Outcomes of first-line osimertinib treatment for epidermal growth factor receptor-mutated non-small cell lung cancer in clinical practice settings


 Background: Real-world data on the clinical outcomes of first-line osimertinib treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations is lacking. This study aimed to evaluate the treatment outcomes and the prognostic factors of osimertinib as first-line therapy in clinical practice settings.Methods: We retrospectively evaluated clinical outcomes of patients with EGFR-mutated NSCLC treated with osimertinib as first-line therapy across 12 institutions in Japan between August 2018 and March 2020.Results: Among 158 enrolled patients, the objective response rate (ORR) was 68% and the estimated median progression-free survival (PFS) was 17.1 months (95% confidence interval [CI], 14.5-19.7). Subgroup analysis showed that PFS in the group with high programmed death-ligand 1 (PD-L1) expression was significantly shorter than that in groups with low or no PD-L1 expression (10.1 vs. 16.1 vs. 19.0 months; p = 0.03). Univariate and multivariate analyses demonstrated that high PD-L1 expression was the only independent adverse prognostic factor of osimertinib outcome for PFS (hazard ratio, 2.71; 95% CI: 1.26-5.84; p = 0.01). In terms of the ORR, there was no statistically significant difference regardless of PD-L1 expression (67% vs. 76% vs. 65%; p = 0.51).Conclusion: Osimertinib showed favorable treatment outcomes in clinical practice. Although the ORR was similar regardless of PD-L1 expression, high PD-L1 expression could be an independent adverse prognostic factor related to PFS in osimertinib treatment.


Introduction
Molecularly targeted therapies have contributed to an improvement in the survival of patients with recurrent or advanced non-small cell lung cancer (NSCLC) harboring driver oncogenes. Mutations in the epidermal growth factor receptor (EGFR), which is a driver oncogene in NSCLC, lead to tumorigenesis and tumor growth via the activated EGFR-signaling pathway [1]. Previous phase III studies demonstrated that EGFR tyrosine kinase inhibitors (EGFR-TKIs) as first-line therapy for EGFR-mutated NSCLC had better outcomes than a platinum-based regimen in terms of both progression-free survival (PFS) and objective response rate (ORR) [2][3][4]. EGFR-TKIs are thus the current standard first-line agents for treating patients with EGFR-mutated advanced NSCLC.
First-to third-generation EGFR-TKIs are available in clinical practice. Of these, osimertinib, categorized as a third-generation EGFR-TKI, has irreversible anti-tumor activity against both EGFRsensitizing and EGFR-resistant T790M mutations. In the global phase III FLAURA trial involving patients with untreated EGFR-mutated recurrent or advanced NSCLC, osimertinib prolonged PFS and overall survival (OS) compared with the standard of care achieved by first-generation EGFR-TKIs [5,6]. Thus, osimertinib is regarded as the most recommended first-line agent in these patients [7].
In clinical practice, osimertinib is indicated for a heterogeneous population, including patients with decreased performance status, symptomatic brain or leptomeningeal metastases, and uncommon mutations. However, as per the criteria of FLAURA trials, these patient groups are ineligible for osimertinib treatment. This discrepancy in recommendations suggests that there is a data gap regarding treatment outcomes between results of the FLAURA trial and those noted in current clinical practice. Therefore, in addition to pivotal clinical trial data, it is important to collect and analyze post-marketing clinical data.
Although the use of osimertinib as a first-line agent has increased since its approval, data regarding outcomes and the prognostic factors with this treatment in clinical practice are still lacking.
To bridge this knowledge gap, we conducted this multi-institutional, retrospective, observational study to evaluate the treatment outcomes and the prognostic factors of first-line osimertinib for treatment of patients with recurrent or advanced EGFR-mutated NSCLC.

