First-line osimertinib in elderly patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer: a retrospective multicenter study (HOT2002)

Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1–73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9–23.9) months. The median overall survival was not reached (95% confidence interval 24.6–not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.


Results
Patient characteristics. The case report form for 147 patients was collected, of whom 2 patients with stage I or II, 1 patient aged 74 years old at the start of osimertinib treatment, and 12 patients starting osimertinib after January 2020, were excluded from the analysis. Ultimately, 132 patients (94 females, 38 males; median age, 80 [range 75-90] years) were included in the analysis. Patient characteristics are summarized in Table 1. Of the 132 patients, 92 reported having never smoked. A total of 93 patients (70.5%) had stage IV NSCLC, and 34 (25.8%) had a postoperative or post-radiotherapy recurrence. A total of 98 patients (74.2%) had a CCI of 0 or 1. Detailed data on the comorbidities of the study participants at baseline are shown in Table 2. Moreover, 113 (85.6%) had a PS of 0-1, 15 (11.4%) had a PS of 2, 3 (2.3%) had a PS of 3, and 1 (0.8%) had a PS of 4. Patients with PS ≥ 2 had significantly more advanced stage and liver metastasis than those with PS 0-1, though there was no apparent difference in CCI (Supplementary Table S1). Therefore, the cause of worsening of PS in our study population could be attributed to the primary disease rather than to comorbidity. The histological type was adenocarcinoma in all patients. Regarding the type of EGFR mutation, 46 (34.9%) and 80 (60.6%) patients exhibited an exon 19 deletion and exon 21 L858R mutation (including patients with concurrent T790M or other uncommon mutations), respectively. One patient had both an exon 19 deletion and L858R mutation. Five patients had uncommon mutations, including G719X, L861Q, and exon 20 insertions.
Treatment efficacy and survival. At the median follow-up time of 20.5 (range 12.3-28.3) months, the primary endpoint (i.e., 1-year PFS) was 65.8% (95% CI 57.1-73.5; Fig. 1A). The median PFS and TTF were 19.4 (95% CI 15.9-23.9) months and 17.7 (95% CI 14.3-22.9) months, respectively ( Fig. 1A and Supplementary Fig. S1). The median OS was not reached (NR; 95% CI 24.6-NR; Fig. 1B). Among the 113 (85.6%) cases with measurable lesions, the ORR and DCR were 75.2% (95% CI 66.5-82.3) and 92.9% (95% CI 86.6-96.3%), respectively. There were 3 patients with complete response, 82 with partial response, 20 with stable disease, and 2 with progressive disease. Table 3 presents the PFS from the initiation of osimertinib in patients according to different subgroups. No significant difference was observed in efficacy between patients aged ≥ 80 and < 80 years, or between CCI 0-1 and ≥ 2, whereas PS 2 or worse was identified as a poor prognostic factor. Patients with exon 19 deletions tended to have a better PFS than those with the L858R mutation (Supplementary Fig. S2; PFS, EGFR exon 19 del vs L858R). The Kaplan-Meier curves of PFS according to EGFR common and uncommon mutation are shown in Supplementary Fig. S3. Univariate analyses showed that a PS of 2 or worse was significantly associated with shorter PFS (HR 1.96; 95% CI 1.01-3.78; p = 0.044). No other significant factors were identified in the univariate or multivariate analyses (Supplementary Table S2).
Although no statistically significant difference was noted, PFS in patients treated with a reduced dose was numerically better than in those without dose reduction ( Fig. 2A). To examine the effect of dose reduction on PFS, we compared patients who experienced dose reduction within 3 months of initiating osimertinib (early dose reduction group) and others (non-early dose reduction group). To reduce potential selection bias, data from patients who discontinued treatment within 3 months were excluded. The Kaplan-Meier curves of the early and non-early dose reduction groups were nearly identical (Fig. 2B). Patients in the early dose reduction group had PFS and treatment responses comparable to those in the non-early dose reduction group ( Fig. 3 and Table 1. Baseline characteristics of patients aged 75 years or older with NSCLC who were treated with osimertinib as first-line therapy (n = 132). BSA body surface area, CCI Charlson comorbidity index, CNS central nervous system, ECOG Eastern Cooperative Oncology Group, EGFR epidermal growth factor receptor, NA not available.  (Fig. 2C). The median OS was 15.8 months (95% CI 11.2-24.5) in patients with pneumonitis and NR in patients without pneumonitis (Fig. 2D). Additionally, the median TTF in the pneumonitis group was 2.3 months (95% CI 1.6-3.7; Supplementary Fig. S6), and 70.0% (14 of 20) of treatment discontinuations due to pneumonitis occurred within 3 months of initiating osimertinib (Fig. 3).
Adverse events. All recorded AEs that occurred during first-line osimertinib therapy are summarized in Table 4. AEs of grade 3 or higher were reported in 41.7% of patients. The most common AE was paronychia (43.9%; grade ≥ 3 in 1.5%), followed by rash or acne (39.4%; grade ≥ 3 in 0%), dry skin (38.6%; grade ≥ 3 in 0%), and anemia (38.6%; grade ≥ 3 in 3.0%). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. The mortality rate of pneumonitis during osimertinib was 13.0% (3 of 23 cases). The median time to discontinuation of osimertinib due to pneumonitis was 2.2 (95% CI 1.4-3.1) months. There was no difference in baseline patient background between patients with or without pneumonitis (Supplementary Table S3).   Table S4). The most frequent causes of dose reduction were anorexia, rash, and diarrhea (17.0%, 11.4%, and 9.1%, respectively). Thirty-five patients (26.5%) discontinued osimertinib, with pneumonitis reported as the most common cause of discontinuation (Supplementary Table S5). There were four treatment-related deaths (three due to pneumonitis and one due to heart failure; Supplementary Table S6).
Treatment after disease progression. Of the 65 patients with disease progression after starting osimertinib, 5 were continuing first-line osimertinib beyond progression at the data cut-off date. Thirty-three patients had received second-line treatment. Cytotoxic chemotherapy was performed in 22 patients; 9 patients received platinum doublet (with or without antiangiogenic agent), and 12 patients received monotherapy. Eight patients received re-administration of EGFR-TKIs. Two patients received an immune checkpoint inhibitor with or without combined chemotherapy. One patient received salvage surgery.

