S, 5′-GTTAAAATTCCCGTCGCTATCAAGACATCT-3′; EGFR 19E746_S752>A-S, 5′-AGAAAGTTAAAATTCCCGTCGCTATCAAGGCTCC-3′; EGFR-L747_S752del-S, 5′-AATTCCCGTCGCTATCAAGGAACC-3′; EGFR-L747_E749del-S, 5′-GTTAAAATTCCCGTCGCTATCAAGGAAGC-3′; EGFR-19-R, 5′-CACAGCAAAGCAGAAACTCACAT-3′; EGFR-21L858R-S, 5′-GCAGCATGTCAAGATCACAGATTTTGGGCG-3′; EGFR-21L861Q-S, 5′-GATCACAGATTTTGGGCTGGCCAAACA-3′; EGFR-21-R, 5′-GTCAGGAAAATGCTGGCTGACCTAAAG-3′; EGFR 20T790M-S, 5′-CCTCACCTCCACCGTGCARCTCATCAT-3′; EGFR-20T790M-R, 5′-GAGCCAATATTGTCTTTGTGTTCCCG-3′; EGFR-18G719A-FR, 5′-TATACACCGTGCCGAACGCACCGGAGG-3′; EGFR-18G719C-FR, 5′-CCGTGCCGAACGCACCGGAGCA-3′; and EGFR-18-FF, 5′-GGAGCCTCTTACACCCAGTGGAGA-3′. ARMS-PCR was carried out using the following thermocycling conditions: Incubation at 95°C for 10 min, followed by 15 cycles of 95°C for 40 sec, 64°C for 40 sec and 72°C for 30 sec, and then 28 cycles of 93°C for 40 sec, 60°C for 45 sec and 72°C for 30 sec. The primer sequences used for ddPCR were: T790M-F, 5′-GCCGCCTGCTGGCAT-3′ and T790M-R, 5′-TGTGTTCCCGGACATAGTCCAG-3′; reference gene primer-F, 5′-ACTACTTGGAGGAGGACCGTCGC-3′ and reference gene primer-R, 5′-TTCTGCATGGTATTCTTTCTC-3′. ddPCR was carried out using the following thermocycling conditions: Incubation at 95°C for 10 min, followed by 40 cycles of 94°C for 15 sec, 58°C for 60 sec and 98°C for 10 min, then a 4°C hold. A total of 18 specimens underwent NGS performed by Xiamen Spacegen Co., Ltd., including 7 specimens at diagnosis and 11 specimens after the development of first-/second-generation EGFR-TKI resistance. The PD-L1 tumor proportion score (TPS) was measured by immunohistochemistry (Dako28-8; Agilent Technologies, Inc.) in 17 patients after progression on EGFR-TKIs. The immunohistochemistry of PD-L1 expression was carried out using the following procedure: 5-µm sections were cut from each biopsy specimen. Tissue sections were incubated at 60°C overnight, and incubated 40°C for 1 h, followed by separation with xylene and ethanol. Tissue sections were treated with PBS at 37°C for 12 h and subjected to IHC staining. Antigen repair was performed by water bath method at 97°C for 20 min, and the repair solution was EnVision Flex TRS(pH 6.1); the antibody of PD-L1 (28–8) was diluted at 1:40 to 1:20, used at room temperature for 20 min. EnVision Flex+ was applied for 20 min, with CuSO4 enhanced DAB color development. A Dako AutoStainer Link 48 platform (Agilent Technologies, Inc.) was used for detection.
Treatment regimens and response evaluation
Enrolled patients had received PD-1 inhibitors every 3 weeks, including 200 mg camrelizumab (Jiangsu Hengrui Medicine Co., Ltd.), 200 mg tislelizumab (BeiGene, Ltd.) and 200 or 240 mg toripalimab (Shanghai Junshi Biosciences Co., Ltd.) plus chemotherapy with or without bevacizumab. RECIST version 1.1 was used to evaluate the treatment responses of the patients (26). Progression-free survival (PFS) represented the length of survival from treatment with PD-1 inhibitor and chemotherapy/bevacizumab to progression, and overall survival (OS) represented the survival from treatment with PD-1 inhibitor to death. The response to PD-1 inhibitor-based therapy was defined as a complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) during the course of therapy. The overall response rate (ORR) was defined as the percentage of patients with a CR or PR: ORR (%)=(CR + PR)/total number of patients ×100. The disease control rate (DCR) was defined as the percentage of patients with a CR, PR or SD: DCR (%)=(CR + PR + SD)/total number of patients ×100. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTC-AE) v5.0 (27).
