Abstract
Background/Aim: Osimertinib has demonstrated promising efficacy in patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC). We investigated the efficacy of osimertinib in such patients presenting with pleural effusion, which has been unclear to date. Patients and Methods: The medical records of all patients treated with osimertinib for advanced NSCLC with EGFR T790M between April 2016 and July 2017 at our Institution were retrospectively reviewed. Time to treatment failure (TTF) and overall survival (OS) were determined as endpoints. Results: Twenty-three patients (seven with pleural effusions) were treated with osimertinib. Patients with pleural effusion had significantly shorter median TTF than those without (3.7 vs. 12.8 months, respectively, p=0.021), as well as shorter median OS (7.8 months vs. not attained, respectively, p=0.002). Metastasis to the brain, bone, and liver did not significantly influence our endpoints. Conclusion: Osimertinib monotherapy is less effective in patients with NSCLC with pleural effusions.
Osimertinib is a third-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The AURA3 trial showed that osimertinib improved progression-free survival (PFS) over first-line chemotherapy in patients with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) whose disease had progressed after EGFR-TKI therapy (1). Additionally, the recent FLAURA trial found that osimertinib led to significantly improved PFS over the first-generation EGFR-TKIs in treatment-naïve patients with EGFR mutation-positive advanced NSCLC (2). As such, osimertinib is expected to exhibit more benefits as it is further explored.
Previous studies found that the presence of EGFR mutation is significantly associated with pleural effusion (3, 4), and that the efficacies of first-or second-generation EGFR-TKIs are limited for patients with pleural effusion (5, 6). However, the efficacy of osimertinib in patients with EGFR T790M-positive NSCLC with pleural effusion remains unclear.
Therefore, this retrospective analysis was conducted to investigate the efficacy of osimertinib in patients with EGFR T790M-positive advanced NSCLC with pleural effusion at presentation.
Patients and Methods
Patients. The data for consecutive NSCLC patients harboring the EGFR T790M mutation who were treated with osimertinib at Osaka Habikino Medical Center between April 2016 and July 2017 were retrospectively examined. The Institutional Review Board at the Osaka Habikino Medical Center approved this study (approval number: 890). Data were obtained from electronic medical records, and the requirement for written informed consent was waived by the Institutional Review Board as this was a retrospective analysis of anonymized clinical data. The research was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments.
Data collection and evaluation. Patients were initially administered oral osimertinib at 80 mg/day;this dose was reduced to 80 mg/day every other day or to 40 mg/day upon the appearance of unacceptable toxicity, and treatment was discontinued if toxicities persisted thereafter. Osimertinib therapy was continued until unacceptable adverse events or remarkable disease progression (PD), defined as PD with a decline in performance status. The endpoints measured in this study were the time to treatment failure (TTF) and overall survival (OS). TTF was defined as the interval between the start of osimertinib therapy and treatment discontinuation for any reason, including disease progression, unacceptable toxicity and death. OS was calculated from the start of osimertinib therapy to the date of death. The treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (7). All patients were confirmed to have the EGFR T790M mutation in tissue or blood samples using the Cobas® EGFR Mutation Test, version 2 (Roche Molecular Diagnostics, Pleasanton, CA, USA).
Patient characteristics at baseline (n=23).
Statistical analysis. TTF and OS were determined using the Kaplan–Meier method, and comparisons between subgroups were performed using a log-rank test. p-Values less than 0.05 were considered significant. Hazard ratios were calculated using the Cox proportional hazards models. All statistical analyses were performed using EZR version 1.27 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).
Results
Patients. Twenty-three patients were treated with osimertinib during the period covered by this study;their baseline characteristics are summarized in Table I. The median age at the time of osimertinib treatment was 73 years (range=43-87 years); 78% of the patients were women, while 74% were never smokers. Moreover, 30% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or higher. All patients had adenocarcinoma histology, and EGFR mutations including exon 19 deletion, L858R, and exon 18 G719S were detected before administering first or second-generation EGFR-TKIs. Disease in approximately 90% of patients was diagnosed using repeat tissue biopsies. A total of 30% of patients had pleural effusions, while 43%, 48%, and 13% had metastatic lesions in the brain, bone, and liver, respectively. Patients were categorized into two groups based on whether pleural effusion was present or not; the characteristics of patients in these groups were not significantly different (Table I).
