The standard therapy for advanced non-small cell lung carcinoma (NSCLC) is systemic drug therapy, which includes cytotoxic agents, targeted therapy, and immune checkpoint inhibitors. Among them, targeted therapy is particularly effective for treating NSCLC harboring driver mutations, and testing for multiple driver mutations is currently available in clinical practice.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the first targeted therapy developed for NSCLC harboring driver mutations. First-generation EGFR-TKIs demonstrated improved progression-free survival (PFS) compared to cytotoxic agents in clinical trials (1). Furthermore, second-generation EGFR-TKIs showed improved PFS (2) and overall survival (OS) (3) compared to first-generation EGFR-TKIs, and third-generation EGFR-TKI, such as osimertinib, also showed improved PFS (4) and OS (5) compared with first-generation EGFR-TKIs.

However, there exist no reports comparing the efficacy of second- and third-generation EGFR-TKIs. A retrospective study using propensity analysis showed no significant difference in “time to discontinuation of any EGFR-TKIs” between patients treated with afatinib or osimertinib (6). Additionally, a meta-analysis reported no significant difference in OS between second-generation EGFR-TKIs and osimertinib (7), but another study suggested that afatinib showed a longer OS than osimertinib (8).

It has also been reported that the response to EGFR-TKIs is not consistent in EGFR-mutant NSCLC; higher tumor programmed death ligand-1 (PD-L1) expression is associated with a poor response to EGFR-TKIs (9,10). The PD-L1 expression is induced by a variety of oncogene signals, including EGFR (11) and ALK (12), and increased PD-L1 expression may be the result of more activated oncogene signals in EGFR-mutant NSCLC (13). Moreover, AXL (14) and epiregulin (15,16), which have been reported to confer resistance to EGFR-TKIs, were correlated with tumor PD-L1 expression.

There is limited information on the comparison between second- and third-generation EGFR-TKIs in PD-L1-positive EGFR-mutant NSCLC. Thus, we analyzed the survival in patients with PD-L1-positive EGFR-mutant NSCLC who were treated with afatinib and osimertinib, using data from a previous observational study, NJLCG2202 (17).

Patient selection. In the previous study (NJLCG2202) (17), we included patients who met the following criteria: 1) patients who had been cytologically or histopathologically diagnosed with NSCLC; 2) patients with tumors confirmed as harboring common EGFR mutations in clinical practice; 3) patients in whom tumor PD-L1 positivity was confirmed using the 22C3 antibody, with a tumor proportion score (TPS) of ≥1%; and 4) patients who had received EGFR-TKI therapy, including EGFR-TKI monotherapy or combined therapy, between January 2015 and June 2021. Among these candidates, we selected patients who were treated with afatinib or osimertinib and retrospectively analyzed them in the present study.

This study was conducted following the Declaration of Helsinki and Ethical Guidelines for Medical and Biological Research Involving Human Subjects (Ministry of Health, Labour and Welfare, Japan). The need to obtain written informed consent was waived under the approval of the ethical committee at the University of Toyama (Ethics Committee, University of Toyama), and we disclosed the study information to study participants (approval number: R2023192).

Outcome. In the NJLCG2202 study, PFS was calculated from the day EGFR-TKI treatment was initiated until the day that disease progression or death from any cause was noted. Disease progression was defined as progressive disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 or clinically judged as progression, whichever occurred first. EGFR-TKI treatment duration was defined as the sum of PFS for first-line treatment with EGFR-TKIs and secondary osimertinib therapy after the acquisition of the T790M mutation. OS was calculated from the day EGFR-TKI treatment was initiated until the day that death was noted and censored at the last visit without death. If the treatment was discontinued due to adverse events and subsequent therapy was initiated without progression, PFS or EGFR-TKI treatment duration was censored at the initiation of the subsequent therapy. However, the change in treatment from afatinib to first-generation EGFR-TKIs without progression was considered an identical treatment and not censored.

Statistical analysis. In the present study, the endpoints are PFS, EGFR-TKI treatment duration, and OS. Kaplan–Meier curves were drawn and compared using the log-rank test. Multivariate analysis using the Cox proportional hazard model was conducted to analyze the association between treatment options and survival adjusting for age, sex, performance status (PS), EGFR mutation status, PD-L1 expression level, and brain metastasis. A p-value of <0.05 was considered significant. The statistical analysis was performed using JMP 15.0.0 (SAS, Cary, NC, USA).

Patient characteristics. A total of 177 patients with PD-L1-positive EGFR-mutant NSCLC were investigated, including 45 and 132 who were treated with afatinib or osimertinib, respectively. Table I shows the patient characteristics. Patients with stage I-III were included because they were treated with EGFR-TKIs, as they were ineligible for local therapy. Patients aged <75 years, male patients, and patients with a PS of 0-1 were more prevalent in the afatinib group. The proportion of patients having brain metastasis was similar.

