Effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with epidermal growth factor receptor-mutated advanced non-small-cell lung cancer: a multi-institute retrospective study

Patients and data collection

Patient data were obtained from the Cancer Registry System in the part of the Chang Gung Research Database [10, 11]. The selected patients were diagnosed with EGFR-mutated NSCLC and treated with first-line EGFR-TKI monotherapy (gefitinib, erlotinib, or afatinib) between May 2014, when Taiwan’s National Health Insurance began to reimburse afatinib, and January 2018. EGFR mutation status was retrospectively reviewed, and only patients with exon 19 deletions and exon 21 L858R mutations were included in the study.

The clinical data of patients who received EGFR-TKIs as first-line treatments were retrospectively reviewed. Their clinicopathological features, including age, sex, smoking history, Eastern Cooperative Oncology Group performance status (PS) score, tumor involvement, EGFR mutation (exon 19 deletion or L858R), dose adjustment (reduction/interruption), drug discontinuation, tumor response, adverse events (AEs), and subsequent treatment, were obtained. The last follow-up time point in this study was September 2021.

Treatment and response evaluation

The patients were treated with EGFR-TKIs administered once daily until disease progression determined based on radiological studies or intolerable AEs as evaluated by clinicians. The dose and schedule of the EGFR-TKIs were adjusted by clinicians according to the patient’s clinical condition and treatment-related AEs. The tumor response was evaluated most frequently with computed tomography and sometimes with chest radiography and/or additional positron emission tomography. The tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (version 1.1). The detailed definitions of tumor response, including complete response, partial response, stable disease, progressive disease, and not assessed, as well as definitions of PFS and OS, were described in our previous study [12].

Adverse events

Data on AEs were collected from electronic medical records and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). Dose adjustments (reductions or interruptions) and drug discontinuations or withdrawals due to AEs were recorded.

Statistical analysis

Continuous variables were compared using the t-test or analysis of variance. Categorical variables were compared using the chi-square test or Fisher’s exact test. A series of univariate Cox proportional hazards models were applied to initially screen for potential factors associated with PFS and OS. Those variables with p-values <0.05 in the univariate Cox analysis were included in a multivariate Cox model. A two-sided p-value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS (2011 release; IBM Corp., Armonk, NY, USA), SPSS Statistics for Windows (version 20.0; IBM Corp.), and R statistical software (version 4.0.5) [13].

Comparison of patient characteristics between younger (aged <65 years) and older (aged ≥65 years) patients

This study included 1343 treatment-naïve patients with EGFR-mutated advanced NSCLC, of whom 554 were aged <65 years and 789 were aged ≥65 years. Compared to older patients, younger patients showed better PS, were less likely to be nonsmokers, were more likely to have stage IV disease, and had a higher incidence of brain, bone, and distant lymph node metastasis. Tumor morphology did not differ significantly between younger and older patients (p = 0.273). The exon 19 deletion was more common in older patients (56.4% vs. 44.6%), while the L858R point mutation was more common in younger patients (55.4% vs. 43.6%, p < 0.0001). Younger patients were more frequently treated with afatinib than older patients (58.3% vs. 39.6%, p < 0.0001). However, afatinib remained the TKI of choice for older patients compared to erlotinib or gefitinib. The characteristics of younger and older patients are presented in Supplementary Table 1.

Progression-free survival did not differ significantly between patients aged <65 years and those aged ≥65 years treated with any of the EGFR-TKIs considered (p = 0.568; gefitinib: p = 0.459; erlotinib: p = 0.920; afatinib: p = 0.858). However, patients aged <65 years had significantly longer OS than those aged ≥65 years when treated with one of the three EGFR-TKIs (median of 25.5 vs. 20.1 months, p < 0.0001; gefitinib: median of 22.5 vs. 17.7 months, p = 0.035; erlotinib: median of 23.7 vs. 18.5 months, p = 0.049; afatinib: median of 28.5 vs. 22.2 months, p = 0.018; Supplementary Figure 1).

Characteristics of elderly patients (aged ≥65 years)

Elderly patients (aged ≥65 years) were further divided into three age groups and differences in their characteristics were examined. There were 383 patients aged 65–74 years, 323 aged 75–84 years, and 83 aged ≥85 years. The different age groups did not differ significantly in sex, smoking status, tumor morphology, and disease stage. PS worsened with age. Interestingly, the L858R point mutation was more common in patients aged ≥85 years (71.1%) than in those aged 75–84 (56.0%) or 65–74 (53.5%) years (p = 0.014). In addition, the choice of EGFR-TKI was age-dependent (p < 0.0001); gefitinib or erlotinib was prescribed more frequently as age increased, while afatinib was prescribed less frequently. The patients’ characteristics and the distribution of EGFR-TKIs among the age groups are summarized in Table 1.