Discussion
To the best of our knowledge, this is the first real-world study of elderly patients aged 75 years or older who received osimertinib as first-line treatment for advanced EGFR-mutant NSCLC. We observed a 1-year PFS of 65.8%, median PFS of 19.4 months, ORR of 75.2%, and DCR of 92.9%, all of which are comparable with those of the FLAURA trial in which osimertinib showed efficacy with 1-year PFS of approximately 70% and median PFS of 18.9 months. The safety profile of osimertinib is similar to that previously reported except for the occurrence of pneumonitis 9 . Although 40.9% of patients required dose reduction of osimertinib, there was no apparent difference in efficacy between patients with and without dose reduction. The frequency of pneumonitis was 17.4%, and the median OS of patients who had developed pneumonitis was poor (15.8 months). These data suggest that osimertinib as first-line therapy is one of the effective therapeutic options for this population; however, particular attention should be paid to the development of pneumonitis. Table 3. Progression-free survival (PFS) according to different subgroups. BSA body surface area, CCI Charlson comorbidity index, CI confidence interval, EGFR epidermal growth factor, receptor, NR not reached. a Recurrence after complete resection or curative-intent (chemo) radiotherapy. b Patients could have more than one type of mutation. A patient who has compound mutation of exon 19 deletion and L858R was excluded from this subgroup analysis. c Patients whose data on height or weight were not available were excluded from this subgroup analysis.      Table S7) [13][14][15][16][17][18][19][20][21][22][23][24] . In fact, the NEJ003 study is the first to report the efficacy and safety of gefitinib in elderly patients aged 75 years or older with a median PFS of 12.3 months 13 . For osimertinib, a phase II clinical trial was conducted in elderly patients with EGFR T790M mutation-positive NSCLC with resistance to prior EGFR-TKI. The study demonstrated that the efficacy and safety were comparable to those in the non-elderly population 12 . A small retrospective study conducted at a single institution also showed similar results 25 . However, no previous data on the efficacy and safety of osimertinib as first-line treatment in elderly patients are available. In this study, the rates of dose reduction and treatment discontinuation due to AEs (40.9% and 26.5%, respectively) in patients were higher than those reported in the FLAURA trial (4% and 13%, respectively). This reflects the fact that our cohort comprised real-world elderly patients, many of whom were not eligible for prospective clinical trials due to their vulnerable profiles 26,27 . Meanwhile, the patients who were treated with reduced doses yielded numerically better PFS than those who were not. Although this may include a bias that patients who were able to take the drug for a long period were more likely to experience AEs leading to dose reduction, the same tendency was observed when the analysis was limited to early dose reduction, i.e., within 3 months of initiating osimertinib. In the AURA study, which evaluated the safety and efficacy of osimertinib at doses of 20-240 mg once daily in patients with NSCLC harboring EGFR mutations and disease progression after previous treatment with EGFR-TKIs, the response rate was similar at doses of 20 mg, 40 mg, and 80 mg daily 28 . Previous studies of first-and second-generation EGFR-TKIs have shown that dose reduction allows for efficacy and tolerability in elderly or frail patients 21,23 . We, therefore, believe that appropriate dose reduction is necessary for the continuation of osimertinib, contributing to PFS prolongation.
The pattern of AEs reported in this study was relatively consistent with the known safety profile of osimertinib characterized in the FLAURA trial 9 . Osimertinib has a limited effect on wild-type EGFR and tends to have fewer side effects of skin rash and diarrhea than gefitinib, erlotinib, or afatinib 8,9 . In our study, the rates of grade ≥ 3 AEs, including diarrhea, paronychia, stomatitis, and rash, were reported in less than 5% of the patients. Meanwhile, the frequency of pneumonitis in the current study appeared higher than that previously reported 29 . The shorter PFS in patients with pneumonitis may be due to reduced dose intensity or due to the fact that frequent imaging Table 4. Adverse events during osimertinib treatment (n = 132). ALT alanine aminotransferase, AST aspartate aminotransferase, CPK creatine phosphokinase, Cre creatinine, WBC white blood cell. a Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. b This category represents a grouped term for the event. www.nature.com/scientificreports/ for toxicity assessment can capture disease progression earlier than routine imaging. Generally, pneumonitis is a well-known adverse event associated with EGFR-TKIs, and the incidence of TKI-associated pneumonitis is higher in the Japanese population than in Western populations 30 . Although there were no obvious demographic differences between the patients with and without pneumonitis in this study, male sex, advanced age, smoking history, pre-existing pulmonary fibrosis, and poor PS have been suggested as potential risk factors for pneumonitis in TKI-treated patients 31 . In addition, osimertinib may be associated with a higher frequency of pneumonitis than first-and second-generation EGFR-TKIs 32 . Since the incidence of pneumonitis is an important poor prognostic factor, further studies are needed to clarify the risk factors for pneumonitis during osimertinib treatment. The strengths of our study include the patient demographic characteristics, which reflect a fragile elderly population and detailed data on dose reduction and discontinuation, in real-world clinical practice. However, our study has several limitations. First, there is a lack of centrally independent verification of radiographic outcomes to confirm local investigator assessment. Second, due to the retrospective nature of the study, the timing of tumor assessment was not uniform among the study sites. This can lead to an over-or underestimation of PFS. However, it has been reported that PFS and TTF are highly correlated in a real-world evidence-based study 33 . Since PFS and TTF were relatively identical in our study, the validity of the results was confirmed. Third, we did not collect detailed information on the causal relationship between osimertinib and AEs. In this study, the number of patients who experienced AEs leading to dose reduction and discontinuation was higher than previously reported; however, the causal relationship with osimertinib is partially unclear. In addition, it is possible that we overestimated the frequency of pneumonitis because there are several conditions that can mimic pneumonitis, transient asymptomatic pulmonary opacities (TAPO) being one example 34 . In this study, we could not differentiate between these mimicking conditions and osimertinib-induced pneumonitis due to the lack of CT images when pneumonitis occurred. Finally, in retrospective observational studies, the heterogeneity in baseline characteristics of the patients other than age may have affected the results 35 . A prospective phase II study is ongoing to explore the role of first-line osimertinib in elderly patients (jRCTs071180007).