Efficacy. The median TTF of the whole patient cohort was 11.6 months [95% confidence interval (CI)=3.75 months–not attained (NA)] (Figure 1A), while the median OS was 17.8 months (95% CI=10.9 months–NA) (Figure 1B). Patients with pleural effusions had a significantly shorter median TTF than those without (3.7 vs. 12.8 months, respectively, p=0.021) (Figure 2A). Similarly, patients with pleural effusions had a significantly shorter median OS than those without (7.8 months vs. NA, respectively, p=0.002) (Figure 2B). On the other hand, the presence of other metastases did not significantly influence the median TTF (Table II). The response rate for the entire cohort was 56.5%, while the disease control rate was 82.6%. In subgroup analysis, the response rate in patients with pleural effusion was 28.6%, while that of patients without was 68.8%; in comparison, the response rate of patients with brain metastases was 70.0% and that in patients without was 46.2%. Only one out of the seven patients with pleural effusions experienced a reduction in effusion volume with treatment.
Kaplan–Meier curves of time to treatment failure (A) and overall survival (B) in the whole patient cohort. Median time to treatment failure was 11.6 months [95% confidence interval (CI)=3.75 months–not attained (NA)] (Figure 1A), while the median overall survival was 17.8 months (95% CI=10.9 months–NA).
Kaplan–Meier curves of time to treatment failure (A) and overall survival (B) for according to presence or not of pleural effusion. Median time to treatment failure was 3.7 (95% CI=0.16–NA) vs. 12.8 (95% CI=10.9–NA) months, respectively (p=0.021). Median overall survival was 7.8 (95% CI=0.59–NA) vs. NA (95% CI=11.0–NA), months respectively (p=0.002).
Discussion
In this retrospective study, we found that patients with pleural effusions upon initiating osimertinib treatment had significantly shorter TTF and OS than those without effusion. In contrast, there were no significant differences in these durations based on the presence of brain, bone, and liver metastases. Our data suggest that osimertinib is less effective in patients with pleural effusion than in those with distant metastasis to other organs.
Prognostic factors associated with time to treatment failure.
Pleural effusions occur as a consequence of tumor cell invasion into the pulmonary artery, which causes embolization of the pulmonary pleura;they can also be seeded by peripheral tumors (8). The existence of pleural effusion is reportedly an independent predictor of poor survival in patients with advanced NSCLC (9). In this study, we found that presentation with pleural effusion at baseline resultsed in significantly shorter TTF and OS in patients treated with osimertinib. This indicates that effectiveness of this agent is reduced in patients with NSCLC with pleural effusions at baseline, which was also shown to be the case in those treated with first-and second-generation EGFR-TKIs (5, 6). While the reason for this reduced effectiveness is not clear, it was shown that the expression of vascular endothelial growth factor (VEGF), a critical cytokine in pleural effusion pathogenesis, is associated with resistance to EFGR-TKIs (10, 11). Therefore, osimertinib likely has the same limitations as its predecessors in this regard. In patients who develop malignant pleural effusion after acquiring resistance to previous-generation EGFR-TKIs, adding the VEGF inhibitor bevacizumab to their regimens reportedly prolongs their PFS (12).
Our study found no differences in survival with osimertinib treatment when comparing patients with vs. without NSCLC metastases to the brain, bone, or liver. Previous studies of the efficacies of first- or second-generation EGFR-TKIs in patients with different sites of metastasis at baseline found that brain, bone, and liver metastases were independent poor predictors of PFS and OS (13-16). Although this discrepancy may be due to the small sample size of our cohort, it remains unclear whether this is a result of differences between EGFR-TKIs. Conversely, a subset of the AURA 3 trial showed that treatment with osimertinib was associated with a median PFS of 8.5 months in patients with brain metastases of NSCLC, while platinum–pemetrexed treatment produced a median PFS of 4.2 months (1). The BLOOM trial also reported 21 patients with leptomeningeal metastases treated with osimertinib (160 mg orally, once daily) who achieved a 43% response rate (17). Although their number was small, the response rate of patients with brain metastases in our study was high at 70.0%. These data indicate that osimertinib may be more effective in patients with brain metastases than previous generation EGFR-TKIs.
Our study had several limitations. Firstly, we retrospectively analyzed data from a single institution, and our sample size was too small to lead to definite conclusions. Secondly, our study included patients who experienced PD, but were nevertheless deemed to derive some benefit from continuing osimertinib.
In conclusion, osimertinib is effective in patients with EGFR T790M-positive advanced NSCLC. However, similarly to first- and second-generation EGFR-TKIs, osimertinib monotherapy appears to be less effective in patients with NSCLC with pleural effusions. Further prospective studies are warranted to confirm these findings.
Footnotes
Conflicts of Interest
The Authors have no conflicts of interest to declare in regard to this study.
- Received April 3, 2018.
- Revision received May 8, 2018.
- Accepted May 9, 2018.
- Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