Outcomes of EGFR-TKI therapy for elderly patients

Of the 789 elderly patients, 218 were treated with gefitinib, 259 with erlotinib, and 312 with afatinib. The effectiveness of the three EGFR-TKIs was evaluated in relation to objective response rate (ORR) and disease control rate (DCR). In the elderly patients, afatinib had a marginally higher ORR (68.6%) than gefitinib (58.7%) and erlotinib (62.2%; p = 0.054), but a significantly higher DCR (83.3%) than gefitinib (74.3%) and erlotinib (77.2%; p = 0.032). However, when the data were analyzed separately for each age subgroup, afatinib had numerically higher ORRs than gefitinib or erlotinib, although the differences were nonsignificant. Afatinib had a significantly higher DCR than gefitinib or erlotinib in patients aged 65–74 years (p = 0.027) but not in the other subgroups. The results are summarized in Table 2.

The PFS and OS of patients aged ≥65 years treated with afatinib were more favorable (PFS: HR = 0.771, 95% CI = 0.656–0.907; OS: HR = 0.820, 95% CI = 0.699–0.962) than those of patients treated with erlotinib or gefitinib (Figure 1). Patients aged ≥65 years treated with afatinib had significantly longer PFS (median of 14.7 vs. 9.9 and 10.8 months, p = 0.003; Figure 2A) and OS (median of 22.2 vs. 17.7 and 18.5 months, p = 0.026; Figure 3A) than those treated with gefitinib or erlotinib. However, when the data were analyzed separately for each age subgroup (Figures 1–3), only PFS of patients aged 65–74 years differed significantly (p = 0.032; Figure 2B).

The PFS of patients aged 65–74 and 75–84 years was longer than that of patients aged ≥85 years when treated with any of the three EGFR-TKIs (p = 0.060) or erlotinib (p = 0.027) but not with gefitinib (p = 0.437) or afatinib (p = 0.803; Figure 4). The OS of patients aged 65–74 and 75–84 years was longer than that of patients aged ≥85 years when treated with any of the three EGFR-TKIs (p < 0.0001), gefitinib (p = 0.001), or erlotinib (p = 0.019; Figure 5).

Adverse events of EGFR-TKIs

The AEs of EGFR-TKIs in elderly patients are presented in Table 3. The most common AEs of EGFR-TKIs, including skin toxicities, paronychia, mucositis, and diarrhea, were analyzed. The patients treated with afatinib experienced more AEs, as well as more grade ≥3 AEs, than those treated with gefitinib or erlotinib. In addition, more patients receiving afatinib required dose reductions or discontinuation compared to those treated with gefitinib or erlotinib.

Univariate and multivariate analysis of prognostic factors of progression-free survival of elderly patients

A univariate analysis was performed to explore the possible prognostic factors of PFS of elderly patients treated with EGFR-TKIs (Table 4). Patients with a PS score of 2–4, stage IV disease, and ≥4 metastatic sites had significantly worse PFS. Patients with liver, brain, bone, pleural, adrenal, and pericardial metastasis showed significantly worse PFS. Treatment with gefitinib also resulted in significantly worse PFS.

Multivariate analysis was performed to identify potential independent prognostic factors of PFS (Table 4). PS of 2–4, stage IV disease, liver, bone, pleural, adrenal, and pericardial metastasis, and EGFR-TKI treatment with gefitinib were independent unfavorable prognostic factors of PFS.

Univariate and multivariate analysis of prognostic factors of overall survival of elderly patients

Univariate analyses were performed to explore the possible prognostic factors of OS of patients aged ≥65 years treated with EGFR-TKIs (Table 5). The OS of patients aged ≥85 years with a PS of 2–4, non-adenocarcinoma morphology, stage IV disease, and ≥4 metastatic sites was significantly worse. In addition, the OS of patients with liver, brain, bone, pleural, adrenal, and pericardial metastasis was significantly worse. EGFR-TKI treatment with gefitinib was also associated with significantly worse OS.

Multivariate analysis was performed to identify the potential independent prognostic factors of OS (Table 5). Age ≥85 years, PS of 2–4, stage IV disease, liver, brain, bone, pleural, adrenal, and pericardial metastasis, and EGFR-TKI treatment with gefitinib were independent unfavorable prognostic factors of OS.