Statistical analysis
Kaplan-Meier analysis and the log-rank test were used to compare differences in survival. The ORR and DCR of different subgroups were compared using Fisher's exact tests. In the tests, two-sided P<0.05 was considered statistically significant. SPSS version 24.0 (IBM Corp.) statistical software was used to perform all the statistical analyses.
Results
Patient population and characteristics
There were 316 patients with EGFR-mutant advanced NSCLC who were treated with EGFR-TKIs from March 1, 2019 to July 15, 2023, of whom 147 had experienced failure when previously treated with TKIs. These included 42 patients who were treated with PD-1 inhibitors after TKI failure. However, 2 patients were lost to follow-up and 3 patients had a ECOG score of 3. Finally, a total of 37 patients with EGFR-mutant advanced NSCLC were included in the study (Fig. 1). The baseline clinicopathological characteristics of these patients are summarized in Table I. The median age was 56 years (range, 32–72 years). A total of 19 patients were female. Most (n=29) patients had an ECOG score of 0 or 1. The EGFR mutation subtypes were EGFR exon 19 deletion mutation (n=18), EGFR exon 21 L858R mutation (n=15) and rare double EGFR rare mutations G719X/L861Q (n=2), G719A/S861I (n=1) and G719X/S861I (n=1). A total of 25 patients received first-generation EGFR-TKIs as first-line treatment, 14 patients acquired the T790M mutation (Table SI) when the disease progressed and were treated with osimertinib, and 12 patients received osimertinib as first-line treatment. The total duration of previous TKI treatment was ≤12 months for 20 patients and >12 months in the remaining 17 patients.
Treatment characteristics
There were 26 patients who immediately received PD-1 inhibitors after TKI failure, which was defined as front-line therapy, and 11 patients who received late-line PD-1 inhibitor therapy because they had received other systemic treatments between EGFR-TKIs and ICI therapy. Regarding the combination treatment strategy, 22 patients were treated with PD-1 inhibitors plus chemotherapy, and the remaining 15 patients were treated with PD-1 inhibitors plus chemotherapy and bevacizumab (Table I).
Overall clinical outcomes
At the last follow-up on January 15, 2024, the median follow-up time was 13.4 months (range, 2.7–32.8 months). The median PFS (mPFS) of all patients was 5.2 months (95% CI, 4.077–6.323 months; Fig. 2B), and the median OS (mOS) was 18.3 months (95% CI, 12.932–23.668 months; Fig. 2C). Disease progression occurred in 94.6% (35/37) of patients, and 75.7% (28/37) of the patients died. Overall, 32.4% (12/37), 48.6% (18/37) and 18.9% (7/37) of the patients exhibited a PR, SD or PD respectively, with a DCR of 81.1% and an ORR of 32.4% (Fig. 2A).
Survival outcomes in selected patient subgroups
Subgroup analyses based on all 37 patients revealed that patients with an ECOG-PS score of 0 or 1 had a similar ORR but longer PFS than those with an ECOG-PS score of 2 (ORR, 34.5 vs. 25.0%, P=1.000; mPFS, 5.4 vs. 2.4 months, P=0.006; Table I, Fig. 3A). The analysis revealed a PFS improvement in EGFR T790M-negative patients, with a median PFS of 6.2 months (95% CI, 3.265–9.135 months), which was longer than that in EGFR T790M-positive patients (4.4 months; 95% CI, 2.923–5.877 months) (P=0.041; Table I; Fig. 3B). The patients treated with ICI-based therapy as front-line therapy showed a higher ORR and longer PFS than those treated with ICI-based therapy as late-line therapy (ORR, 46.2 vs. 0%, P=0.007; mPFS, 6.2 vs. 2.4 months, P<0.001; Table I; Fig. 3C). In the subgroups based on different types of EGFR mutations, TNM stage, the presence or absence of brain metastases, the total duration of previous TKI treatment and the type of ICI-based therapy (with or without bevacizumab), no significant differences in PFS were observed (Table I; Fig. 3D). However, the ORR and DCR of patients treated with ICIs plus chemotherapy and bevacizumab were higher than those of patients treated with ICIs plus chemotherapy (ORR, 53.3 vs. 18.2%, P=0.036; DCR, 100 vs. 68.1%, P=0.028; Table I). Cox multivariate regression analysis revealed that the ECOG-PS score, EGFR T790M status post-EGFR-TKIs and timing of immunotherapy were independent predictors of PFS in patients treated with immunotherapy-based combinations (P<0.05; Table II).
