In a phase III study (FLAURA), osimertinib was found to significantly prolong the PFS compared with gefitinib or erlotinib in NSCLC patients harboring sensitive EGFR mutations . Moreover, the osimertinib group of the Japanese subset of the FLAURA study had a PFS of 19.1 months, indicating the efficacy of osimertinib as first-line therapy in the Japanese population . However, the poor PS population was not included in the FLAURA study, and existing data remain insufficient to determine the efficacy of osimertinib as first-line treatment in patients with poor PS. We found, for the first time, that first-line treatment with osimertinib provided a response rate of 56.3% and a median PFS of 10.5 months in this patient population.
Osimertinib treatment for patients with poor PS could be beneficial and clinically meaningful, considering that cytotoxic chemotherapy provides limited benefits to NSCLC patients with a PS score of 2 and that, currently, the only option for patients with PS scores of 3–4 is best supportive care. Regarding the changes in PS scores during osimertinib treatment, the PS scores were improved in 8 of 16 patients (50%), including notable improvements to a score of 1 from a score of 3 in two patients who had a partial response to osimertinib. In general, the preservation of the PS is indispensable for connecting patients to post-treatment with sequential chemotherapy, which prolongs patient survival. Of the 11 patients with disease progression on osimertinib, 6 patients (55%) received second-line chemotherapy based on the preservation of PS with the osimertinib treatment. Notably, three of these patients received carboplatin plus pemetrexed, suggesting the clinical usefulness of osimertinib in patients with poor PS.
The incidence of drug-induced ILD in the Japanese subgroup of the FLAURA study was approximately 1.8% in those administered gefitinib but was 12.3% in those administered osimertinib . Inoue et al. reported the safety of gefitinib for EGFR-TKI-naive patients with poor PS , showing that the incidence of ILD was 3.3%. A phase II study reported that the incidence of ILD induced by osimertinib was observed in 17% of patients with poor PS with EGFR T790M mutation-positive advanced NSCLC who were pretreated with other EGFR-TKIs . Additionally, ILD due to osimertinib was observed in two patients (12%), indicating that ILD incidence may be high in poor PS patients treated with osimertinib.Meanwhile, the patients with drug-induced ILD recovered after corticosteroid therapy, and no mortality due to drug-induced ILD was observed in our study. A previous study demonstrated that 80% of patients with ILD complicated by osimertinib recovered, and that the mortality from drug-induced ILD was lower in those administered osimertinib (11.8%) than in those treated with gefitinib (38.9%) and erlotinib (35.6%) , suggesting that recovery from ILD is mostly expected in patients receiving osimertinib.
The proportion of patients with brain metastases was 56% here, and most patients initially received systemic chemotherapy with osimertinib, except for two patients who received radiotherapy for brain metastasis prior to osimertinib treatment. As for patients with pre-existing brain metastases prior to osimertinib treatment, the FLAURA study  showed that central nervous system progression was less frequent in patients receiving osimertinib than in those receiving first-generation EGFR-TKIs, such as gefitinib and erlotinib (6% vs. 15%). Other studies have shown that osimertinib is effective for both systemic and brain metastatic lesions in patients with pre-existing brain metastases [25, 26]. Here, no statistically significant difference was observed in PFS according to the presence or absence of pre-existing brain metastases; as such, our findings were consistent with those of the above studies. Therefore, it may be reasonable to mention that osimertinib is expected to be effective for brain metastatic lesions in both poor and good PS populations.
Table 4 provides a summary of previous studies on patients with poor PS who were treated with first-line EGFR-TKIs, showing that the response rate found here was identical to that found in previous studies of other EGFR-TKIs; however, the PFS of our patients appeared to be longer than that of patients who were treated with other EGFR-TKIs.
This study has several limitations. First, the cohort size is very small, and the study was performed at a single institution. Second, we did not include patients with a PS score of 4, for which the clinical efficacy and safety of osimertinib remains unclear. Third, the evaluation of the PS is very difficult. While the PS score of each patient was assessed by two investigators in our study, bias arising from the subjectivity of investigators might not be completely excluded. Fourth, while the individuals included in this study had poor PS, their quality of life was not evaluated.
Considering our findings, osimertinib appears to be an effective and safe treatment option for patients with poor PS and advanced NSCLC harboring sensitive EGFR mutations. To obtain conclusive results, further studies with larger cohorts are warranted.