Conclusion
Our study showed that osimertinib as first-line therapy is effective in patients aged 75 years or older, and is tolerable with appropriate dose reduction, with the exception of pneumonitis. However, the high frequency of pneumonitis, which was associated with poor prognosis, is a serious concern. Further large prospective studies are needed to assess the association of drug-related toxicities, especially pneumonitis, and baseline clinical characteristics. The requirement for informed consent was waived by all the approving IRBs due to the retrospective nature of the study. This study was registered at UMIN-CTR (UMIN000044101).

Materials and methods
We evaluated consecutive elderly patients aged 75 years or older with advanced NSCLC harboring EGFR-TKIsensitizing mutations who had started first-line osimertinib treatment between August 2018 and December 2019. Eligibility criteria were histologically-or cytologically-confirmed NSCLC, tumors with EGFR-TKI-sensitizing mutation, and aged 75 years or older when starting the first-line osimertinib. Patients who had received other EGFR-TKIs before receiving osimertinib were excluded. Data collection. Patient demographics and clinical characteristics, including age, sex, smoking status, tumor histology, cancer stage, number and sites of metastases, type of EGFR mutations, PS, height, weight, and Charlson comorbidity index (CCI), were obtained retrospectively from the patient files. Treatment exposure to osimertinib was also collected, including duration, doses, dose reduction, and discontinuation. The data cut-off date was December 31, 2020.
Study endpoints and statistical analysis. The primary endpoint was the proportion of patients who had progression-free survival at 1 year (1-year PFS). The secondary endpoints were safety profile, objective response rate (ORR), disease control rate (DCR), PFS, time to treatment failure (TTF), and OS. Reported adverse events (AEs) during osimertinib treatment were graded according to the Common Terminology Criteria for AEs (version 5.0). Radiographic tumor responses were defined according to the Response Evaluation Criteria in Solid Tumors version 1.1.
PFS, OS, and TTF were estimated using the Kaplan-Meier method, and the log-rank test was used for intergroup comparisons. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards regression model. Patients who had uncommon mutations alone and who had a compound mutation with exon 19 deletion and L858R were excluded from the Cox proportional hazards analysis. Without