 | Table II.Univariate and multivariable analyses of covariables associated with progression-free survival in patients treated with immunotherapy. |
Efficacy according to PD-L1 TPS
The PD-L1 TPS was measured in 45.9% (17/37) of patients with re-biopsy specimens post-EGFR-TKI treatment (Table SII). Four patients were negative for the PD-L1 TPS and 7 patients had a PD-L1 TPS ≥50% (Fig. 4). In these 17 patients, the optimal efficacy was achieved in patients with a PD-L1 TPS ≥50%, with an ORR of 100%, while patients with a PD-L1 TPS <50% had an ORR of only 20% (Fig. 5A). The mPFS was 8.3 months (95% CI, 6.247–10.353 months) for patients with a PD-L1 TPS ≥50%, which was longer than that for patients with a PD-L1 TPS <50% (median PFS, 4.0 months; 95% CI, 2.450–5.550 months) (P=0.050; Fig. 5B). In addition, the mOS was 22.5 months for patients with a PD-L1 TPS ≥50%, which tended to be prolonged compared with that of patients with a PD-L1 TPS <50% (P=0.054; Fig. 5C).
Safety
The median number of PD-1 inhibitor cycles was 6 (range, 1–35). AEs associated with any component of treatment occurred in 28/37 (75.7%) patients. However, no mortalities associated with the treatment occurred. The grade 3 or 4 AEs associated with the treatment were leukopenia in 4/37 (10.8%) patients, as well as fatigue, rash and pneumonitis, each of which occurred in 1/37 (2.7%) of patients (Table III). One patient discontinued immunotherapy due to grade 3 fatigue, and 4 patients discontinued immunotherapy due to grade 2/3 pneumonitis.
Discussion
PD-1/PD-L1 inhibitors have become a standard treatment option for EGFR/ALK-negative advanced NSCLC. The potential of immunotherapy in patients with EGFR mutations, who account for ~50% of Asian patients with NSCLC (28), requires further exploration. In the present study, the effect and safety of PD-1 inhibitors combined with chemotherapy with or without bevacizumab were evaluated. The results showed that the mPFS of patients receiving PD-1 inhibitor-based combination therapy was 5.2 months, which is similar to that of patients receiving platinum-based double drug chemotherapy as a first-line treatment in advanced NSCLC but longer than that of immune monotherapy reported in previous studies (21,23,29). Data from a multicenter phase II trial of the PD-1 inhibitor toripalimab plus chemotherapy showed an mPFS of 7.0 months when used as a second-line treatment in patients with EGFR-mutant advanced NSCLC after the failure of prior EGFR-TKIs (30). However, in real-world settings, the mPFS was found to be ~5 months for patients treated with these immunotherapy-based combinations (31–35). Unfortunately, the outcome of patients with EGFR-mutant tumors in the IMpower130, CheckMate-722 and KEYNOTE-789 clinical trials also did not suggest an advantage for immunotherapy combined with chemotherapy in TKI-refractory EGFR-mutant NSCLC (36–38). Therefore, the interplay between the tumor immune microenvironment (TME), PD-L1 expression in tumors, tumor mutation burden (TMB) and vascular endothelial growth factor (VEGF) receptor inhibitors may be affecting the efficacy of treatment.