Data collection
Twelve institutions in Ibaraki Prefecture, Japan participated in this study. We enrolled patients with recurrent or advanced NSCLC with EGFR mutations who received osimertinib as a first-line agent between August 2018 and March 2020. The data cut-off was May 31, 2020.
The following clinical data were collected: age, sex, smoking status (current, former, or never), Eastern Cooperative Oncology Group performance status (PS), stage at diagnosis according to the TNM Classification of Malignant Tumors (eighth edition), histology, type of EGFR mutation, presence of central nervous system (CNS) metastasis, and programmed death-ligand 1 (PD-L1) expression status using immunohistochemistry. Based on previous studies, PD-L1 expression was classified as none, low, and high if the tumor percentage score (TPS) of PD-L1 was < 1%, 1%-49%, and > 50%, respectively [8,9].

Statistical analysis
The endpoints in this study were the efficacy outcomes. The radiological anti-tumor response was evaluated based on Response Evaluation Criteria in Solid Tumors (version 1.0.10). The ORR was defined as the proportion of patients who achieved anti-tumor response with complete response (CR) or partial response (PR). Disease control rate (DCR) was defined as the ORR plus the proportion of patients achieving stable disease (SD).
In this study, PFS was defined as the duration from the initiation of osimertinib treatment to disease progression or death from any cause. OS was defined as the duration from the initiation of osimertinib treatment to death from any cause. If death did not occur at the cut-off date, patients were censored. If patients were lost during the observation period, they were censored on the last day of confirmed survival. Clinical evaluations of PFS and OS were conducted using the Kaplan-Meier method.
Log-rank test was used to compare two different survival curves. A Cox regression model was applied to examine prognostic factors related to survival. Univariate and multivariate hazard ratios (HRs) were reported with 95% confidence intervals (CIs). Statistical analysis was performed using IBM SPSS Statistics for Windows (version 24.0; IBM Corp., Armonk, NY, USA). All tests were two-sided and were judged statistically significant if the calculated p-values were < 0.05.

Patient characteristics
Among 161 patients initially enrolled, three were excluded from the analysis owing to the lack of data, resulting in a total of 158 eligible patients for the current study. Table 1 shows the patient characteristics.

Survival
The median follow-up period of the present study was 12.5 months. The estimated median PFS was 17.1 months (95% CI, 14.5-19.7). OS did not reach the median.
Next, we performed univariate and multivariate analyses to evaluate prognostic factors associated with PFS. Among collected patient characteristics, we selected the eight factors mentioned above.
As shown in Table 2, only high TPS was found to be a statistically significant adverse prognostic factor related to PFS (HR = 2.71; 95% CI = 1.26-5.84; p = 0.01).

Anti-tumor response
At the cut-off date, a response assessment was obtained for 140 patients. The best overall responses to osimertinib in the overall population included a CR of 3% (n = 6), PR of 65% (n = 102), SD of 14% (n = 22), and PD of 6% (n = 10), with an ORR of 68% and a DCR of 82%. We further evaluated anti-tumor responses to osimertinib based on PD-L1 expression (Table 3). There was no statistically significant difference in the ORR among the high, low, and no TPS groups (67%, 76%, and 65%, respectively; p = 0.51). DCR was also similar among the high, low, and no TPS groups (81%, 88%, and 80%, respectively; p = 0.57).