Survival. Figure 1 shows the Kaplan–Meier curves for PFS, EGFR-TKI treatment duration, and OS from the initiation of the treatment with afatinib or osimertinib. The median 95% confidence interval (CI) of PFS was 15.3 (11.0-22.9) and 17.0 (13.7-22.3) months in patients treated with afatinib and osimertinib, respectively (p=0.632, log-rank test). Of the 45 patients treated with afatinib, 33 showed disease progression during the treatment. Among them, the T790M mutation was detected in 9/33 patients (27.3%). Additionally, the T790M mutation was detected in a patient in whom afatinib therapy was discontinued due to adverse events. A total of 10 patients subsequently received the administration of osimertinib. The median (95% CI) of EGFR-TKI treatment duration was 18.2 (11.6-31.1) and 17.0 (13.7-22.3) months in patients treated with afatinib and osimertinib, respectively (p=0.925, log-rank test). The median (95% CI) of OS was 52.4 (26.8-not estimated (NE)) and 39.7 (28.5-NE) months in patients treated with afatinib and osimertinib, respectively (p=0.492, log-rank test). In addition, 10 patients who were treated with afatinib and osimertinib presenting the T790M mutation showed a median (95% CI) OS of 44.5 (20.7-NE) months.

We evaluated the hazard ratio (HR) of the EGFR-TKI treatment duration (Table II) and OS (Table III), adjusting for clinical parameters, including age, sex, PS, EGFR mutation status, PD-L1 expression level, and brain metastasis, using the Cox proportional hazard model. The results revealed no significant difference in risk for progression (HR=0.99, 95% CI=0.64-1.53) or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib.

Despite accumulating evidence on the association between PD-L1 expression and prognosis in EGFR-mutant NSCLC, information on the effectiveness of different treatments for patients with PD-L1-positive EGFR-mutant NSCLC is lacking. The present study showed a comparable PFS, EGFR-TKI treatment duration, and OS between afatinib and osimertinib in PD-L1-positive EGFR-mutant NSCLC. Furthermore, the detection rate of the T790M mutation after treatment with afatinib was as low as 27.3%, which was consistent with previous studies showing lower detection rates of the T790M mutation in PD-L1-positive EGFR-mutant NSCLC (9,13,18,19).

The PFS after the initial treatment with osimertinib is relatively short in PD-L1-positive EGFR-mutant NSCLC (10,20). The relevant mechanisms may include AXL (14) and epiregulin expression (15,16). AXL is a tyrosine kinase receptor associated with resistance to a variety of chemotherapy and targeted drugs (14). Epiregulin, from the ErbB family of ligands, is also associated with the aggressive nature of tumors, including cell proliferation, invasion, metastasis, angiogenesis, and resistance to apoptosis (15). AXL (21) and epiregulin (16) expression are correlated with PD-L1 expression. These factors may explain the low effectiveness of front-line treatment with osimertinib. Additionally, PD-L1-positive EGFR-mutant NSCLC shows a lower detection rate of the T790M mutation after treatment with first-/second-generation EGFR-TKIs (9,13,18,19). Therefore, although the efficacy of sequential therapy with afatinib plus osimetinib has been reported from real-world data (22), a long survival may not be expected by employing sequential therapy with first-/second-generation EGFR-TKIs plus osimertinib in patients with PD-L1-positive EGFR-mutant NSCLC. For this population, combined therapy may improve prognosis. In the NJLCG2202 study, combined therapy with EGFR-TKIs plus vascular endothelial growth factor inhibitor or cytotoxic agents showed a significant risk reduction in progression against first-/second-generation EGFR-TKIs (17). Moreover, a recent clinical trial demonstrated the novel combination therapy of amivantamab plus lazertinib for EGFR-mutant NSCLC (23). On the other hand, EGFR-mutant NSCLC with PD-L1-negative or lower expression showed a longer PFS with osimertinib therapy and a higher detection rate of the T790M mutation. Therefore, a favorable prognosis is expected for both the front-line treatment with osimertinib and sequential therapy with first-/second-generation EGFR-TKIs plus osimertinib (19,20).

The tumor response to EGFR-TKIs is not consistent in patients with EGFR-mutant NSCLC. Thus, it may be appropriate to select a treatment option based on tumor background including PD-L1 expression. One issue, however, is the cutoff value for PD-L1 expression: the NJLCG2202 study included patients with EGFR-mutated NSCLC with a PD-L1 TPS of ≥1% (17), while other previous studies used a cutoff value of TPS of ≥50% (20). It has been reported that EGFR-mutant NSCLC with PD-L1 TPS of 1%-49% showed a more favorable clinical course compared with those with TPS of ≥50%.

The present study was limited by its small sample size. Thus, especially in the afatinib-treated group, it is not clear whether the study sample is representative of PD-L1-positive EGFR-mutant NSCLC. Although the present study revealed no significant difference in PFS, EGFR-TKI treatment duration, or OS between the afatinib and osimertinib groups, the small sample size may have provided insufficient statistical power.

In summary, there was no significant difference in the risk of progression (HR=0.99, 95% CI=0.64-1.53) or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib, suggesting that the EGFR-TKI treatment duration and OS are similar in patients with PD-L1-positive EGFR-mutant NSCLC. EGFR-TKI monotherapy may have limited efficacy in PD-L1-positive NSCLC harboring an EGFR mutation, and combined therapy may provide improved outcome in this population. Further validation through accumulation of more evidence is warranted.

The Authors do not have any conflicts of interest to declare.

MI and EM designed the study. YK, RS, DM, HN, MS, YS, SY, TK, DJ, NY, and TH contributed to the data collection and investigation. MI wrote the main manuscript. All the Authors read and approved the final manuscript.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.