The precise mechanisms underlying the unsatisfactory response to immunotherapy in patients with EGFR-mutant NSCLC remain unclear. The generation of tumor neoantigens, antigen presentation and identification, and activation of T cells have been suggested to impact the effect of immunotherapy (39). The low TMB in patients with EGFR mutations who do non-smoke has been suggested as a potential reason for the poor effect of immunotherapy (40). In addition, low PD-L1 expression may impact the efficacy of immunotherapy in patients with EGFR mutations (19,21). Although chemotherapy can kill tumor cells, increase tumor neoantigen levels and improve the efficacy of immunotherapy (41,42), no survival benefit was observed in patients treated with immunotherapy combined with chemotherapy in previous studies (36,38). Based on the approach of combining immunotherapy with other treatments, the final exploratory analyses of the IMpower 150 trial showed a survival benefit in patient subgroups with EGFR mutations when treated with a combination of atezolizumab, bevacizumab and chemotherapy, even in those patients who had previously been treated with TKIs (43,44). In addition, the ORIENT-31 trial reported the successful use of a PD-1 inhibitor with bevacizumab biosimilar plus chemotherapy (45). However, the use of a PD-1 inhibitor combined with chemotherapy and bevacizumab did not show a clear advantage on mPFS compared with the use of a PD-1 inhibitor combined with chemotherapy alone in the present study, although the ORR and DCR were improved. VEGFs can regulate the TME and stimulate regulatory T cells, thereby improving the efficacy of immunotherapy (46). Therefore, the combination of chemotherapy and immunotherapy with antiangiogenic agents may be a promising treatment strategy for EGFR-mutant advanced NSCLC. However, further clinical studies are necessary to confirm this.
In the present study, a subgroup analysis was performed to evaluate the patients who were more likely to benefit from immunotherapy-based combinations. Patients with an ECOG-PS score of 0 or 1 were found to have an improved response to PD-1 inhibitor-based combination therapy (mPFS, 5.4 months) compared with those with an ECOG-PS score of 2, and EOCG-PS was identified as an independent predictor of PFS in patients treated with immunotherapy-based combinations (P=0.017). T790M mutation status was identified as another independent predictor of the efficacy of immunotherapy-based combinations (P=0.021) in the present study. The T790M-negative patients had an mPFS of 6.2 months, which was longer than the 4.4 months of T790M-positive patients (P=0.041). One possible explanation for this is that T790M-negative tumors are characterized by high PD-L1 expression and a high TMB. Unfortunately, only some of the patients in our study were suitable for PD-L1 testing, and none of the patients underwent TMB testing because of insufficient specimens or the expense of testing after EGFR-TKI failure. A study by Haratani et al (47) indicated that patients with T790M-negative tumors are more likely than those with T790M-positive tumors to benefit from nivolumab after EGFR-TKIs, and suggested that this may be due to high PD-L1 expression in T790M-negative tumors. Similar results were also reported in a IMMUNOTARGET registry study (48). However, prospective clinical trials are required to verify these findings.
The TME contains immune cells and immune factors, and is a key factor affecting the efficacy of immunotherapy. PD-L1 expression and the TME dynamically change with tumor treatment (49). Regrettably, information on the TME was lacking in the present study. However, in a previous study of a lung cancer model with EGFR mutations, it was observed that as EGFR-TKI resistance developed, immune effector cells gradually disappeared, and myeloid-derived suppressor cells continued to proliferate with subsequent increases in IL-10 and chemokine (C-C motif) ligand 2 levels (50). Therefore, the timing of immunotherapy may impact its efficacy. In the present study, front-line PD-1 inhibitor-based combination therapy was associated with a longer PFS than late-line therapy following TKI failure (mPFS, 6.2 vs. 2.4 months; P<0.001). As NSCLC progresses, the TME becomes more complex and less conducive to immunotherapy. Consequently, front-line immunotherapy-based combinations could be recommended for clinical use after TKI failure.
Currently, biomarkers for the efficacy of immunotherapy in EGFR-mutant NSCLC have not been clearly identified. However, PD-L1 is the most important predictor of the efficacy of immunotherapy in patients with NSCLC (51,52). Preclinical evidence suggests that EGFR mutations can upregulate PD-L1 expression (53,54), and EGFR-TKIs may even increase PD-L1 expression in EGFR-mutant tumors (55,56). However, some studies have reported opposite findings (57,58). In the present study, PD-L1 expression was evaluated in 17 patients. Of these, the 7 patients with a PD-L1 TPS ≥50% had an ORR of 100% and a median PFS of 8.3 months, which were improved compared with those of patients with a PD-L1 TPS <50%. The Keynote-010 study revealed the preliminary efficacy of the PD-1 inhibitor pembrolizumab in patients with EGFR-mutant, PD-L1-positive NSCLC (20). In addition, in the ATLANTIC study, durvalumab exhibited greater clinical activity in patients with EGFR-mutant and heavily pretreated NSCLC with ≥25% PD-L1 expression than in those with <25% PD-L1 expression (59). Similarly, the ATTLAS trial showed that patients with EGFR-mutant NSCLC who were PD-L1 positive could benefit from immunotherapy plus chemotherapy and bevacizumab, and that patients with high PD-L1 expression had a longer PFS (60). Further investigations are required to verify the utility of PD-L1 expression as a predictive biomarker of treatment in patients with EGFR mutations.