Discussion
The present study investigated the clinical outcomes and the prognostic factors of osimertinib as a first-line treatment for advanced or recurrent NSCLC harboring EGFR mutations in a clinical practice setting. The results showed that the efficacy of osimertinib in the overall population was favorable. Although there was no statistically significant difference in the ORR among the high, low, and no TPS groups, the PFS of osimertinib in the high TPS group was inferior to that in the low or no TPS groups. Furthermore, univariate and multivariate analyses showed that high PD-L1 expression was an independent adverse prognostic factor associated with PFS in osimertinib treatment.
Compared to the FLAURA study, there were several differences in baseline patient characteristics in the present study. Specifically, in our study, there were more elderly patients and a higher frequency of decreased PS and presence of CNS metastases, while there was a lower frequency of never smokers. Racial differences were also observed. Some clinical factors such as decreased PS and the presence of CNS metastasis are poor prognostic factors for advanced NSCLC. Therefore, we conducted a subgroup analysis to evaluate whether these clinical factors affected the efficacy of osimertinib. The results showed that factors other than TPS did not affect the outcome (PFS) of osimertinib treatment. A previous phase II trial showed that osimertinib treatment provides a clinical benefit for EGFR T790M-mutated NSCLC whose PS score has declined to 2-4 [10]. In the FLAURA study, osimertinib resulted in significantly longer survival than the standard of care with first-generation EGFR-TKIs, even in patients who had CNS metastases at diagnosis [11]. Together with these previous reports, the present study indicates that osimertinib could be administered to such patients in clinical practice.
The estimated median PFS of osimertinib in the high TPS group was 10.1 months (95% CI; 7.3-13.0), which was significantly shorter than that in the low or no TPS groups. Additionally, the present study showed that high TPS was an independent adverse factor associated with the PFS of osimertinib treatment.
Several previous studies showed that EGFR-mutated advanced NSCLC with high TPS had poorer treatment outcomes with first-or second-generation EGFR-TKI compared with the weak or negative PD-L1 population [12,13]. Regarding osimertinib, a recent study of 71 patients who received first-line osimertinib revealed that patients with ind PD-L1 expression had poorer PFS than those with low or negative PD-L1 (median PFS, 5.0 vs. 17.4 months, p < 0.001) [14]. The present study demonstrated similar results in a larger sample size. However, there was a discrepancy in the anti-tumor response between the previous and present studies. The previous study showed both ORR and DCR in the elevated PD-L1 group to be inferior to that in the low or negative PD-L1 group (p = 0.043 in ORR, and p = 0.006 in DCR). In addition, the previous study also reported that the group with high PD-L1 expression had more frequent primary resistance to osimertinib compared with the group with low or no PD-L1 expression. In contrast, the present study showed no statistically significant difference in ORR and DCR regardless of PD-L1 expression (p = 0.51 in ORR and p = 0.57 in DCR). The results of the present study suggest that once osimertinib showed favorable tumor shrinkage in the high TPS group similar with that in the low or no TPS group, it may become resistant in a short period thereafter. It remains controversial whether increased PD-L1 expression contributed to primary or acquired resistance to osimertinib treatment. Several preclinical studies showed that PD-L1 contributed to acquired resistance to EGFR-TKIs via the upregulation of Bcl-2-associated athanogene-1 and Yes-associated protein 1 [15,16]. Another preclinical study using EGFR-mutated NSCLC cell lines showed that PD-L1 is associated with primary resistance to EGFR-TKI by epithelialmesenchymal transition via the transforming growth factor-β signal pathway [17]. Further basic research to reveal the molecular mechanism of the correlation between response to osimertinib and PD-L1 expression and clinical validation with a large cohort are warranted.
This study had some limitations. First, there was a bias originating from its retrospective nature.
Second, OS was not reached owing to the short observation period. Third, information regarding TPS was not obtained in approximately 20% of participants. Finally, the current study included only Japanese patients; hence, ethnic differences may affect the results.
In conclusion, the current study provided clinically relevant data on the outcomes of first-line osimertinib for advanced or recurrent NSCLC with EGFR mutations. The favorable efficacy of osimertinib in this study was similar to that in the FLAURA trial. However, a high TPS could be an independent adverse prognostic factor for PFS in osimertinib therapy.

Corresponding author
Correspondence regarding this study to Toshihiro Shiozawa.

Data availability
Data concerning the results of this study are available from the corresponding author on reasonable request.

Ethical approval
This study was initiated after the study protocol was approved by the institutional review board of all institutions (approval number in Tsukuba University Hospital: R01-385). This retrospective observational study was conducted in compliance with the Helsinki Declaration. Individual patient data were anonymized prior to enrollment.

Informed consent
Informed consent was waived because the present study was a retrospective observational research. Optout was done on the website of each institution.     CI, con dence interval; NR, not reached