In conclusion, the treatment options for EGFR-mutant advanced NSCLC after TKI failure are limited. Immunotherapy-based combinations may be a potentially effective strategy, and treatment outcomes are influenced by the TME, the TMB, PD-L1 expression in tumors and prior TKI treatment. In the present study, immunotherapy-based combination therapy was the recommended treatment option for patients with EGFR-mutant advanced NSCLC after TKI failure. In addition, ECOG-PS scores of 0 or 1, T790M-negativity or high PD-L1 expression indicated an improved prognosis for patients with EGFR-mutant NSCLC who experienced tumor progression following EGFR-TKI treatment. Immunotherapy and chemotherapy in combination with antiangiogenic agents appears to be a promising combination therapy for these patients.
Supplementary Material
Supporting Data
Acknowledgements
Not applicable.
Funding
The present study was supported by the Natural Science Foundation of Fujian Province (grant no. 2022J011047), High-level Talent Development Program (grant no. 2024YNG11) and the Innovation of Science and Technology, Fujian Province (grant no. 2021Y0056).
Availability of data and materials
The original NGS data generated in the present study may be found in the SRA under accession number PRJNA1092050. All other data generated in the present study may be requested from the corresponding author.
Authors' contributions
ML and ZH designed the study. CL, JL, SC and LW contributed to data collection and investigation. ML and CL wrote the original draft of the manuscript. ML and ZH confirm the authenticity of all the raw data. All authors read and approved the final version of the manuscript.
Ethics approval and consent to participate
The present study was approved by the Ethics Committee of the Fujian Cancer Hospital (approval no. SQ2021-176-01). Written informed consent was obtained from all participants.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References Uncategorized References
|
Siegel RL, Miller KD, Wagle NS and Jemal A: Cancer statistics, 2023. CA Cancer J Clin. 73:17–48. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, et al: Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 382:41–50. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Lin JJ, Cardarella S, Lydon CA, Dahlberg SE, Jackman DM, Jänne PA and Johnson BE: Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol. 11:556–565. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, et al: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12:735–742. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361:947–957. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, et al: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol. 11:121–128. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, et al: Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): A randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 14:953–961. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T, Hirsh V, Yang JC, Lee KH, Lu S, et al: Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial. Lancet Oncol. 17:577–589. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG and Halmos B: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 352:786–792. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M and Eck MJ: The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA. 105:2070–2075. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Gainor JF and Shaw AT: Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol. 31:3987–3996. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Wu SG and Shih JY: Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer. 17:382018. View Article : Google Scholar : PubMed/NCBI | |
|
Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, et al: AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 372:1689–1699. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, et al: Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 376:629–640. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, Feeney N, Sholl LM, Dahlberg SE, Redig AJ, et al: Assessment of resistance mechanisms and clinical implications in patients WithEGFRT790M-Positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. 4:1527–1534. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Wang S, Tsui ST, Liu C, Song Y and Liu D: EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer. J Hematol Oncol. 9:592016. View Article : Google Scholar : PubMed/NCBI | |
|
Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E and Tiseo M: Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 121:725–737. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Lisberg A, Cummings A, Goldman JW, Bornazyan K, Reese N, Wang T, Coluzzi P, Ledezma B, Mendenhall M, Hunt J, et al: A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naive Patients With Advanced NSCLC. J Thorac Oncol. 13:1138–1145. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 373:1627–1639. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet. 387:1540–1550. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, et al: Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 389:255–265. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Lee CK, Man J, Lord S, Cooper W, Links M, Gebski V, Herbst RS, Gralla RJ, Mok T and Yang JC: Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: A systematic review and meta-analysis. JAMA Oncol. 4:210–216. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, Gerber DE, Shepherd FA, Antonia S, Goldman JW, et al: Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 34:2980–2987. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Azam F, Latif MF, Farooq A, Tirmazy SH, AlShahrani S, Bashir S and Bukhari N: Performance Status Assessment by Using ECOG (Eastern Cooperative Oncology Group) score for cancer patients by oncology healthcare professionals. Case Rep Oncol. 12:728–736. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Lim W, Ridge CA, Nicholson AG and Mirsadraee S: The 8(th) lung cancer TNM classification and clinical staging system: Review of the changes and clinical implications. Quant Imaging Med Surg. 8:709–718. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Freites-Martinez A, Santana N, Arias-Santiago S and Viera A: Using the common terminology criteria for adverse events (CTCAE-Version 5.0) to evaluate the severity of adverse events of anticancer therapies. Actas Dermosifiliogr (Engl Ed). 112:90–92. 2021.(In English, Spanish). View Article : Google Scholar : PubMed/NCBI | |
|
Shi Y, Li J, Zhang S, Wang M, Yang S, Li N, Wu G, Liu W, Liao G, Cai K, et al: Molecular epidemiology of EGFR mutations in asian patients with advanced non-small-cell lung cancer of adenocarcinoma Histology-Mainland China subset analysis of the PIONEER study. PLoS One. 10:e01435152015. View Article : Google Scholar : PubMed/NCBI | |
|
Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 378:2078–2092. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Jiang T, Wang P, Zhang J, Zhao Y, Zhou J, Fan Y, Shu Y, Liu X, Zhang H, He J, et al: Toripalimab plus chemotherapy as second-line treatment in previously EGFR-TKI treated patients with EGFR-mutant-advanced NSCLC: a multicenter phase-II trial. Signal Transduct Target Ther. 6:3552021. View Article : Google Scholar : PubMed/NCBI | |
|
Hu R, Zhao Z, Shi Y, Shi M, Xia G, Yu S and Feng J: Immune checkpoint inhibitors combined with chemotherapy/bevacizumab therapy for patients with advanced lung cancer and heavily treated with EGFR mutation: A retrospective analysis. J Thorac Dis. 13:2959–2967. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Yang L, Hao X, Hu X, Wang Z, Yang K, Mi Y, Yang Y, Xu H, Yang G and Wang Y: Superior efficacy of immunotherapy-based combinations over monotherapy for EGFR-mutant non-small cell lung cancer acquired resistance to EGFR-TKIs. Thorac Cancer. 11:3501–3509. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Lam TC, Tsang KC, Choi HC, Lee VH, Lam KO, Chiang CL, So TH, Chan WW, Nyaw SF, Lim F, et al: Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure. Lung Cancer. 159:18–26. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Shen CI, Chao HS, Shiao TH, Chiang CL, Huang HC, Luo YH, Chiu CH and Chen YM: Comparison of the outcome between immunotherapy alone or in combination with chemotherapy in EGFR-mutant non-small cell lung cancer. Sci Rep. 11:161222021. View Article : Google Scholar : PubMed/NCBI | |
|
Tian T, Yu M, Li J, Jiang M, Ma D, Tang S, Lin Z, Chen L, Gong Y, Zhu J, et al: Front-Line ICI-Based combination therapy Post-TKI resistance may improve survival in NSCLC patients with EGFR mutation. Front Oncol. 11:7390902021. View Article : Google Scholar : PubMed/NCBI | |
|
Mok T, Nakagawa K, Park K, Ohe Y, Girard N, Kim HR, Wu YL, Gainor J, Lee SH, Chiu CH, et al: Nivolumab plus chemotherapy in epidermal growth factor receptor-mutated metastatic non-small-cell lung cancer after disease progression on epidermal growth factor receptor tyrosine kinase inhibitors: Final results of checkmate 722. J Clin Oncol. 42:1252–1264. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
Yang JC, Lee DH and Lee JS: Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: Phase 3 KEYNOTE-789 study. J Clin Oncol. Jun 7–2023.(Epub ahead of print). doi: doi.org/10.1200/JCO.2023.41.17_suppl.LBA90. View Article : Google Scholar | |
|
West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, Kopp HG, Daniel D, McCune S, Mekhail T, et al: Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 20:924–937. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Chen DS and Mellman I: Oncology meets immunology: The cancer-immunity cycle. Immunity. 39:1–10. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Schumacher TN and Schreiber RD: Neoantigens in cancer immunotherapy. Science. 348:69–74. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Galluzzi L, Zitvogel L and Kroemer G: Immunological mechanisms underneath the efficacy of cancer therapy. Cancer Immunol Res. 4:895–902. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Zappasodi R, Merghoub T and Wolchok JD: Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell. 33:581–598. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Reck M, Mok TSK, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, 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. Lancet Respir Med. 7:387–401. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Socinski MA, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, et al: IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC. J Thorac Oncol. 16:1909–1924. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Lu S, Wu L, Jian H, Cheng Y, Wang Q, Fang J, Wang Z, Hu Y, Han L, Sun M, et al: Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med. 11:624–636. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao Y, Guo S, Deng J, Shen J, Du F, Wu X, Chen Y, Li M, Chen M, Li X, et al: VEGF/VEGFR-Targeted therapy and immunotherapy in non-small cell lung cancer: targeting the tumor microenvironment. Int J Biol Sci. 18:3845–3858. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Haratani K, Hayashi H, Tanaka T, Kaneda H, Togashi Y, Sakai K, Hayashi K, Tomida S, Chiba Y, Yonesaka K, et al: Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment. Ann Oncol. 28:1532–1539. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, Thai AA, Mascaux C, Couraud S, Veillon R, et al: Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 30:1321–1328. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Isomoto K, Haratani K, Hayashi H, Shimizu S, Tomida S, Niwa T, Yokoyama T, Fukuda Y, Chiba Y, Kato R, et al: Impact of EGFR-TKI treatment on the tumor immune microenvironment in EGFR mutation-positive non-small cell lung cancer. Clin Cancer Res. 26:2037–2046. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Jia Y, Li X, Jiang T, Zhao S, Zhao C, Zhang L, Liu X, Shi J, Qiao M, Luo J, et al: EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors: Implications for combination therapies. Int J Cancer. 145:1432–1444. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al: Pembrolizumab versus Chemotherapy for PD-L1-Positive non-small-cell lung cancer. N Engl J Med. 375:1823–1833. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, et al: Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet. 393:1819–1830. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Chen N, Fang W, Zhan J, Hong S, Tang Y, Kang S, Zhang Y, He X, Zhou T, Qin T, et al: Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-Driven NSCLC: Implication for optional immune targeted therapy for NSCLC Patients with EGFR Mutation. J Thorac Oncol. 10:910–923. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Hsu PC, Jablons DM, Yang CT and You L: Epidermal growth factor receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the regulation of programmed Death-Ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). Int J Mol Sci. 20:38212019. View Article : Google Scholar : PubMed/NCBI | |
|
Suda K, Rozeboom L, Furugaki K, Yu H, Melnick MAC, Ellison K, Rivard CJ, Politi K, Mitsudomi T and Hirsch FR: Increased EGFR phosphorylation correlates with higher programmed death ligand-1 expression: Analysis of TKI-Resistant lung cancer cell lines. Biomed Res Int. 2017:76942022017. View Article : Google Scholar : PubMed/NCBI | |
|
Omori S, Kenmotsu H, Abe M, Watanabe R, Sugino T, Kobayashi H, Nakashima K, Wakuda K, Ono A, Taira T, et al: Changes in programmed death ligand 1 expression in non-small cell lung cancer patients who received anticancer treatments. Int J Clin Oncol. 23:1052–1059. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Dong ZY, Zhang JT, Liu SY, Su J, Zhang C, Xie Z, Zhou Q, Tu HY, Xu CR, Yan LX, et al: EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer. Oncoimmunology. 6:e13561452017. View Article : Google Scholar : PubMed/NCBI | |
|
Soo RA, Lim SM, Syn NL, Teng R, Soong R, Mok TSK and Cho BC: Immune checkpoint inhibitors in epidermal growth factor receptor mutant non-small cell lung cancer: Current controversies and future directions. Lung Cancer. 115:12–20. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Garassino MC, Cho BC, Kim JH, Mazières J, Vansteenkiste J, Lena H, Corral Jaime J, Gray JE, Powderly J, Chouaid C, et al: Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): An open-label, single-arm, phase 2 study. Lancet Oncol. 19:521–536. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Park S, Kim TM, Han JY, Lee GW, Shim BY, Lee YG, Kim SW, Kim IH, Lee S, Kim YJ, et al: A phase III, randomized study of atezolizumab plus bevacizumab and chemotherapy in patients with EGFR or ALK mutated in non-small cell lung cancer (ATTLAS, KCSG-LU19-04). J Clin Oncol. 42:1241–1251. 2024. View Article : Google Scholar : PubMed/NCBI |
